Quinolone compound and pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to new quinolin-4-one derivatives of formula (1) or to its pharmaceutically acceptable salt, wherein R₁ represents: (1) hydrogen, (2) C1-C6 alkyl, (35) carbamoyl-C1-C6 alkyl optionally containing morpholinyl-C1-C6 alkyl, or (36) phosphonoxy-C1-C6 alkyl optionally containing one or two C1-C6 alkyl groups on a phosphonoxy group; R₂ represents: (1) hydrogen or (2) C1-C6 alkyl; R₃ represents phenyl, thienyl or furyl, wherein a phenyl ring presented by R₃, can be substituted by one C1-C6 alkoxy group; R₄ and R₅ are bound to form a group presented by any of the following formulas: , , , , , , or a group presented by the following formula: a group optionally containing one or more substitutes specified in a group consisting of C1-C6 alkyl groups and oxogroups; R₆ represents hydrogen; and R₇ represents C1-C6 alkoxy group. The invention also refers to a pharmaceutical composition based on the compound of formula , to a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method for preparing the compound of formula , as well as to specific compounds.

EFFECT: there are prepared new quinolin-4-one derivatives effective in treating neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases caused by mitochondrial dysfunction.

18 cl, 1 tbl, 257 ex

Area of technology

The present invention relates to quinoline compounds and pharmaceutical compositions.

The level of technology in this area

Parkinson's disease is a chronic, progressive neurodegenerative disease that usually occurs in the elderly. Initial symptoms include unilateral resting tremor, akinesia and rigidity. Tremors, akinesia and rigidity call the main symptoms of Parkinson's disease, and the cause of each of these features is the selective destruction of dopaminergic neurons projected from the substantia nigra to the striatum. The etiology of the disease is still not fully understood; however, the accumulated evidence indicates that the damage-producing energy of the system, accompanied by dysfunction of the mitochondria nigrostriatum dopaminergic neurons causes a neurodegenerative disorder. Mitochondrial dysfunction is believed that subsequently causes oxidative stress and insufficiency of calcium homeostasis, leading, thus, to neurodegeneration (non-Patent document 1).

The treatment of Parkinson's disease is divided loosely on conservative treatment (drug therapy) and surgical treatment (stereotactic surgery). Among them, drug therapy �is an established therapy and is considered as the main treatment. When drug therapy, symptomatic therapeutic agent used to compensate for the changed Parkinson's functions nigrostriatum dopaminergic neurons. The drug L-DOPA shows the most significant therapeutic effects. Some researchers believe that there is such a tool that is more effective than L-DOPA. Currently, L-DOPA is used together with an inhibitor of DOPA-decarboxylase to prevent its metabolism in peripheral tissues, and thus was obtained the desired clinical effects.

However, treatment with L-DOPA has flaws that are that after a few years of use, there is the re-emergence of the movement disorders such as dyskinesia, and the reproducibility and stability of the effects of drugs is lost, leading to oscillations in the course of each day. In addition, side effects include digestive problems such as nausea and vomiting caused by excessive release of dopamine, the problems of the circulatory system, such as orthostatic hypotension, tachycardia, and arrhythmia, and neurological symptoms, such as hallucinations, delusions and psychological arousal, were a cause for concern.

Thus, to reduce the dosage of the drug L-DOPA and thus for reducing�Oia side effects, used in the treatment of multiple drugs, in which dopamine receptor agonists, inhibitors of enzymes of the metabolism of dopamine, relizer dopamine, Central anticholinergic agents, and the like are used in combination. Despite the fact that such success in therapy substantially improve forecasts, fundamental method of treatment of Parkinson's disease and other neurodegenerative diseases still exist. Drug therapy should be adopted for the remainder of the life of the patient, and the above-described disadvantages, i.e. the decrease in efficiency over extended periods of administration, side effects and uncontrolled progression of the disease, can be the result of monotherapy with L-DOPA. In addition, it is difficult to expect a strong effect, even when using therapies sets medicines.

Alzheimer's disease is a progressive neurodegenerative disease that affects various cognitive functions, primarily causing memory impairment. Pathophysiologically Alzheimer's disease is characterized by degeneration of synapses or neurons in the hippocampus and the cortex, and the accumulation of two types of abnormal fibrils, i.e. senile plaques and changes in neurofibrillar. Although the etiology is not fully Viasna�and, β-amyloid protein (β), which derives from the amyloid precursor protein (APP) by various mechanisms, as is well known, plays an important role. Currently, cholinesterase inhibitors (tacrine, Aricept, rivastigmine and galantamine) are used in the treatment of Alzheimer's disease to reduce the severity of symptoms, as acetylcholinergic nervous system of the brain involved in cognitive functions, and visible abnormalities in the cholinergic system are observed in Alzheimer's disease. Receptor antagonists N-methyl-D-spartathlon (memantine) also have practical use, because the increased activation of the mechanism of glutamate neurotransmission associated with neuronal degeneration or defeat. Neither monotherapy or combination therapy with the use of these medicines, however, does not reach a sufficient therapeutic effect, they are also not able to stop the progression of the disease. In addition, gastrointestinal symptoms such as nausea and diarrhea, are observed as side effects of cholinesterase inhibitors.

Against ischemic neurodegenerative disorders caused by cerebral infarctions such as atherothrombotic cerebral infarction, lacunar infarction, cardiogenic cerebral embolism, etc., very R�nee the use of thrombolytic therapy with tissue plasminogen activator (tPA) is increasing rapidly. This therapy, however, has many problems, including a time interval as short as three hours after the onset of the disease, hemorrhagic complications, etc., In Japan, scavenger free radicals, edaravone, used for protective therapy of the brain. Although the drug edaravone can be used simultaneously with tPA, informed clinical results have not been obtained.

Thus, there is a great need in the pharmaceutical means of having a new mechanism of action, or in neuroprotectant to prevent neuronal degeneration or damage due to causes diseases, such as mitochondrial dysfunction, etc.

A list of references

Non-patent literature

NPL 1: Ann. N. Y. Acad. Sci. 991: 111-119 (2003)

Summary of the invention

Technical problem

The object of the present invention is to provide a new compound which inhibits chronic progressive Parkinson's disease or protects dopamine neurons from the disease itself, thereby suppressing the progression of neurological dysfunction in order to extend the time period before the introduction of the drug L-DOPA and thus to improve neuronal function.

Another object of the invention is the provision of means suitable for the treatment of disease�, which cause cell death and, more specifically, providing a means of showing efficacy in the treatment of Alzheimer's disease or enhance dysfunction or neurological disorders caused by cerebral stroke.

Solution

The authors of the present invention have conducted extensive studies to solve the above problem. As a result, they have succeeded in the preparation of the compound represented by formula (1) shown below, which protects and improves mitochondrial function and/or protects neurons and restores neuronal function. These results were the basis for the present invention.

The invention provides quinoline compound, method for producing the compounds and pharmaceutical composition as set forth in the following paragraphs 1-23.

Paragraph 1. Quinoline compound represented by the formula (1):

or its salt,

where R₁represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) low alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy-lower alkyl,

(8) protected at the hydroxy-group of lower alkyl,

(9) hydroxy-lower alkanoyl,

(10) is protected by a hydroxy-group low alkanoyl,

(11) lower alkylthio-�ISSI alkyl,

(12) amino lower alkylthio-lower alkyl, optionally containing one or more lower alkyl groups,

(13) hydroxy-lower alkylthio-lower alkyl,

(14) carboxy lower alkylthio-lower alkyl,

(15) low alkoxycarbonyl-lowest alkylthio-lower alkyl,

(16) amino-lower alkylthiomethyl-lower alkyl, optionally containing one or more lower alkyl groups,

(17) hydroxy-lower alkylsulfonyl-lower alkyl,

(18) carboxy lower alkylsulfonyl-lower alkyl,

(19) low alkoxycarbonyl-lower alkylsulfonyl-lower alkyl,

(20) low alkanoyl-lower alkylsulfonyl-lower alkyl,

(21) a piperazinyl-lower alkylsulfonyl-lower alkyl, optionally containing one or more lower alkyl groups on the piperazine ring,

(22) piperazinylcarbonyl-lower alkylsulfonyl-lower alkyl, optionally containing one or more lower alkyl groups on the piperazine ring,

(23) low alkanoyl-lower alkyl,

(24) carboxy-lower alkyl,

(25) low alkoxycarbonyl-lower alkyl,

(26) a piperazinyl-lower alkoxycarbonyl-lower alkyl, optionally containing one or more lower alkyl groups on the piperazine ring,

(27) morpholinyl-lower alkyl,

(28) oxazepan-lower alkyl,

(29) amino-lower alkyl, optionally containing one or more lower ALC�from among groups,

(30) piperazin-lower alkyl, optionally containing, in the piperazine ring, one or more substituents selected from the group consisting of lower alkyl, lower alkoxy-lower alkyl and pyridyl,

(31) piperidyl-lower alkyl, optionally containing one or more morpholinyl groups,

(32) azetidin-lower alkyl, optionally containing one or more hydroxy groups in azetidinone ring,

(33) isoindoline-lower alkyl, optionally containing one or more oxoprop,

(34) amino-lower alkanoyloxy-lower alkyl, optionally containing one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl,

(35), carbamoyl-lower alkyl, optionally containing one or more substituents selected from lower alkyl; morpholinyl-lower alkyl; piperidyl, optionally containing one or more substituents selected from the group consisting of lower alkyl and lower alkoxycarbonyl; and piperazinyl-lower alkyl, optionally containing one or more lower alkyl groups,

(36) phosphono-lower alkyl, optionally containing one or more protected hydroxy groups

(37) phosphono-lowest alkanoyloxy-lower alkyl, optionally containing one or more protected hydroxy groups

(38) benzoyloxy-lower alkyl, optional�tive containing, in the benzene ring one or more substituents selected from the group consisting of hydroxy, protected hydroxyl groups and phosphonopropyl, optionally containing one or more protected hydroxy groups

(39) tetrahydropyranyl, optionally containing one or more substituents selected from the group consisting of hydroxy, hydroxy-lower alkyl and carboxy, or

(40) the lower alkanolamine-lower alkyl, optionally containing, in the lower alkanoyloxy group one or more substituents selected from the group consisting of halogen; hydroxy; amino; lower alkoxycarbonyl; piperazinyl optionally containing one or more lower alkoxy-lower alkyl groups; imidazolyl; and morpholinylmethyl;

R₂represents:

(1) hydrogen,

(2) lower alkyl,

(3) low alkanoyl,

(4) hydroxy-lower alkyl,

(5) carboxy,

(6) low alkoxycarbonyl,

(7) carbamoyl, optionally containing one or more substituents selected from the group consisting of lower alkyl; halogen-substituted lower alkyl; hydroxy-lower alkyl; piperazinyl-lower alkyl, optionally containing one or more lower alkyl groups; and morpholinyl-lower alkyl,

(8) carbamoyl-lower alkyl, optionally containing one or more lower alkyl groups,

(9) morpholinylmethyl alkyl,

(10) a piperazinyl-lower alkyl, optionally containing one or more substituents selected from the group consisting of lower alkyl and pyridyl, optionally containing one or more lower alkyl groups,

(11) diazepan-lower alkyl,

(12) amino lower alkyl optionally containing one or more substituents selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, hydroxy-lower alkyl and morpholinyl-lower alkyl,

(13) low alkoxycarbonyl-lower alkyl, or

(14) carboxy lower alkyl;

R₃represents phenyl, thienyl, furyl, pyrazolyl or pyrimidinyl where:

aromatic or heterocyclic ring represented by R₃may be substituted by one or more substituents selected from the group consisting of the following substituents (1) to (14):

(1) lower alkyl,

(2) the lower alkoxygroup,

(3) the lower alkanoyl,

(4) halogen free,

(5) hydroxy,

(6) hydroxy-lower alkyl,

(7) hydroxy lower alkoxygroup,

(8) protected at the hydroxy-group of the lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl-lower alkoxygroup, optionally containing one or more lower alkyl groups,

(13) carbamoyl�, optionally containing one or more morpholinyl-lower alkyl groups, and

(14) morpholinylcarbonyl;

R₄represents halogen, lower alkyl or lower alkoxygroup;

R₅represents hydrogen or halogen;

R₄and R₅may be associated with the formation of the group represented by any of the following formulas:

or the group represented by the following formula:

group, optionally having one or more substituents selected from the group consisting of lower alkyl groups and oxoprop;

R₆represents hydrogen or lower alkoxygroup;

R₇is any one of the following groups (1) to (11):

(1) hydrogen,

(2) the lower alkoxygroup,

(3) hydroxy-lower alkoxygroup,

(4) protected by a hydroxy-group lowest alkoxygroup,

(5) lower alkoxy-lower alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing one or more substituents selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(7) an amino group optionally containing one or two substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy,

9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup, and

(11) pyrrolidinyl; and

R₆and R₇may be associated with the formation of the group represented by any of the following formulas:

Item 2. Quinoline compound of the General formula (1) or its salt according to claim 1 wherein:

R₄and R₅may be associated with the formation of the group represented by any of the following formulas:

or group,represented by the following formula:

group, optionally containing one or two substituent selected from the group consisting of lower alkyl groups or oxoprop.

Item 3. Quinoline compound of the General formula (1) or its salt according to paragraph 2, where:

R₁represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) low alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy-lower alkyl,

(8) a phenyl-lower alkoxy-lower alkyl,

(9) hydroxy-lower alkanoyl,

(10) a phenyl-lower alkoxy-lower alkanoyl,

(11) lower alkylthio-lower alkyl,

(12) amino lower alkylthio-lower alkyl, optionally containing, amino groups, two lower alkyl groups,

(13) hydroxy-lower alkylthio-lower alkyl,

(14) carboxy lower �kiltia-lower alkyl,

(15) low alkoxycarbonyl-lowest alkylthio-lower alkyl,

(16) amino-lower alkylthiomethyl-lower alkyl, optionally containing, amino groups, two lower alkyl groups,

(17) hydroxy-lower alkylsulfonyl-lower alkyl,

(18) carboxy lower alkylsulfonyl-lower alkyl,

(19) low alkoxycarbonyl-lower alkylsulfonyl-lower alkyl,

(20) low alkanoyl-lower alkylsulfonyl-lower alkyl,

(21) a piperazinyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(22) piperazinylcarbonyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(23) low alkanoyl-lower alkyl,

(24) carboxy-lower alkyl,

(25) low alkoxycarbonyl-lower alkyl,

(26) a piperazinyl-lower alkoxycarbonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(27) morpholinyl-lower alkyl,

(28) oxazepan-lower alkyl,

(29) amino-lower alkyl, optionally containing one lower alkyl group in the amino group,

(30) piperazin-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl, lower alkoxy-lower alkyl and pyridyl,

(31) PI�uridyl-lower alkyl, optionally containing one morpholinyl group in piperidinium ring,

(32) azetidin lower alkyl, optionally containing one hydroxy-group in azetidinone ring,

(33) isoindoline-lower alkyl, optionally containing two carbonyl group in isoindoline ring,

(34) amino-lower alkanoyloxy-lower alkyl, optionally containing, in the amino group, one or two substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl,

(35), carbamoyl-lower alkyl, optionally containing, in carbamoyl group, one substituent selected from lower alkyl; morpholinyl-lower alkyl; piperidyl, optionally containing one substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl; and piperazinyl-lower alkyl, optionally containing one lower alkyl group,

(36) phosphono-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(37) phosphono-lowest alkanoyloxy-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(38) benzoyloxy-lower alkyl, optionally containing, in the benzene ring, one substituent selected from the group consisting of hydroxyl groups, benzyloxy and phosphonopropyl, optionally containing one or DV� lower alkyl group,

(39) tetrahydropyranyl, optionally containing three hydroxyl groups and one hydroxy-lower alkyl group, or

(40) the lower alkanolamine-lower alkyl, optionally containing, in the lower alkanoyloxy group, one or two substituent selected from the group consisting of halogen; hydroxy; amino; lower alkoxycarbonyl; piperazinyl optionally containing one lower alkoxy-lower alkyl group; imidazolyl; and morpholinylmethyl;

R₂represents:

(1) hydrogen,

(2) lower alkyl,

(3) low alkanoyl,

(4) hydroxy-lower alkyl,

(5) carboxy,

(6) low alkoxycarbonyl,

(7) carbamoyl, optionally containing one or two substituent selected from the group consisting of lower alkyl; halogen-substituted lower alkyl; hydroxy-lower alkyl; piperazinyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring; and morpholinyl-lower alkyl,

(8) carbamoyl-lower alkyl, optionally containing one lower alkyl group in carbamoyl group,

(9) morpholinyl-lower alkyl,

(10) a piperazinyl-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl and pyridyl, optionally containing one lower alkyl group,

11) diazepan-lower alkyl, or

(12) amino lower alkyl optionally containing, in the amino group, one or two substituent selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, hydroxy-lower alkyl and morpholinyl-lower alkyl;

R₃represents phenyl, thienyl, furyl, pyrazolyl or pyrimidinyl where:

aromatic or heterocyclic ring represented by R₃may be substituted by one or two substituents selected from the group consisting of the following substituents (1) to (14):

(1) lower alkyl,

(2) the lower alkoxygroup,

(3) the lower alkanoyl,

(4) halogen free,

(5) hydroxy,

(6) hydroxy-lower alkyl,

(7) hydroxy lower alkoxygroup,

(8) tetrahydropyranyloxy-lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl-lower alkoxygroup, optionally containing one lower alkyl group in carbamoyl group,

(13) carbamoyl, optionally containing one morpholinyl-lower alkyl group, and

(14) morpholinylcarbonyl;

R₆represents hydrogen or lower alkoxygroup; and

R₇is any one of the following groups (1) to (11):

(1) hydrogen,

(2) the lower alkoxygroup,

(3) g�droxi-lowest alkoxygroup,

(4) benzyloxy-lowest alkoxygroup,

(5) lower alkoxy-lower alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing, in carbamoyl group, one alternate selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(7) an amino group optionally containing a substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup and

(11) pyrrolidinyl.

Item 4. Quinoline compound of the General formula (1) or its salt according to paragraph 3, where

R₁represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(24) carboxy-lower alkyl,

(25) low alkoxycarbonyl-lower alkyl,

(27) morpholinyl-lower alkyl,

(28) oxazepan-lower alkyl,

(30) piperazin-lower alkyl, optionally containing, in the piperazine ring, one lower alkoxy-lower alkyl group,

(31) piperidyl-lower alkyl,

(35), carbamoyl-lower alkyl, optionally containing one morpholinyl-lower alkyl or

(36) phosphono-lower alkyl, optionally containing one or two lower alkyl groups;

R₂represents:

(1) hydrogen or

(2) Nissi� alkyl,

R₃represents phenyl, thienyl or furyl where:

aromatic or heterocyclic ring represented by R₃may be substituted with one lower alkoxygroup,

R₆represents hydrogen; and

R₇represents the lowest alkoxygroup.

Item 5. Quinoline compound of the General formula (1) or its salt according to claim 1 wherein

R₆and R₇may be associated with the formation of the group represented by any of the following formulas:

.

Item 6. Quinoline compound of the General formula (1) or its salt according to paragraph 5, where

R₁represents:

(1) hydrogen,

(2) lower alkyl, or

(36) phosphono-lower alkyl, optionally containing one or two lower alkyl groups;

R₂represents hydrogen,

R₃represents phenyl, where the aromatic or heterocyclic ring represented by R₃may be substituted with one lower alkoxygroup;

R₄represents a lower alkyl or lower alkoxygroup; and

R₅represents hydrogen.

Item 7. Quinoline compound of the General formula (1) or its salt according to claim 1 wherein

R₁represents:

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) low alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy-lower alkyl,

(8) a phenyl-lower alkoxy-lower alkyl,

(9) hydroxy-lower alkanoyl,

(10) a phenyl-lower alkoxy-lower alkanoyl,

(11) lower alkylthio-lower alkyl,

(12) amino lower alkylthio-lower alkyl, optionally containing one or two lower alkyl groups,

(13) hydroxy-lower alkylthio-lower alkyl,

(14) carboxy lower alkylthio-lower alkyl,

(15) low alkoxycarbonyl-lowest alkylthio-lower alkyl,

(16) amino-lower alkylthiomethyl-lower alkyl, optionally containing one or two lower alkyl groups,

(17) hydroxy-lower alkylsulfonyl-lower alkyl,

(18) carboxy lower alkylsulfonyl-lower alkyl,

(19) low alkoxycarbonyl-lower alkylsulfonyl-lower alkyl,

(20) low alkanoyl-lower alkylsulfonyl-lower alkyl,

(21) a piperazinyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(22) piperazinylcarbonyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(23) low alkanoyl-lower alkyl,

(24) carboxy-lower alkyl,

(25) low alkoxycarbonyl-lower alkyl,

(26) a piperazinyl-lower alkoxycarbonyl-lower alkyl, optionally containing one lower alkyl group in piperazin�new ring,

(27) morpholinyl-lower alkyl,

(28) oxazepan-lower alkyl,

(29) amino-lower alkyl, optionally containing one or two lower alkyl groups,

(30) piperazin-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl, lower alkoxy-lower alkyl and pyridyl,

(31) piperidyl-lower alkyl, optionally containing one morpholinyl group,

(32) azetidin-lower alkyl, optionally containing one hydroxy-group in azetidinone ring,

(33) isoindoline-lower alkyl, optionally containing one or two carbonyl group,

(34) amino-lower alkanoyloxy-lower alkyl, optionally containing one or two substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl,

(35), carbamoyl-lower alkyl, optionally containing one or two substituent selected from lower alkyl; morpholinyl-lower alkyl; piperidyl, optionally containing one substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl; and piperazinyl-lower alkyl, optionally containing one lower alkyl group,

(36) phosphono-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(37) phosphono-lowest alkanoyloxy-and lower�Kil, optionally containing one or two lower alkyl groups in phosphonopropyl,

(38) benzoyloxy-lower alkyl, optionally containing, in the benzene ring, one substituent selected from the group consisting of hydroxyl groups, benzyloxy and phosphonopropyl, optionally containing one or two lower alkyl groups,

(39) tetrahydropyranyl, optionally containing from one to four substituents selected from the group consisting of hydroxy, hydroxy-lower alkyl and carboxy, or

(40) the lower alkanolamine-lower alkyl, optionally containing, in the lower alkanoyloxy group, one or two substituent selected from the group consisting of halogen; hydroxy; amino; lower alkoxycarbonyl; piperazinyl optionally containing one lower alkoxy-lower alkyl group; imidazolyl and morpholinylmethyl;

R₂represents:

(1) hydrogen,

(2) lower alkyl,

(3) low alkanoyl,

(4) hydroxy-lower alkyl,

(5) carboxy,

(6) low alkoxycarbonyl,

(7) carbamoyl, optionally containing one or two substituent selected from the group consisting of lower alkyl; halogen-substituted lower alkyl; hydroxy-lower alkyl; piperazinyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring; and morpholine�-lower alkyl,

(8) carbamoyl-lower alkyl, optionally containing one lower alkyl group in carbamoyl group,

(9) morpholinyl-lower alkyl,

(10) a piperazinyl-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl and pyridyl, optionally containing one lower alkyl group,

(11) diazepan-lower alkyl, or

(12) amino lower alkyl optionally containing, in the amino group, one or two substituent selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, hydroxy-lower alkyl and morpholinyl-lower alkyl;

R₃represents phenyl, thienyl, furyl, pyrazolyl or pyrimidinyl where:

aromatic or heterocyclic ring represented by R₃may be substituted by one or two substituents selected from the group consisting of the following substituents (1) to (14):

(1) lower alkyl,

(2) the lower alkoxygroup,

(3) the lower alkanoyl,

(4) halogen free,

(5) hydroxy,

(6) hydroxy-lower alkyl,

(7) hydroxy lower alkoxygroup,

(8) tetrahydropyranyloxy-lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl-lower alkoxygroup needed�optionally containing one or two lower alkyl groups,

(13) carbamoyl, optionally containing one morpholinyl-lower alkyl group, and

(14) morpholinylcarbonyl;

R₄represents halogen, lower alkyl or lower alkoxygroup;

R₅represents hydrogen or halogen;

R₆represents hydrogen or lower alkoxygroup; and

R₇is any one of the following groups (1) to (11):

(1) hydrogen,

(2) the lower alkoxygroup,

(3) hydroxy-lower alkoxygroup,

(4) benzyloxy-lowest alkoxygroup,

(5) lower alkoxy-lower alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing one substituent selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(7) an amino group optionally containing one or two substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup and

(11) pyrrolidinyl.

Item 8. Quinoline compound of the General formula (1) or its salt according to paragraph 7, where

R₁represents:

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) low alkanoyl,

(6) halogen-substituted lower alkanoyl,

(8) benzyloxy-and lower�Kil,

(10) benzyloxy-low alkanoyl,

(11) lower alkylthio-lower alkyl,

(12) amino lower alkylthio-lower alkyl, optionally containing one or two lower alkyl groups,

(13) hydroxy-lower alkylthio-lower alkyl,

(14) carboxy lower alkylthio-lower alkyl,

(15) low alkoxycarbonyl-lowest alkylthio-lower alkyl,

(16) amino-lower alkylthiomethyl-lower alkyl, optionally containing one or two lower alkyl groups,

(17) hydroxy-lower alkylsulfonyl-lower alkyl,

(18) carboxy lower alkylsulfonyl-lower alkyl,

(19) low alkoxycarbonyl-lower alkylsulfonyl-lower alkyl,

(20) low alkanoyl-lower alkylsulfonyl-lower alkyl,

(21) a piperazinyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(22) piperazinylcarbonyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(24) carboxy-lower alkyl,

(25) low alkoxycarbonyl-lower alkyl,

(26) a piperazinyl-lower alkoxycarbonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(27) morpholinyl-lower alkyl,

(29) amino-lower alkyl, optionally containing one or two lower alkyl groups,

(30) Piper�Il-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl, lower alkoxy-lower alkyl and pyridyl,

(31) piperidyl-lower alkyl, optionally containing one morpholinyl group,

(32) azetidin-lower alkyl, optionally containing one hydroxy-group in azetidinone ring,

(33) isoindoline-lower alkyl, optionally containing one or two carbonyl group,

(34) amino-lower alkanoyloxy-lower alkyl, optionally containing one or two substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl,

(35), carbamoyl-lower alkyl, optionally containing one or two substituent selected from lower alkyl; morpholinyl-lower alkyl; piperidyl, optionally containing one substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl; and piperazinyl-lower alkyl, optionally containing one lower alkyl group,

(36) phosphono-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(37) phosphono-lowest alkanoyloxy-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(38) benzoyloxy-lower alkyl, optionally containing, in the benzene ring, one substituent in�who was from the group, consisting of hydroxyl groups, benzyloxy and phosphonopropyl, optionally containing one or two lower alkyl groups,

(39) tetrahydropyranyl, optionally containing one or four Deputy selected from the group consisting of hydroxy, hydroxy-lower alkyl and carboxy, or

(40) the lower alkanolamine-lower alkyl, optionally containing, in the lower alkanolamide, one or two substituent selected from the group consisting of halogen; hydroxy; amino; lower alkoxycarbonyl; piperazinyl optionally containing one lower alkoxy-lower alkyl group; imidazolyl and morpholinylmethyl;

R₂represents hydrogen;

R₃represents phenyl, pyrazolyl or pyrimidinyl,

where:

aromatic or heterocyclic ring represented by R₃may be substituted by one or two substituents selected from the group consisting of the following substituents(1), (2), (4), (5), (7), (8), (10), (11) and (12):

(1) lower alkyl,

(2) the lower alkoxygroup,

(4) halogen free,

(5) hydroxy,

(7) hydroxy lower alkoxygroup,

(8) tetrahydropyranyloxy-lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl and

(12) carbamoyl-lower alkoxygroup;

R₄is a halogen;

R_{5 represents hydrogen or halogen;}

_{R6represents hydrogen; and}

R₇is any one of the following groups(2), (7), (8) and (11):

(2) the lower alkoxygroup,

(7) an amino group optionally containing one or two substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy and

(11) pyrrolidinyl.

Item 9. Quinoline compound of the General formula (1) or its salt according to claim 1 wherein

R₁represents:

(1) hydrogen or

(2) lower alkyl;

R₂represents:

(3) low alkanoyl,

(4) hydroxy-lower alkyl,

(5) carboxy,

(6) low alkoxycarbonyl,

(7) carbamoyl, optionally containing one or two substituent selected from the group consisting of lower alkyl; halogen-substituted lower alkyl; hydroxy-lower alkyl; piperazinyl-lower alkyl, optionally containing one lower alkyl group; and morpholinyl-lower alkyl,

(8) carbamoyl-lower alkyl, optionally containing one lower alkyl group,

(9) morpholinyl-lower alkyl,

(10) a piperazinyl-lower alkyl, optionally containing one substituent selected from the group consisting of lower alkyl and pyridyl, optionally containing one lower alkyl group,

(11) d�of azepane-lower alkyl,

(12) amino lower alkyl optionally containing one or two substituent selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, hydroxy-lower alkyl and morpholinyl-lower alkyl,

(13) low alkoxycarbonyl-lower alkyl, or

(14) carboxy lower alkyl;

R₃represents phenyl, thienyl, furyl, pyrazolyl or pyrimidinyl where:

aromatic or heterocyclic ring represented by R₃may be substituted with one substituent selected from the group consisting of the following substituents (1) to (14):

(1) lower alkyl,

(2) the lower alkoxygroup,

(3) the lower alkanoyl,

(4) halogen free,

(5) hydroxy,

(6) hydroxy-lower alkyl,

(7) hydroxy lower alkoxygroup,

(8) protected at the hydroxy-group of the lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl-lower alkoxygroup, optionally containing one lower alkyl group,

(13) carbamoyl, optionally containing one morpholinyl-lower alkyl group, and

(14) morpholinylcarbonyl;

R₄represents halogen, lower alkyl or lower alkoxygroup;

R₅represents hydrogen or halogen;

R₆isone hydrogen or lower alkoxygroup; and

R₇is any one of the following groups (1) to (11):

(1) hydrogen,

(2) the lower alkoxygroup,

(3) hydroxy-lower alkoxygroup,

(4) benzyloxy-lowest alkoxygroup,

(5) lower alkoxy-lower alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing one substituent selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(7) an amino group optionally containing one or two substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup and

(11) pyrrolidinyl.

Paragraph 10. Quinoline compound of the General formula (1) or its salt according to paragraph 9, where

R₁represents hydrogen;

R₂represents:

(3) low alkanoyl,

(4) hydroxy-lower alkyl,

(5) carboxy,

(6) low alkoxycarbonyl,

(7) carbamoyl, optionally containing one or two substituent selected from the group consisting of lower alkyl; halogen-substituted lower alkyl; hydroxy-lower alkyl; piperazinyl-lower alkyl, optionally containing one lower alkyl group; and morpholinyl-lower alkyl,

(8) carbamoyl-lower alkyl, neobyazatelnostyu one lower alkyl group,

(9) morpholinyl-lower alkyl,

(10) a piperazinyl-lower alkyl, optionally containing one substituent selected from the group consisting of lower alkyl and pyridyl, optionally containing one lower alkyl group,

(11) diazepan-lower alkyl,

(12) amino lower alkyl optionally containing one or two substituent selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, hydroxy-lower alkyl and morpholinyl-lower alkyl, or

(14) carboxy lower alkyl;

R₃represents phenyl, where:

phenyl, represented by R₃substituted with one lower alkoxygroup,

R₄is a halogen;

R₅represents hydrogen;

R₆represents hydrogen; and

R₇represents the lowest alkoxygroup.

Paragraph 11. Quinoline compound of the General formula (1) or its salt according to claim 1 wherein

R₁represents:

(1) hydrogen or

(2) lower alkyl;

R₂represents hydrogen;

R₃represents phenyl, thienyl, furyl, pyrazolyl or pyrimidinyl where:

aromatic or heterocyclic ring represented by R₃may be substituted with one substituent selected from the group consisting of the following substituents(7), (8), (9), (10), (12), (13) and (14):

(7) hydroxy-lower alcohol�syrupy,

(8) benzyloxy-lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(12) carbamoyl-lower alkoxygroup, optionally containing one lower alkyl group,

(13) carbamoyl, optionally containing one morpholinyl-lower alkyl group, and

(14) morpholinylcarbonyl;

R₄represents halogen, lower alkyl or lower alkoxygroup;

R₅represents hydrogen or halogen;

R₆represents hydrogen or lower alkoxygroup; and

R₇is any one of the following groups (1) to (11):

(1) hydrogen,

(2) the lower alkoxygroup,

(3) hydroxy-lower alkoxygroup,

(4) benzyloxy-lowest alkoxygroup,

(5) lower alkoxy-lower alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing one substituent selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(7) an amino group optionally containing one or two substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup and

(11) pyrrolidinyl.

Item 12. Quinoline compound of the General�th of formula (1) or its salt according to item 11, where

R₁represents hydrogen;

R₃represents phenyl, where:

phenyl, represented by R₃may be substituted with one substituent selected from the group consisting of the following substituents from (7) to (14):

(7) hydroxy lower alkoxygroup,

(8) benzyloxy-lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl-lower alkoxygroup, optionally containing one lower alkyl group,

(13) carbamoyl, optionally containing one morpholinyl-lower alkyl group, and

(14) morpholinylcarbonyl;

R₄is a halogen;

R₅represents hydrogen;

R₆represents hydrogen; and

R₇is any one of the following groups (2) and (11):

(2) the lower alkoxygroup; and

(11) pyrrolidinyl.

Paragraph 13. Quinoline compound of the General formula (1) or its salt according to claim 1 wherein

R₁represents:

(1) hydrogen or

(2) lower alkyl;

R₂represents hydrogen;

R₃represents phenyl, where:

phenyl, represented by R₃substituted with one lower alkoxygroup,

R₄represents halogen, lower alkyl or lower alkoxygroup;

R₅pre�represents a hydrogen or halogen;

R₆represents hydrogen or lower alkoxygroup; and

R₇is any one of the following groups(4), (6), (9) and (10):

(4) benzyloxy-lowest alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing one substituent selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(9) carboxy lower alkoxygroup and

(10) low alkoxycarbonyl-lowest alkoxygroup.

Paragraph 14. Quinoline compound of the General formula (1) or its salt according to item 13, where

R₁represents hydrogen;

R₃represents phenyl, where:

phenyl, represented by R₃may be substituted with one lower alkoxygroup,

R₄is a halogen;

R₅represents hydrogen;

R₆represents hydrogen; and

R₇is any one of the following groups(4), (6), (9), (10) and (11):

(4) benzyloxy-lowest alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing one substituent selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup and

(11) pyrrolidinyl.

Item 15. Pharmaceutical composition containing a quinoline compound of the General formula (1) according to any one�in paragraphs 1-14 or its salt as an active ingredient; and pharmaceutically acceptable carrier.

Paragraph 16. Preventive and/or therapeutic agent for the treatment of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by abnormal function of the mitochondria, the tool comprising as active ingredient a quinoline compound of the General formula (1) according to any one of paragraphs 1-14, or its salt.

Paragraph 17. Preventive and/or therapeutic agent according to item 16, where the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, strongley degeneration, progressive supranuclear palsy, true akinesia, Alzheimer's disease, pick's disease, prion disease, corticobasal degeneration, dementia with Lewy bodies, Huntington's chorea, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonia, syndrome of Gilles de La Tourette, rett syndrome, degenerative coarse hyperkinesia limbs, deforming muscular dystonia, athetosis, spastic torticollis, syndrome Maia, cerebral palsy, Wilson's disease, the disease of Segawa, disease Hallervorden-Spitze, neuroaxonal dystrophy syndrome Hunte, Spinoza�balleroy degeneration, atrophy of the cerebral cortex, cerebellar atrophy Holmes, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, disease Joseph, dentatorubral-pallidoluysian atrophy, disease Gerstmann-Straussler-Sheinker, hereditary Friedreich's ataxia, hereditary syndrome, Roussy-levy syndrome Mae white, congenital cerebellar ataxia, hereditary episodic ataxia, teleangiectatic ataxia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, disease werdnig-Hoffmann, disease Kugelberg-Welander, hereditary spastic paraparesis, syringomyelia, syringobulbia, syndrome, Arnold-Chiari malformation, syndrome fettered man, disease, Klippel-Feil syndrome Fazio-Londe, myelopathy lower limb syndrome Dandy-Walker, spina bifida, syndrome, Sjogren-Larsson, radiation myelopathy, age-related macular degeneration and stroke selected from the group consisting of ischemic stroke and intracerebral hemorrhage and/or concomitant dysfunction or neurological disorders.

Paragraph 18. Preventive and/or therapeutic agent according to item 16, where the disease is caused by neurological dysfunction, choose �h group, consisting of spinal cord injury, neuropathy due to chemotherapy, diabetic neuropathy, radiation damage and demyelinizing disease selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing leukoencephalitis, chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome.

19. Preventive and/or therapeutic agent according to item 16, where the disease caused by mitochondrial dysfunction, which are selected from the group consisting of Pearson syndrome, diabetes, deafness, malignant migraine syndrome Leber's syndrome MELAS, MERRF syndrome, overlap syndrome MERRF/MELAS, NARP, true myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency, congenital variants of cytochrome b, diffuse lipoma of the neck, ataxia, myoclonia, retinopathy, MNGIE, disease ANTl, the flicker in his eyes, POLG disease, paralytic myoglobinuria, SANDO, ARCO, deficiency of complex I, deficiency of complex II, optic nerve atrophy, failure, fatal infantile complex IV deficiency, mitochondrial DNA, the syndrome of deficiency of mitochondrial DNA, encephalomyelopathy Lee, syndrome, chronic progressive external ophthalmoplegia (CPEO), Kearns syndrome-they, encephalopathy, lactic-acidosis, myoglobinuria, drug induced mitochondrial diseases, schizophrenia, major depression, bipolar disorder type I, bipolar disorder type II, episode mixed type, dysthymic disorder, atypical depression, seasonal affective disorder, postpartum depression, minor depression, recurrent brief depressive disorder resistant depression/chronic depression, double depression and acute renal failure.

Item 20. Preventive and/or therapeutic agent containing as an active ingredient the compound according to any one of paragraphs 1-14, or its salt, where the specified prophylactic and/or therapeutic agent is intended for the treatment or prevention of ischemic heart disease and/or concomitant dysfunction, heart failure, myocardosis, dissections of the aorta, immune deficiency, autoimmune diseases, pancreatic insufficiency, diabetes, atheroembolic kidney disease, polycystic kidney disease, medullary cystic disease, necrosis of the cortical layer of the kidney, AVC�eroticheskoe nephrosclerosis, renal failure, hepatic encephalopathy, hepatic failure, chronic obstructive pulmonary disease, pulmonary embolism, bronchiectasis, silicosis, coal miners pneumoconiosis, diffuse interstitial pulmonary fibrosis, and syndrome of Stevens-Johnson, toxic epidermal necrolysis, muscular dystrophy, clostridial muscle necrosis and necrosis of femoral condyle.

Paragraph 21. The use of quinoline compounds of the General formula (1) according to any one of paragraphs 1-20 or its salts as a drug.

Item 22. A method for the treatment or prevention of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by mitochondrial dysfunction, including the introduction of quinoline compounds of the General formula (1) in paragraph 1, or salts thereof to a human or animal.

Paragraph 23. A method of producing quinoline compounds represented by formula (1b):

where R₂, R₃, R₄, R₅, R₆and R₇are as defined in paragraph 1, and R₁'is a group represented by R₁as defined in paragraph 1, other than hydrogen, or salts thereof; the method comprising the interaction of the compounds represented by the formula:

R₁'-X₂,

where X₂pre�represents a group which undergoes the same substitution reaction as the reaction of substitution of a halogen or halogen atom, with a compound represented by the formula:

where R₂, R₃, R₄, R₅, R₆and R₇are as defined in paragraph 1.

Another option quinoline compounds represented by formula (1) is the following option:

Formula (1):

where R₁represents:

(1) hydrogen,

(2) lower alkyl,

(3) halogen-substituted lower alkyl,

(4) lower alkenyl,

(5) low alkanoyl,

(6) halogen-substituted lower alkanoyl,

(7) hydroxy-lower alkyl,

(8) a phenyl-lower alkoxy-lower alkyl,

(9) hydroxy-lower alkanoyl,

(10) a phenyl-lower alkoxy-lower alkanoyl,

(11) lower alkylthio-lower alkyl,

(12) amino lower alkylthio-lower alkyl, optionally containing, in the amino group, one or two, and preferably two lower alkyl groups;

(13) hydroxy-lower alkylthio-lower alkyl,

(14) carboxy lower alkylthio-lower alkyl,

(15) low alkoxycarbonyl-lowest alkylthio-lower alkyl,

(16) amino-lower alkylthiomethyl-lower alkyl, optionally containing, in the amino group, one or two, and preferably two lower alkyl groups,

(17) hydroxy-lower alkylsulfonyl�-lower alkyl,

(18) carboxy lower alkylsulfonyl-lower alkyl,

(19) low alkoxycarbonyl-lower alkylsulfonyl-lower alkyl,

(20) low alkanoyl-lower alkylsulfonyl-lower alkyl,

(21) a piperazinyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(22) piperazinylcarbonyl-lower alkylsulfonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(23) low alkanoyl-lower alkyl,

(24) carboxy-lower alkyl,

(25) low alkoxycarbonyl-lower alkyl,

(26) a piperazinyl-lower alkoxycarbonyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring,

(27) morpholinyl-lower alkyl,

(28) oxazepan-lower alkyl,

(29) amino-lower alkyl, optionally containing one lower alkyl group in the amino group,

(30) piperazin-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl, lower alkoxy-lower alkyl and pyridyl,

(31) piperidyl-lower alkyl, optionally containing one morpholinyl group in piperidinium ring,

(32) azetidin-lower alkyl, optionally containing one hydroxy-group in azetidinone ring,

(33) isoindoline-lower alkyl, neo�Astelin containing two carbonyl group in isoindoline ring,

(34) amino-lower alkanoyloxy-lower alkyl, optionally containing, in the amino group, one or two substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl,

(35), carbamoyl-lower alkyl, optionally containing, in carbamoyl group, one or two substituent selected from lower alkyl; morpholinyl-lower alkyl; piperidyl, optionally containing one substituent selected from the group consisting of lower alkyl and lower alkoxycarbonyl; and piperazinyl-lower alkyl, optionally containing one lower alkyl group,

(36) phosphono-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(37) phosphono-lowest alkanoyloxy-lower alkyl, optionally containing one or two lower alkyl groups in phosphonopropyl,

(38) benzoyloxy-lower alkyl, optionally containing, in the benzene ring, one substituent selected from the group consisting of hydroxyl groups, protected hydroxyl groups and phosphonopropyl, optionally containing one or two lower alkyl groups,

(39) tetrahydropyranyl, optionally containing from one to four, and preferably four, of substituent selected from the group consisting of hydroxy, hydroxy-lower-alkyl, and carboxy; and, more preferably, tetrahydropyrane�, containing three hydroxyl groups and one hydroxy-lower alkyl group, or

(40) the lower alkanolamine-lower alkyl, optionally containing, in the lower alkanoyloxy group, one or two substituent selected from the group consisting of halogen; hydroxy; amino; lower alkoxycarbonyl; piperazinyl optionally containing one lower alkoxy-lower alkyl group; imidazolyl; and morpholinylmethyl;

R₂represents:

(1) hydrogen,

(2) lower alkyl,

(3) low alkanoyl,

(4) hydroxy-lower alkyl,

(5) carboxy;

(6) low alkoxycarbonyl,

(7) carbamoyl, optionally containing one or two substituent selected from the group consisting of lower alkyl; halogen-substituted lower alkyl; hydroxy-lower alkyl; piperazinyl-lower alkyl, optionally containing one lower alkyl group in the piperazine ring; and morpholinyl-lower alkyl,

(8) carbamoyl-lower alkyl, optionally containing one lower alkyl group in carbamoyl group,

(9) morpholinyl-lower alkyl,

(10) a piperazinyl-lower alkyl, optionally containing, in the piperazine ring, one substituent selected from the group consisting of lower alkyl and pyridyl, optionally containing one lower alkyl group,

(11) diazepan-lower alkyl, or

(12) and�eno-lower alkyl, optionally containing, in the amino group, one or two substituent selected from the group consisting of lower alkyl, halogen-substituted lower alkyl, hydroxy-lower alkyl and morpholinyl-lower alkyl;

R₃represents phenyl, thienyl, furyl, pyrazolyl or pyrimidinyl where:

aromatic or heterocyclic ring represented by R₃may be substituted by one or two substituents selected from the group consisting of the following substituents (1) to (14):

(1) lower alkyl,

(2) the lower alkoxygroup,

(3) the lower alkanoyl,

(4) halogen free,

(5) hydroxy,

(6) hydroxy-lower alkyl,

(7) hydroxy lower alkoxygroup,

(8) protected at the hydroxy-group of the lower alkoxygroup,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lower alkoxygroup,

(11) pyrrolidinylcarbonyl,

(12) carbamoyl-lower alkoxygroup, optionally containing one lower alkyl group in carbamoyl group,

(13) carbamoyl, optionally containing one morpholinyl-lower alkyl group, and

(14) morpholinylcarbonyl;

R₄represents halogen, lower alkyl or lower alkoxygroup;

R₅represents hydrogen or halogen;

R₄and R₅may be associated with the formation of the group, predstavlen�th any of the following formulas:

or the group represented by the following formula:

group, optionally containing one or two substituent selected from the group consisting of lower alkyl or carbonyl group;

R₆represents hydrogen or lower alkoxygroup;

R₇is any one of the following groups (1) to (11):

(1) hydrogen,

(2) the lower alkoxygroup,

(3) hydroxy-lower alkoxygroup,

(4) protected by a hydroxy-group lowest alkoxygroup,

(5) lower alkoxy-lower alkoxygroup,

(6) carbamoyl-lowest alkoxygroup, optionally containing, in carbamoyl group, one alternate selected from the group consisting of lower alkyl and morpholinyl-lower alkyl,

(7) an amino group optionally containing a substituent selected from the group consisting of lower alkyl and cyclo C₃-C₈of alkyl,

(8) cyclo C₃-C₈alkyloxy,

(9) carboxy lower alkoxygroup,

(10) low alkoxycarbonyl-lowest alkoxygroup and

(11) pyrrolidinyl; and

R₆and R₇may be associated with the formation of the group represented by any of the following formulas:

.

Preferred embodiments of the various definitions used in the description and included in volume from�retenu, presented next.

The term “lower” refers to a group containing from 1 to 6 carbons (preferably 1 to 4 carbons), unless otherwise noted.

Examples of lower alkyl groups include straight or branched C_1-6(preferably C_1-4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl, etc.

Examples of lower alkenyl groups include straight or branched C_2-6the alkenyl group with 1 to 3 double bonds, including both TRANS-and CIS-forms. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatriene, 1,3-hexadienyl, 1,4-hexadienyl, etc.

Examples of C₃-C₈cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

C₃-C₈cycloalkyl fragments of C₃-C₈cycloalkylation are as described above.

Note�ry C ₃-C₈cycloalkyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) C₃-C₈cycloalkyl group(s) described above.

Examples of lower alkoxy groups include straight or branched C_1-6(preferably C_1-4) alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, h-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, isohexane, 3-methylpentane, etc.

Examples of the lower alkoxy-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) of lower alkoxy groups(s) described above.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine.

Examples of halogen-substituted lower alkyl groups include lower alkyl groups containing from one to seven atom(s) is halogen, preferably one to three atom(s) is halogen. Examples of these groups include vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, dichloromethyl, 2,2-defloratin, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-bromacil, 2-chloroethyl, 3-bromopropyl, 3-chloropropyl, 3,3,3-cryptochromes, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl�, 4,4,4-tripcomputer, 4,4,4,3,3-PENTACARBONYL, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-tryptophanyl, 5-chloropentyl, 6,6,6-triptorelin, 6-chlorhex, perferences, etc.

Examples of halogen-substituted lower alkoxy groups include lower alkoxygroup containing from one to seven atom(s) is halogen, preferably one to three atom(s) is halogen. Examples of these groups include formatosi, deformedarse, triptoreline, chloromethoxy, dichloromethoxy, trichlormethane, bromoethoxy, dibromethane, dichloromethoxy, 2,2,2-triptoreline, pentaborate, 2-chloroethoxy, 3,3,3-cryptocracy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropane, 4,4,4-triptoreline, 4,4,4,3,3-pentafluorobutane, 4-chloroethoxy, 4-bromoethoxy, 2-chloroethoxy, 5,5,5-triterpenes, 5-chlorphenoxy, 6,6,6-triptoreline, 6-chlorhexidine, etc.

Examples of the lower alkylthio include ancilliary, where the alkyl fragment represents a lower alkyl group described above.

Examples of the lower alkanoyl groups include straight or branched C_1-6(preferably C_1-4) alcoholnye groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbamoyl, hexanoyl, etc.

Examples of halogen-substituted lower alkanoyl groups include lower alkanoyl� group, containing from one to seven atom(s) is halogen, preferably one to three atom(s) is halogen. Examples of these groups include peracetyl, divercity, triptorelin, chloroacetyl, dichloroacetyl, bromacetyl, dibromoethyl, 2,2-defloratin, 2,2,2-triptocaine, pentafluoropropionic, 3-chlorbutanol, 3,3,3-trichloroethanol, 4-chlorobutanol, etc.

Examples of protected hydroxy groups include the lower alkyl groups described above, the lower alcoholnye group described above, phenyl-(lower) alkyl group (such as benzyl, 4-methoxybenzyl, trityl, etc.), tetrahydropyranyl group, etc.

Examples of hydroxy-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) of hydroxy groups(s).

Examples are protected at the hydroxy-group of the lower alkyl groups include lower alkyl groups containing from one to three (preferably one) a protected hydroxy-group(s) described above.

Examples of amino-lower alkanoyl groups include lower alcoholnye group containing from one to three (preferably one) amino group(s).

Examples of hydroxy-lower alkanoyl groups include lower alcoholnye group containing from one to three (preferably one) of the hydroxy-group(s).

Examples are protected at the hydroxy-group of the lower alkanoyl groups �fied lower alcoholnye group, containing from one to three (preferably one) a protected hydroxy-group(s) described above.

Examples phosphono-lower alkanoyl groups include lower alcoholnye group containing from one to three (preferably one) protected phosphonopropyl(s).

Phosphono-lower alkanolamine fragments phosphono-lower alkanoyloxy are such as those described above.

Examples phosphono-lowest alkanoyloxy-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) phosphono-lowest alkanoyloxy(s) described above.

Examples of amino-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) amino group(s).

Examples of carboxy-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) carboxypropyl(s).

Examples of carbamoyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) carbamoyl group(s).

Examples of low alkanoyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) of the lower alkanoyloxy group(s).

Examples of the lower alkoxy-lower alkyl groups include lower alkyl groups containing from one to �Rech (preferably one) the lowest alkoxygroup(s).

Examples phosphono-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) phosphonopropyl(s).

Examples of the lower alkylthio-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) the lowest allylthiourea(s) described above.

Lower alcoholnye fragments of the lower alkanolamines are as described above.

Examples of the lower alkanolamine-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) the lowest alkanolamine(s) described above.

Amino-lower alkyl fragments of the amino-lower alkylthio are as described above.

Examples of amino-lower alkylthio-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) amino-lower allylthiourea(s) described above.

Hydroxy-lower alkyl fragments hydroxy-lower alkylthio are as described above.

Examples of hydroxy-lower alkylthio-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) hydroxy-lower allylthiourea(s) described above.

Carboxy-lower alkyl fragments carboxy-lower alkylthio are as described in�above.

Examples of carboxy-lower alkylthio-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) carboxy lower allylthiourea(s) described above.

Low alkoxyphenyl lower alkoxycarbonyl groups are as described above.

Lower alkoxycarbonyl fragments of the lower alkoxycarbonylmethyl are as described above.

Examples of low alkoxycarbonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) of the lower alkoxycarbonyl group(s) described above.

Low alkoxycarbonyl-lower alkyl fragments low alkoxycarbonyl-lower alkylthio are as described above.

Examples of low alkoxycarbonyl-lowest alkylthio-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) low alkoxycarbonyl-lowest allylthiourea(s) described above.

Lower alkyl fragments lower alkylthiomethyl groups are as described above.

Amino-lower alcoholnye fragments of the amino-lower alkanoyloxy are as described above.

Examples of amino-lower alkanoyloxy-lower alkyl groups include lower alkyl groups containing from one to three (pre�occhialino one) amino-lower alkanoyloxy(s).

Examples of amino-lower alkylthiomethyl groups include lower alkylthiomethyl group containing from one to three (preferably one) amino group(s).

Examples of amino-lower alkylthiomethyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) amino-lower alkylthiomethyl group(s) described above.

Examples benzoyloxy-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) benzoyloxy(s).

Hydroxy-lower alkyl fragments hydroxy-lower alkylsulfonyl groups are as described above.

Examples of hydroxy-lower alkylsulfonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) hydroxy-lower alkylsulfonyl group(s) described above.

Carboxy-lower alkyl fragments carboxy-lower alkylsulfonyl groups are as described above.

Examples of carboxy-lower alkylsulfonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) carboxy lower alkylsulfonyl group(s) described above.

Low alkoxycarbonyl-lower alkyl fragments low alkoxycarbonyl-lower alkylsulfonyl �Rupp are such, as explained above.

Examples of low alkoxycarbonyl-lower alkylsulfonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) low alkoxycarbonyl-lower alkylsulfonyl group(s) described above.

Low alkanoyl-lower alkyl fragments low alkanoyl-lower alkylsulfonyl groups are as described above.

Examples of low alkanoyl-lower alkylsulfonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) low alkanoyl-lower alkylsulfonyl group(s) described above.

Examples of hydroxy-lower alkoxy groups include lower alkoxygroup containing from one to three (preferably one) of the hydroxy-group(s).

Examples are protected at the hydroxy-group of lower alkoxy groups include lower alkoxygroup containing from one to three (preferably one) a protected hydroxy-group(s) described above.

Examples of carboxy-lower alkoxy groups include lower alkoxygroup containing from one to three (preferably one) carboxypropyl(s).

Examples of low alkoxycarbonyl-lower alkoxy groups include lower alkoxygroup containing from one to three (preferably one) of the lower alkoxycarbonyl group described above.

Examples ka�bamol-lower alkoxy groups include lower alkoxygroup, containing from one to three (preferably one) carbamoyl group(s).

Examples of the lower alkoxy-lower alkoxy groups include lower alkoxygroup containing from one to three (preferably one) the lowest alkoxygroup(s) described above.

Examples of the piperazinyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) piperazinilnom group(s).

Examples of the piperazinyl-lower alkylsulfonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) piperazinyl-lower alkylsulfonyl group(s) where the piperazinyl-lower alkyl fragments are as described above.

Examples of piperazinylcarbonyl-lower alkylsulfonyl groups include lower alkylsulfonyl group containing from one to three (preferably one) piperazinylcarbonyl group(s).

Examples of piperazinylcarbonyl-lower alkylsulfonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) piperazinylcarbonyl-lower alkylsulfonyl group(s) described above.

Examples of the piperazinyl-lower alkoxycarbonyl groups include lower alkoxycarbonyl group containing from one to three (preferably one) piperazinilnom group(s.

Examples of the piperazinyl-lower alkoxycarbonyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) piperazinyl-lower alkoxycarbonyl group(s).

Examples of morpholinyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) morpholinyl group(s).

Examples of oxazepan-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) occasianally group(s).

Examples piperidyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) piperidino group(s).

Examples azetidin-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) azetidinol group(s).

Examples isoindolyl-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) isoindolyl group(s).

Examples of diazepan-lower alkyl groups include lower alkyl groups containing from one to three (preferably one) diazepino group(s).

A method of producing the compounds according to the invention is described in detail below.

Quinoline compound represented by the General formula (1) (the description also n�called as compound (1)), can be obtained in various ways; for example, the method according to the following reaction scheme 1 or 2.

A reaction scheme 1

where R₁, R₂, R₃, R₄, R₅, R₆and R₇are as defined above, and X₁represents a halogen atom.

Examples of halogen atoms represented X₁include fluorine, chlorine, bromine and iodine.

Preferred leaving groups in the reaction include Halogens. Among them, iodine is the most preferred.

The compound (1) can be prepared by reacting compounds represented by the General formula (2), with a compound represented by the General formula (3), in an inert solvent or without using any solvent, in the presence or absence of a basic compound, in the presence of palladium catalyst.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; ketones, such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid � acetonitrile. These inert solvents may be used alone or in combination of two or more solvents.

Palladium compounds used in the reaction, not really limited, but include, for example, tetravalent palladium catalysts, such as hexachloropalladate(IV) sodium tetrahydrate and hexachloropalladate(IV) potassium; divalent palladium catalysts such as palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetrafluoroethane(II), dichloro(cycloocta-1,5-diene)palladium(II), palladium(II) triptorelin and a complex of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II), dichloro methane; nonvalence palladium catalyst such as Tris(dibenzylideneacetone)2 palladium(0) complex of Tris(dibenzylideneacetone)2 palladium(0) chloroform and tetrakis(triphenylphosphine)palladium(0), etc., These palladium compounds are used one by one or in combination of two or more compounds.

In the reaction, the amount of palladium catalyst is not particularly limited, but is usually in the range from 0.000001 to 20 moles of a in terms of palladium relative to 1 mole of the compounds of the General formula (2). The amount of palladium catalyst is preferably in the range�zones from 0.0001 to 5 moles in terms of palladium relative to 1 mole of the compounds of the General formula (2).

This reaction preferably occurs in the presence of a suitable ligand. Examples of the palladium catalyst ligands include 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(BINAP), tri-o-tolylphosphino, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-t-butylphosphine and 9,9-dimethyl-4,5-bis(diphenylphosphino)Xanten (XANTPHOS). These ligands are used singly or in combination of two or more ligands.

The proportion of palladium catalyst and a ligand is not particularly limited. The amount of ligand is from about 0.1 to 100 moles, preferably from about 0.5 to 15 moles per mole of palladium catalyst.

Various known inorganic and organic bases may be used as basic compounds.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium; phosphates such as sodium phosphate and potassium phosphate; amides such as sodium amide; and hydrides of alkali metals such as sodium hydride and potassium hydride.

Organic DOS�tion include, for example, lower alkoxides of alkali metals such as sodium methylate, sodium ethylate, t-butylate sodium, potassium methylate, ethylate and potassium t-butylate potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

These basic compounds may be used alone or in combinations of two or more. More preferably, the basic compound used in the reaction include carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate.

The basic compound is usually used in an amount of from 0.5 to 10 moles, preferably from 0.5 to 6 moles, per mole of the compounds of the General formula (2).

In reaction scheme 1 above, the compound of the General formula (3) is usually used in an amount of at least about 1 mole, preferably about 1 to 5 moles, per mole of the compounds of the General formula (2).

The reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction generally proceeds at a temperature of from room temperature to 150°C and is usually imple�applied for about from 1 hour to 30 hours. The reaction is also carried out by heating at a temperature of from 100 to 200°C for from 5 minutes to 1 hour with the use of a reactor with microwave radiation.

The compound represented by the General formula (3), which is used as a starting material, as shown in reaction scheme 1, is readily available known compound. The compound represented by the General formula (2), includes a new connection, and get the connection in accordance with reaction scheme 6, below.

A reaction scheme 2

where R₁, R₂, R₃, R₄, R₅, R₆and R₇are as defined above, and R₈represents the lowest alkoxygroup.

Lowest alkoxygroup provided R₈in the General formula (5) has the same definition as described above.

The compound represented by the General formula (4), interacts with the compound represented by the General formula (5), in an inert solvent or without using any solvent, in the presence or absence of an acid catalyst to obtain an intermediate compound represented by the General formula (6). Then, the resulting compound cyclized to produce a compound represented by the General formula (1).

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. These inert solvents may be used alone or in combinations of two or more.

Different types of known acid catalysts can be used, including toluensulfonate, methanesulfonate, killswitches, sulfuric acid, glacial acetic acid, boron TRIFLUORIDE boron, ion exchangers containing acid groups, etc., These acid catalysts may be used alone or in combinations of two or more.

Among these acid catalysts, ion exchangers containing acid groups, is preferably used. Examples of ion exchangers containing an acid group include a polymer cation exchangers commercially available, such as Lewatit S100, Zeo-karb 225, Dowex 50, Amberlite IR120 or Amberlyst 15, and similar polymers of styrelseledamot; Lewatit PN, Zeo-karb 215 or 315 and similar polysulphonate; Lewatit CNO, Duolite CS100 and similar m-phenol-carboxylic resin; or Permutit C, Zeo-karb 226 or Amberlite IRC 50 and similar �aliability. Of these ion exchangers, Amberlyst 15 is particularly preferred.

The acid catalyst is usually used in amounts of from 0.0001 to 100 moles, preferably from 0.5 to 6 moles, per mole of the compounds of the General formula (4).

The compound of the General formula (5) described in reaction scheme 2, is usually used in an amount of at least about 1 mole, preferably about 1 to 5 moles, per mole of the compounds of the General formula (4).

The reaction can be conducted at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction is carried out usually at a temperature of from room temperature to 200°C and preferably at a temperature from room temperature to 150°C. during the reaction, the azeotropic removal of water is carried out until, until the formation of reaction water. The reaction is typically accomplished in a period of about from 1 hour to 30 hours.

A method of producing compounds of the General formula (1) by reaction of cyclization of the intermediate represented by the General formula (6) can be carried out by heating the compound in a solvent such as diphenyl ether, or by heating the compound in the absence of solvent. The reaction is conducted at a temperature of from 150 to 300°C for a time from 5 minutes to 2 hours�V.

The compound represented by the General formula (4) used as the starting material, as shown in reaction scheme 2 described above, is a known compound or can be easily obtained using known compounds. The compound represented by the General formula (5), includes a new connection, and the compound synthesized in accordance with methods presented in reaction scheme 4 and reaction scheme 5, below.

A reaction scheme 3

where R₂, R₃, R₄, R₅, R₆and R₇are as defined above, and R₁'is a group represented by R₁different from hydrogen, and X₂represents a group which undergoes the same substitution reactions, substitution of a halogen or halogen atom.

The Halogens represented by X₂in the General formula (7) include a halogen atom described above. Groups, which are the same substitution reactions, substitution of the halogen atoms represented X₂include lower alkane of sulfonyloxy, aryl of sulfonyloxy, Arakelova of sulfonyloxy, etc.

Examples of the lower alkane sulfonyloxy include straight or branched C_1-6alkane of sulfonyloxy, such as methanesulfonate, econsult�yloxy, n-propanesulfonate, isopropylphenoxy, butanesulfonate, tert-butanesulfonate, pentanesulfonate and n-hexanesulfonate.

Examples of aryl sulfonyloxy include naftiliaki and phenylsulfonyl, optionally substituted in the phenyl ring by one to three substituent(s) selected from the group consisting of straight or branched C_1-6alkyl groups, straight or branched C_1-6of the alkoxy groups, nitro groups and halogen atoms as a substituent(s). Examples of phenylsulfonylacetate, optionally substituted as described above substituent(s), include phenylsulfonyl, 4-methylphenylsulfonyl, 2-methylphenylsulfonyl, 4-nitrophenylacetylene, 4-methoxyphenylalanine, 2-nitrophenylacetylene, 3-chlorophenylsulfonyl etc. Examples of matterantimatter include α-naftiliaki, β-naftiliaki, etc.

Examples Arakelova of sulfonyloxy include phenylsilane straight or branched C_1-6alkane of sulfonyloxy, which may contain in the phenyl ring from one to three substituent(s) selected from the group consisting of straight or branched C_1-6alkyl groups, straight or branched C_1-6of the alkoxy groups, nitro group and halogen atoms as the Deputy�(s); and naphthylamine straight or branched C_1-6alkane of sulfonyloxy. Examples of alkane sulfonyloxy substituted as described above for the phenyl group(s) include benzylmalonate, 2-phenylethylperoxo, 4-phenylmethylsulfonyl, 4-methylbenzenesulfonate, 2-methylbenzenesulfonate, 4-nitrobenzenesulfonate, 4-methoxybenzenesulfonyl, 3-chlorobenzenesulfonic etc alkane sulfonyloxy substituted as described above naftilos group(s) include α-naphthylenediisocyanate, β-naphthylenediisocyanate, etc.

The compound represented by the General formula (1b) may be prepared by reacting compounds represented by the General formula (1a), with a compound represented by the General formula (7), in an inert solvent or without using any solvent, in the presence or absence of a basic compound.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; ketones, such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF, dimethyl sulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. These inert solvents may be used alone or in combinations of two or more solvents.

As the basic compounds, various known inorganic bases and organic bases may be used.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium; amides such as sodium amide; and hydrides of alkali metals such as sodium hydride and potassium hydride.

Organic bases include, for example, lower alkoxides of alkali metals such as sodium methylate, sodium ethylate, t-butylate sodium, potassium methylate, ethylate and potassium t-butylate potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

Such basic �couplers can be used individually or in combinations of two or more. More preferably, the basic compound used in the reaction include inorganic bases such as sodium hydride and potassium hydride.

The basic compound is usually used in an amount of from 0.5 to 10 moles, preferably from 0.5 to 6 moles, per mole of the compounds of the General formula (1A).

In reaction scheme 1 above, the compound of the General formula (7) is usually used in an amount of at least about 1 mole, preferably about 1 to 5 moles, per mole of the compounds of the General formula (1A).

The reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction proceeds usually at a temperature from 0 ° C to 200 and preferably at a temperature from room temperature to 150 º C, and is usually accomplished within about 1 hour to 30 hours.

The compound represented by the General formula (7), which is used as a starting material, as shown in reaction scheme 3, is easily accessible by known connection.

The compound (5) and the compound (2) which are the starting materials for the compounds according to the invention include novel compounds and can be obtained in various ways; for example, ways, respectively, following reaction schemes 4 to 6.

The scheme re�functions 4

where R₂, R₃and R₈are as defined above, and R₉represents the lowest alkoxygroup.

Lowest alkoxygroup provided R₉in the General formula (9), has the same definition as described above.

The compound represented by the General formula (5) may be prepared by reacting compounds represented by the General formula (8), with a compound represented by the General formula (9), in an inert solvent or without using any solvent, in the presence or absence of a basic compound.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; ketones, such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. These inert solvents may be used alone or in combinations of two or more solvents.

As the basic compounds, various known inorganic bases and organic bases �might be used.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metals such as sodium and potassium; amides such as sodium amide; and hydrides of alkali metals such as sodium hydride and potassium hydride.

Organic bases include, for example, lower alkoxides of alkali metals such as sodium methylate, sodium ethylate, t-butylate sodium, potassium methylate, ethylate and potassium t-butylate potassium, and amines, such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

These basic compounds may be used alone or in combinations of two or more. More preferred examples of the basic compounds used in the reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, etc.

The basic compound is usually used in an amount from about 1 to 10 �Olya, preferably from about 1 to 6 moles, per mole of the compounds of the General formula (8).

In reaction scheme 4, the compound of the General formula (9) is usually used in an amount of at least about 1 mole, preferably about 1 to 5 moles, per mole of the compounds of the General formula (8).

The reaction can be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction proceeds usually at a temperature of from room temperature to 200, and preferably at a temperature from room temperature to 150 º C, and is usually accomplished within about 1 hour to 30 hours.

Compounds represented by the General formulas (8) and (9), which are used as starting materials, as shown in reaction scheme 4, are readily available known compounds.

A reaction scheme 5

whereR₂, R₃and R₈are as defined above, and X₃represents a halogen atom.

The halogen represented by X₃in the General formula (9'), has the same definition as described above.

The compound represented by the General formula (5) may be prepared by reacting compounds represented by the General formula (8') with a compound represented by the General form�Oh (9'), in an inert solvent or without using any solvent, in the presence or absence of a basic compound such as cesium carbonate and a copper catalyst such as copper iodide.

Preferred examples of the inert solvent include polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. These inert solvents may be used alone or in combinations of two or more solvents.

The reaction can be carried out in the presence of amino acids such as L-Proline.

The reaction can be conducted at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction generally proceeds at a temperature of from room temperature to 200°C, and preferably at a temperature from room temperature to 150 º C, and is usually accomplished within about 1 hour to 30 hours.

Compounds represented by the General formulas (8') and (9'), which are used as starting materials, as shown in reaction scheme 5, are readily available known compounds.

A reaction scheme 6

where R₄, R₅, R₆and R₇are as defined above, and X_1ais an atom g�lagena. The radical R₁₀represents a lower alkyl group.

The lower alkyl group represented by R₁₀and a halogen atom, represented by X_1ahave the same definitions as described above.

The compound represented by the General formula (12) can be obtained by the condensation reaction of the compounds represented by the General formulas (4), (10) and (11), in an inert solvent or without using any solvents.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. The compound represented by the General formula (11), can be used as the solvent instead of the solvents described above. These inert solvents may be used alone or in combinations of two or more solvents.

In reaction scheme 6, the compound of the General formula (10) is usually used�form in the quantity at least 1 mole, preferably about 1 to 5 moles, per mole of the compounds of the General formula (4).

The compound represented by the General formula (11), is used in an amount in excess of the compounds of the General formula (10).

The reaction may be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction generally proceeds at a temperature of from room temperature to 200°C, and preferably at a temperature from room temperature to 150 º C, and is usually accomplished within about 1 hour to 30 hours.

The compound represented by the General formula (13) can be obtained by the cyclization reaction of the compound represented by the General formula (12), in an inert solvent or without using any solvents.

Examples of inert solvents include ethers such as diphenyl ether.

The reaction may be carried out at normal pressure in an atmosphere of inert gas, including nitrogen, argon, etc., or at elevated pressures.

The reaction generally proceeds at a temperature of from room temperature to 300°C, and preferably at a temperature from 150°C to 300°C, and is usually accomplished within about 1 hour to 30 hours.

The compound represented by the General formula (2a), can be� prepared by reacting compounds represented by the General formula (13), with a compound represented by the General formula (14), in an inert solvent or without using any solvent, in the presence or absence of a basic compound.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; ketones, such as acetone and methyl ethyl ketone; polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. These inert solvents may be used alone or in combinations of two or more solvents.

As the basic compounds, various known inorganic bases and organic bases may be used.

Inorganic bases include, for example, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate and bicarb�at potassium; alkaline metals such as sodium and potassium; amides such as sodium amide; and hydrides of alkali metals such as sodium hydride and potassium hydride.

Organic bases include, for example, alkoxides of alkali metals such as sodium methylate, sodium ethylate, t-butylate sodium, potassium methylate, ethylate and potassium t-butylate potassium; and amines such as triethylamine, Tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiethanolamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

These basic compounds may be used alone or in combinations of two or more compounds. Preferred basic compounds used in the reaction include carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, etc.

The basic compound is usually used in an amount of from 0.5 to 10 moles, preferably from 0.5 to 6 moles, per mole of the compounds of the General formula (13).

The compound of the General formula (14) described in reaction scheme 6, usually used in an amount of at least 0.5 moles, preferably from about 0.5 to 5 moles, per mole of the compounds of the General formula (13).

The reaction can be conducted at normal pressure in the atmosphere�'ere inert gas, include nitrogen, argon, etc., or at elevated pressures.

The reaction generally proceeds at a temperature of from room temperature to 200°C, and preferably at a temperature from room temperature to 150°C, and is usually accomplished within about 1 hour to 30 hours.

Compounds represented by the General formulas (10), (11) and (14), which are used as starting materials in the synthesis shown in reaction scheme 6, are readily available known compounds.

A reaction scheme 7

where R₂, R₃, R₄, R₅, R₆and R₇are as defined above; R₁a represents phosphono-lower alkyl group containing one or more hydroxyamine groups, phosphono-lowest alkanoyloxy-lower alkyl group containing one or more hydroxyamine groups, or benzoyloxy-lower alkyl group containing one or more phosphonopropyl substituted with one or more hydroxybudesonide groups in the benzene ring; and R₁b represents phosphono-lower alkyl group, phosphono-lowest alkanoyloxy-lower alkyl group or a benzoyloxy-lower alkyl group containing one or more phosphonopropyl in the benzene ring.

The compound (1d) can be obtained by removing the protection from hydroc�Izumisano group of compound (1c) in an inert solvent or without using any solvents.

Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; lower alcohols such as methanol, ethanol and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamid and acetonitrile. The compound represented by the General formula (1C) can also be used as the solvent instead of the above-described solvents. These inert solvents may be used alone or in combinations of two or more solvents.

The specified reaction is carried out in conventional manner such as hydrolysis or recovery.

The hydrolysis is preferably carried out in the presence of bases or acids, including the Lewis acid.

Suitable examples of bases include inorganic bases such as hydroxides of alkali metals (e.g. sodium hydroxide, potassium hydroxide, hydroxides of alkaline earth metals (e.g. magnesium hydroxide, calcium hydroxide), carbonates of alkali metals (for example, carbon�tons of sodium, potassium carbonate), carbonates of alkaline earth metals (e.g. magnesium carbonate, calcium carbonate), bicarbonates of alkali metals (e.g. sodium bicarbonate, potassium bicarbonate); and organic bases, such as trialkylamine (e.g. trimethylamine, triethylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene and 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]undec-7-ene.

Examples of suitable acids include organic acids (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid). The removal of the protective groups when using Lewis acids, such as trigalogenmetany acid (e.g. trichloroacetic acid, trifluoroacetic acid), carried out in the presence of cationic purifier (e.g. anisole, phenol). In the reaction, the liquid base or acid can also be used as a solvent.

Reaction temperature is not limited, and the reaction is usually carried out under cooling or heating.

Recovery methods applicable to cleavage reactions include chemical reduction and catalytic reduction.

Suitable reducing agents for use in chemical reactions p�establet a combination of metal (for example, tin, zinc, iron) or metallic compound (e.g. chromium chloride, chromium acetate) and organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluensulfonic acid, hydrochloric acid, Hydrobromic acid).

Suitable catalysts for use in the reaction of catalytic reduction are conventional catalysts such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum dioxide, platinum wire), palladium catalysts (e.g. spongy palladium, palladium black, palladium dioxide, palladium catalyst on a carbon carrier, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate), Nickel catalysts (e.g. restored Nickel, Nickel dioxide, Raney-Nickel), cobalt catalysts (for example, the recovered cobalt, Raney cobalt), iron catalysts (e.g. reduced iron, Raney iron), copper catalysts (for example, deoxidized copper, Raney copper, copper Ulman), and the like.

The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water; an alcohol, such as methane�l, ethanol, triptorelin or ethylene glycol; ether, such as acetone, diethyl ether, dioxane or tetragidrofuran; a halogenated hydrocarbon such as chloroform, methylene chloride or telengard; an ester such as methyl acetate or ethyl acetate; acetonitrile; N,N-dimethylformamide; pyridine; any other organic solvent; or a mixture of these solvents. The reaction generally proceeds at a temperature of from room temperature to 200°C, and preferably at a temperature from room temperature to 150°C, and is usually accomplished within about 1 hour to 30 hours.

Furthermore, the reaction conditions for the removal of protection from hydroxyamino groups are not limited to the reaction conditions described above. For example, the reaction described by T. W. Green and P. G. M. Wuts (Protective Groups in Organic Synthesis, 4th edition), John Wiley & Sons (New York, 1991, p. 309), can also be used for the reaction process.

The starting compounds used in the reactions presented on each of the schemes described above, may include suitable salts, and the compounds according to the invention, obtained by any of the reactions that can form a suitable salt. These preferred salts include the following preferred salts of the compounds (1).

Suitable salts of the compounds (1) are pharmacologically acceptable salts, including,for example, salts of inorganic bases, such as metal salts, including alkali metal salts (e.g. sodium salt, potassium salt, etc.), and salts of alkaline earth metals (e.g. calcium salt, magnesium salt, etc.), ammonium salts, carbonates of alkali metals (e.g. lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate etc.), bicarbonates of alkali metals (such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.) and hydroxides of alkali metals (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); salts of organic bases, such as tri(lower)alkyl amine (e.g. trimethylamine, triethylamine, N-ethyldiethanolamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkalifying (for example, N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and trihydroxypyrimidine; salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate; and salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, aconsultant, p-toluensulfonate and glutamate.

Furthermore, compounds VI in�e, in which the solvate (e.g. hydrate, ethylate, etc.) is added to the source materials and the connection according to the invention, are presented for each of the reaction schemes are also included in each of the General formulas. The hydrate can be marked as preferred solvate.

Each of the compounds according to the invention, obtained respectively described above reaction schemes can be isolated and purified from the reaction mixture by, for example, initially cooling the reaction mixture, the procedure of separation, such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then by implementing the conventional procedure of purifying crude reaction product, such as column chromatography, recrystallization, etc.

The compound represented by the General formula (1) according to the present invention of course includes geometric isomers, stereoisomers, optical isomers, and these isomers.

The following points should be noted regarding the compounds of the General formula (1) presented above. In particular, when R₁the General formula (1) represents a hydrogen atom, the compound includes the tautomer of quinoline ring. That is, in the quinoline compound of the General formula (1), when R₁represents a hydrogen atom (1'),

DG� R ₂, R₃, R₄, R₅, R₆and R₇are as defined above, the compound of tautomer can be represented by formula (1"),

where R₂, R₃, R₄, R₅, R₆and R₇are as defined above. That is, both compounds represented by formulas (1') and (1"), are in tautomeric equilibrium, represented by the following formula balance.

where R₂, R₃, R₄, R₅, R₆and R₇are as defined above. Such tautomerism between 4-quinoline compound and 4-hydroxyquinolinium connection is technically known, and for the person skilled in the art it is clear that both of the above tautomer are balanced and interchangeable.

Therefore, the compound represented by the General formula (1) according to the present invention naturally includes tautomers, as noted above.

In the description, the structural formula of 4-quinoline compounds suitably used as a structural formula of the compounds according to the invention or of the source material, including compounds such tautomers.

The present invention also includes isotopically labeled compounds, which are identical to compounds represented by formula (1), for IP�the shutdown, that one or more atoms replaced by one or more atoms that have a specific atomic mass or mass number. Examples of isotopes that can be incorporated into compounds according to the present invention include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as²H,³H,¹³C,¹⁴C,¹⁵N¹⁸O,¹⁷O,¹⁸F and³⁶Cl. Certain isotopically labeled compounds according to the present invention that are described above include isotopes and/or other isotopes of other atoms, for example, such compounds that include radioactive isotopes such as³H and¹⁴C, used in the analysis of the distribution into the tissues of the drug and/or substrate. Tritium-labeled (ie,³(H) and carbon-14 (T. e.,¹⁴C) isotopes are the most preferred due to easy for their preparation and detection. In addition, the substitution of heavy isotopes, such as deuterium (T. e.,²H), may have some therapeutic benefits, due to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds according to the present invention can be obtained by substitution of readily available isotopically labeled reagent for not isotopically labeled reagent according�on the way presented in the diagrams above and/or in the examples below.

The compound of the General formula (1) and its salt are used in the form of conventional pharmaceutical preparations. Preparations are prepared using generally used diluents or excipients such as fillers, cheaper additives, binders, moisturizers, dezintegriruetsja funds, surfactants, lubricants, etc., the Form of such pharmaceutical products can be selected according to the task of therapy. Typical examples of drugs include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.

For the preparation of tablets, any of various carriers, well known in this field can be used. Examples of carriers include lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, kelp powder, bicarbonate, calcium carbonate, esters of fatty acids and polyoxyethylenesorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose and other dezintegriruetsja funds; white sugar, stearin, cacao butter, hydrogensource oil and other inhibitors of disintegration; Quaternary ammonium bases, sodium lauryl sulfate and other amps absorption; glycerin, starch and other moisturizing products; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricating substances; etc. furthermore, such tablets can be coated with a conventional covering materials, if necessary, to prepare, for example, sugar-coated tablets, coated gelatin tablets, enteric tablets, film-coated tablets, two - or multi-layer tablets, etc.

For the preparation of pills, any of various carriers, well known in this field can be used. Examples of carriers include glucose, lactose, starch, cacao butter, hydrogensource vegetable oils, kaolin, talc and other auxiliary substances; powder Arabian gum, powder tragakant, gelatin, ethanol and other binders; laminarin, agar and other desintegrates�e means; etc.

For preparing suppositories, any of various carriers, well known in this field can be used. Examples of carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

Capsules can be prepared by mixing the active main connection with the above-described media for enclosing them in a hard gelatin capsule, soft gelatin capsule or the like.

To prepare the injection, solution, emulsion or suspension is sterilized and preferably do is isotonic to the blood. Any of the solvents commonly used for such forms in the field, can be used to prepare injections. Examples of such diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, esters of fatty acid and polyoxyethylenesorbitan, etc.

In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerin in an amount sufficient to prepare isotonic solution, and may contain conventional solubilizers tools, buffers, analgesics, etc. furthermore, if necessary, the pharmaceutical preparation can �to win dyes, preservatives, flavors, sweeteners, etc., and/or other medicines.

The amount of the compound represented by the General formula (1) or its salt contained in the pharmaceutical preparation according to the present invention is not limited and may be appropriately selected from a wide range. The proportion is usually from about 0.1 to about 70 wt.%, preferably from about 0.1 to about 30 wt%. pharmaceutical drug.

Method of administering a pharmaceutical preparation according to the present invention is not particularly limited, and the drug is administered in a manner suitable to the form of the drug, a patient's age, sex and other conditions, and the severity of the disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. The injection is administered intravenously by themselves or as a mixture with conventional transfusion systems, such as glucose solutions, amino acid solutions or the like, or by themselves is administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, if necessary. The suppositories are administered into the rectum.

The dosage of the pharmaceutical preparation according to the invention is suitably chosen according to the method of use, a patient's age, sex and other conditions, and severity Zab�of indicated here. The number of active main connection is usually from about 0.1 to about 10 mg/kg body weight/day. In addition, it is desirable that the pharmaceutical drug in each unit of input form contains the main active compound in amounts of from about 1 to about 200 mg.

The use of the compounds according to the present invention in combination with the drug L-DOPA, agonists dopamine receptor, inhibitors of enzymes of the metabolism of dopamine, drugs that increase the rate of release of dopamine, anticholinergic means Central action and the like, helps to achieve effects such as the reduction in the dose, decreased side effects, increased therapeutic efficiency, etc., which are not achieved by known therapies.

The useful effect of the invention

The compounds according to the invention protect and improve the function of mitochondria and/or protect neurons and restore neuronal function and are therefore effective in treating or preventing neurodegenerative diseases, diseases induced by neurological dysfunction, and diseases induced by mitochondrial dysfunction.

Examples of neurodegenerative diseases include Parkinson's disease, Parkinson's syndrome, juvenile �parkinsonism, strongely degeneration, progressive supranuclear palsy, true akinesia, Alzheimer's disease, pick's disease, prion disease, corticobasal degeneration, dementia with Lewy bodies, Huntington's chorea, chorea-acanthocytes, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, the essential myoclonus syndrome, Gilles de La Tourette, rett syndrome, degenerative coarse hyperkinesia limbs, deforming muscular dystonia, athetosis, spastic Krivoshey syndrome Maia, cerebral palsy, Wilson's disease, a disease of Segawa, disease Hallervorden-Spitze, neuroaxonal dystrophy, hunt syndrome, spinocerebellar degeneration, atrophy of the cerebral cortex, cerebellar atrophy Holmes, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, a disease Joseph, dentatorubral-pallidoluysian atrophy, a disease of Gerstmann-Straussler-Sheinker, hereditary Friedreich's ataxia, an inherited syndrome, Roussy-levy syndrome Mae white, congenital cerebellar ataxia, hereditary episodic ataxia, teleangiectasias ataxia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, a disease of werdnig-�Hoffmann, 's disease Kugelberg-Welander, hereditary spastic paraparesis, syringomyelia, syringobulbia syndrome, Arnold-Chiari syndrome fettered human disease, Klippel-Feil syndrome, Fazio-Londe, myelopathy lower limb syndrome, Dandy-Walker, spina bifida syndrome, Sjogren-Larsson, radiation myelopathy, age-related macular degeneration and stroke (for example, ischemic stroke and intracerebral hemorrhage) and/or dysfunction or neurological disorders associated with stroke.

Examples of diseases caused by neurological dysfunction include damage to the spinal cord, the chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage and demyelinating disease (such as multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing leukoencephalitis, chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome).

Examples of diseases caused by mitochondrial dysfunction include Pearson syndrome, diabetes, deafness, malignant migraine syndrome, Leber's syndrome, MELAS, MERRF syndrome, overlap syndrome MERRF/MELAS, NARP, true myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastro-celecoxi, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency, congenital variants of cytochrome b, diffuse lipoma of the neck, ataxia, myoclonus, retinopathy, MNGIE disease ANTl, the twinkle in his eyes, POLG disease, the paralytic myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, failure, fatal infantile complex IV deficiency, mitochondrial DNA deficiency syndrome, mitochondrial DNA, encephalomyelopathy Lee's syndrome, chronic progressive external ophthalmoplegia (CPEO), Kearns syndrome-they, encephalopathy, lactic-acidosis, myoglobinuria, induced drug mitochondrial disease, schizophrenia, major depression, bipolar disorder type I, bipolar disorder type II, episode mixed type, dysthymic disorder, atypical depression, seasonal affective disorder, postpartum depression, minor depression, recurrent brief depressive disorder, persistent depression/chronic depression, double depression and acute renal failure.

In addition, the compound is effective in the prevention or treatment of diseases such as coronary heart disease (e.g. myocardial infarction and/or related products.�existing dysfunction, arrhythmia, angina, a blockage after RTS, etc.) and/or concomitant dysfunction, heart failure, micardis, aortic dissection, immunologic failure, autoimmune diseases, pancreatic insufficiency, diabetes, atheroembolic kidney disease, polycystic kidney disease, medullary cystic disease, necrosis of the cortical layer of the kidney, arteriolosclerosis nephrosclerosis, renal failure, hepatic encephalopathy, hepatic failure, chronic obstructive pulmonary disease, pulmonary embolism, bronchiectasis, silicosis, coal miners pneumoconiosis, diffuse interstitial pulmonary fibrosis syndrome, Stevens-Johnson, toxic epidermal necrolysis, muscular dystrophy, clostridial muscle necrosis and necrosis of the condyle of the femur.

The connection according to the invention can exhibit the effects are not achieved is still known therapies, such as dose reduction, reduction of side effects and potentiation of therapeutic effects when administered in combination with the drug L-DOPA, agonists dopamine receptor, inhibitors of enzymes of the metabolism of dopamine, drugs that increase the rate of release of dopamine, anticholinergic means Central action, cholinesterase inhibitors, antagonists of glutamate receptors N-methyl--aspartate or other means, used in thrombolytic therapy, therapy of brain edema, protective therapy of the brain, antithrombotic therapy and therapy aimed at dilution of blood plasma.

Some of the compounds (1) according to the invention or their salts exhibit exceptionally high solubility, for example, in the water.

In particular, the compound (1d) or its salt exhibits an exceptionally high solubility, for example, in the water.

Description of embodiments of the invention

Further, the present invention is described in detail with reference to reference examples, examples, examples and pharmacological tests.

Referential example 1

GettingN(3-hydroxynaphthalene-2-yl)acetamide

The acetone solution (60 ml) of 3-amino-2-naphthol (5.0 g, and 31.4 mmol) was added to the aqueous solution (20 ml) of sodium carbonate (4.77 g, to 34.5 mmol). The mixture was cooled in a bath with ice-water mixture and then acetyl chloride (2,27 ml, 32,0 mmol) was added dropwise to the mixture over 5 minutes. The resulting mixture was stirred at 0°C for 4 hours and then left at room temperature over night. To the reaction mixture was added 2N hydrochloric acid to bring the pH of the mixture to pH 3. Formed are not soluble substance was separated, washed with water and then dried to give a white p�Rosca N(3-hydroxynaphthalene-2-yl)acetamide (4,9 g, yield: 78%).

Referential example 2

GettingN(3-propoxylation-2-yl)acetamide

N-(3-Hydroxynaphthalene-2-yl)acetamide (4,87 g, 24.2 mmol) was suspended in acetonitrile (50 ml). A solution of 1-jumprope (4,52 g, 26.6 mmol) in acetonitrile (40 ml) and potassium carbonate (4.35 g, 31.5 mmol) was added to the resulting suspension, and the resulting mixture was stirred for 3 hours under heating to reflux. Then, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Water was added to the residue, followed by extraction with dichloromethane. The thus obtained organic layer was concentrated to dryness under reduced pressure and then the residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=20:1). The purified product was concentrated to dryness under reduced pressure to give a white powderN(3-propoxylation-2-yl)acetamide (5,64 g, yield: 96%).

Referential example 3

Obtaining 3-propoxylation-2-ylamine

N-(3-Propoxylation-2-yl)acetamide (2.5 g, 10.2 mmol) was dissolved in ethanol (10 ml). To the solution was added concentrated hydrochloric acid (5.2 ml) and the resulting mixture was stirred for 4 hours under heating�research Institute to reflux. The reaction mixture was cooled to room temperature and 5N aqueous sodium hydroxide solution (12.5 ml) was added to the reaction mixture to bring the pH to 11, followed by extraction with dichloromethane. The thus obtained organic layer was concentrated to dryness under reduced pressure and then the residue was purified by column chromatography on silica gel (dichloro methane). The product after purification was concentrated to dryness under reduced pressure to give a white powder of 3-propoxylation-2-ylamine (2.05 g, yield: 100%).

Referential example 4

Obtain 2,2-dimethyl-5-[(3-propoxylation-2-ylamino)methylene][1,3]dioxane-4,6-dione

Acid, Meldrum (2,59 g, a 17.9 mmol) was added to methylacetamide (16 ml), and the mixture was stirred for 2 hours under heating to reflux. 3-Propoxylation-2-ylamine (2.5 g, 12.4 mmol) was added to the mixture and the resulting mixture was stirred for 4 hours under heating to reflux. The reaction mixture was cooled to room temperature and then concentrated to dryness under reduced pressure for recrystallization of the residue from methanol to obtain a light brown powder 2,2-dimethyl-5-[(3-propoxylation-2-ylamino)methylene][1,3]dioxane-4,6-dione (4,19 g, yield: 95%).

Referential example 5

Paul�within 5 propoxy-4H-benzo[f]quinolin-1-one

2,2-Dimethyl-5-[(3-propoxylation-2-ylamino)methylene][1,3]dioxane-4,6-dione (4,19 g, 11.7 mmol) was added to diphenyl ether (15 ml) and the mixture was heated by a heating mantle and then supported by boiling with reflux for 2 hours. The mixture was cooled to room temperature and was purified by column chromatography on silica gel (dichloro methane:methanol=70:1→9:1). The product after purification was concentrated to dryness under reduced pressure to obtain a dark brown powder 5 propoxy-4H-benzo[f]quinolin-1-one (3,15 g, yield: 61%).

Referential example 6

Obtain 2-iodo-5-propoxy-4H-benzo[f]quinolin-1-one

5 Propoxy-4H-benzo[f]quinoline-1-he (2.66 g, 10.5 mmol) was suspended in DMF (20 ml). Potassium carbonate (1.63 g, 11.8 per mmol) and iodine (2,95 g, 11.6 mmol) was added to the suspension followed by stirring at room temperature for 3 hours. The reaction mixture was poured into an aqueous solution of sodium thiosulfate (9,14 g, 100 ml) followed by stirring for 5 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was stirred. Further, not soluble substance was collected by filtration and then the filtrate was separated. The thus obtained organic layer was washed with a saturated aqueous solution of sodium chloride and then concentrated to dryness under reduced pressure. The residue was added with�Brandau insoluble substance with subsequent purification column chromatography on silica gel (dichloro methane:methanol=50:1→> 20:1). The purified product was concentrated to dryness under reduced pressure to obtain a light brown powder of 2-iodo-5-propoxy-4H-benzo[f]quinolin-1-one (3,48 g, yield: 87%).

Referential example 7

Getting oxime 1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone

1-(3-Propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)alanon (8,88 g, the 38.2 mmol) was dissolved in solvent mixture of chloroform (20 ml) and methanol (80 ml). Hydroxylamine hydrochloride (4,05 g, a 58.2 mmol) and pyridine (of 9.46 ml, 117 mmol) was added to the solution and stirred for 16 hours under heating to reflux. The reaction mixture was cooled to room temperature and then concentrated to dryness under reduced pressure. To the residue was added 2N hydrochloric acid (30 ml) and water, followed by extraction with dichloromethane. The thus obtained organic layer was concentrated to dryness under reduced pressure and then the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1). The purified product was concentrated to dryness under reduced pressure to obtain a pale yellow powder of the oxime of 1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone (8,87 g, yield: 94%).

Referential example 8

GettingN-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide

Referential example 9

Obtaining 3-propoxy-5,6,7,8-tetrahydronaphthalen-2-ylamine

3 Propoxy-5,6,7,8-tetrahydronaphthalen-2-ylamine was obtained in the same manner as described in Referential example 3.

Referential example 10

Obtain 5-bromo-6-propoxyimino

5-Bromo-6-propoxide prepared in the same manner that described in Reference example 2.

Referential example 11

Getting 6-propoxide-5-ylamine

To a solution of 5-bromo-6-proposing�to (8,24 g, of 32.2 mmol) in toluene (80 ml) was added a solution of benzophenone (6,40 g, with 35.3 mmol) in toluene (40 ml), Tris(dibenzylideneacetone)dipalladium (742 mg, 0.8 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)Xanten (XANTPHOS, 936 mg, 1.6 mmol) and cesium carbonate (15,72 g, 48,3 mmol). The resulting mixture was stirred at 100°C in a nitrogen atmosphere for 47 hours and then cooled to room temperature. Water and a saturated solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was dissolved in diethyl ether (130 ml). Concentrated hydrochloric acid (25 ml) was added to the solution, followed by stirring for 2 hours. To the reaction mixture was added 5N aqueous sodium hydroxide solution (72 ml) to bring the pH of the reaction mixture to 11, then concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with aqueous saturated solution of sodium chloride. The thus obtained organic layer was concentrated to dryness under reduced pressure and then the resulting residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=90:1). The purified product was concentrated to dryness under reduced pressure to obtain pale brown�th oily substances 6-propoxide-5-ylamine (1,02 g, yield: 17%).

Referential example 12

Obtaining 1-(7-propoxylate-6-yl)ethanone

1-(7-Hydroxychromone-6-yl)alanon (3.0 g, 15.6 mmol) was dissolved in DMF (20 ml). The sodium hydride (60% oil basis, 686 mg, 1,1 equivalent weight) was added to the solution under cooling with ice, and then the mixture was stirred for 10 minutes. 1-Jumprope (2,92 g, 1,1 equivalent weight) was added to the mixture and then stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The thus obtained organic layer was concentrated to dryness under reduced pressure and then the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:0→0:1). The purified product was concentrated to dryness under reduced pressure to give a white powder of 1-(7-propoxylate-6-yl)ethanone (4.2 g, yield: quantitative).

Referential example 13

Getting oxime 1-(7-propoxylate-6-yl)ethanone

The oxime of 1-(7-propoxylate-6-yl)ethanone was obtained in the same manner as described in Referential example 7.

Referential example 14

GettingN-(7-propoxylate-6-yl)acetamide

N-(7-Propoxylate-6-yl)acetamide was obtained in the same way that is described in Saleclonidine 8.

Referential example 15

Getting 7-propoxylate-6-ylamine

7-Propoxylate-6-ylamine was obtained in the same manner as described in Referential example 3.

Referential example 16

Getting oxime 1-(6-propoxylate-7-yl)ethanone

The oxime of 1-(6-propoxylate-7-yl)ethanone was obtained in the same manner as described in Referential example 7.

Reference example 17

GettingN-(6-propoxylate-7-yl)acetamide

N-(6-Propoxylate-7-yl)acetamide was obtained in the same manner as described in Reference example 8.

Referential example 18

Getting 6-propoxylate-7-ylamine

6-Propoxylate-7-ylamine was obtained in the same manner as described in Referential example 3.

Referential example 19

Obtaining 1-(5-propoxy-2,3-dihydrobenzofuran-6-yl)ethanone

1-(5-Propoxy-2,3-dihydrobenzofuran-6-yl)Etalon was obtained in the same manner as described in Referential example 12.

Referential example 20

Getting oxime 1-(5-propoxy-2,3-dihydrobenzofuran-6-yl)ethanone

The oxime of 1-(5-propoxy-2,3-dihydrobenzofuran-6-yl)ethanone was obtained in the same manner as described in Referential example 7./p>

Referential example 21

GettingN-(5-propoxy-2,3-dihydrobenzofuran-6-yl)acetamide

N-(5-Propoxy-2,3-dihydrobenzofuran-6-yl)acetamide was obtained in the same manner as described in Reference example 8.

Reference example 22

Getting 5 propoxy-2,3-dihydrobenzofuran-6-ylamine

5 Propoxy-2,3-dihydrobenzofuran-6-ylamine was obtained in the same manner as described in Referential example 3.

Reference example 23

Getting benzhydrylidene(5-methylbenzofuran-7-yl)amine

To a solution of 7-bromo-5-methylbenzofuran (of 9.71 g, 46 mmol) in toluene (100 ml) was added a solution of benzophenone (10,25 g, 56 mmol) in toluene (55 ml), Tris(dibenzylideneacetone)dipalladium (1.1 g, 1 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 2.1 g, 3,45 mmol) andt-butylate sodium (3.1 g, 31 mmol). Then, the resulting mixture was stirred for 4 hours under heating to reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and a saturated solution of ammonium chloride was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica�Le ( n-hexane:ethyl acetate=10:1). The solvent was removed under reduced pressure to obtain a yellow oily substance benzhydrylidene(5-methylbenzofuran-7-yl)amine (17,9 g, yield: 81%).

Reference example 24

Getting 5-methylbenzofuran-7-ylamine

Benzhydrylidene(5-methylbenzofuran-7-yl)amine (17,9 g of 0.57 mmol) was dissolved in THF (150 ml). To the solution was added 5N hydrochloric acid (50 ml) followed by stirring the mixture at room temperature for 2 hours. To the reaction mixture was added a 5N aqueous solution of sodium hydroxide (40 ml) followed by extraction with ethyl acetate. Next, the extract was washed with aqueous saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=50:1→>10:1). The purified product was concentrated to dryness under reduced pressure to obtain a dark brown oily substance 5-methylbenzofuran-7-ylamine (2.5 g, yield: 30%).

Reference example 25

Getting 5-methyl-2,3-dihydrobenzofuran-7-ylamine

5-Methylbenzofuran-7-ylamine (1.3 g, 8.8 mmol) and 10% palladium catalyst on a carbon carrier (500 mg) DOB�Lyali to ethanol (50 ml) followed by catalytic reduction at room temperature under normal pressure. The catalyst was removed by filtration through celite, and the filtrate obtained was condensible under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to give a white powder of 5-methyl-2,3-dihydrobenzofuran-7-ylamine (1.15 g, yield: 87%).

Example 1

Obtaining 2-(4-methoxyphenyl)-5-propoxy-4H-benzo[f]quinolin-1-one

To a benzene solution (50 ml) containing 3-propoxylation-2-ylamine (2.05 g, 10,18 mmol) and ethyl α-(hydroxymethylene)-4-methoxyphenylacetate (2,29 g, 10.3 mmol) was added 350 mg of Amberlyst 15 (Sigma-Aldrich). The resulting mixture was heated to reflux for 21 hours using a trap Dean stark. Then, the reaction mixture was cooled to room temperature, filtered to remove the resin, and then the filtrate was concentrated under reduced pressure. Diphenyl ether (2.2 ml) was added to the residue and the mixture is then heated for a heating mantle and stirred for 1.5 hours at boiling to reflux. The resulting reaction mixture was cooled to room temperature and then directly subjected to purification column chromatography on silica gel (dichloro methane:methanol=100:1→60:1). The purified product was concentrated under reduced pressure to recrystallization of the residue from cm�si ethyl acetate- n-hexaneobtaining a pale yellow powder of 2-(4-methoxyphenyl)-5-propoxy-4H-benzo[f]quinolin-1-one (1.55 g, yield: 42%).

Melting point: 172-174°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.08 (3H, t, J=7.3 Hz), 1.87 a and 1.95 (2H, m), with a score of 3.77 (3H, s), of 4.22 (2H, t, J=6,5 Hz), 6,97 (2H, d, J=8,8 Hz), 7,47-7,52 (3H, m), of 7.64 (2H, d, J=8,8 Hz), 7,83-a 7.87 (1H, m), 7,92 (1H, s), 10,24-10,28 (1H, m) 11,60 (1H, br.C).

Example 2

Obtaining 2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one

3-Iodo-5-propoxy-4H-benzo[f]quinoline-1-he (1,06 g, to 2.79 mmol) was suspended in dimethoxyethane (20 ml). Furan-3-boric acid (354 mg, 3,16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane (PdCl₂(DPPF)·CH₂Cl₂, 123 mg, 0.11 mmol) and 2N aqueous sodium carbonate solution (4.0 ml) were successively added to the suspension. The mixture was stirred at a temperature of from 90 to 100°C in a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture and the resulting mixture was subjected to extraction with dichloromethane. The thus obtained organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=80:1). The purified product was concentrated under reduced pressure, the residue was washed with ethyl acetate and then dried to obtain a pale brown powder of 2-four�n-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (430 mg, yield: 48%).

Melting point: 252-254°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.10 (3H, t, J=7,4 Hz), 1,87-of 1.98 (2H, m), of 4.27 (2H, t, J=6,5 Hz), 7,03 (1H, s) of 7.48 and 7.55 (2H, m), EUR 7.57 (1H, s), 7,72 (1H, s), 7,84-to 7.89 (1H, m), 8,22 (1H, s), to 8.71 (1H, s), 10,24-10,30 (1H, m), RS 11.80 (1H, br.C).

Example 3

Obtaining 2-furan-3-yl-4-methyl-5-propoxy-4H-benzo[f]quinolin-1-one

To a solution of 2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (300 mg, 0.94 mmol) in DMF (5 ml) was added sodium hydride (60% oil basis, 61 mg, 1.4 mmol) and the mixture is then stirred at room temperature for 5 minutes. The methyl iodide (181 mg, 1.27 mmol) was added and the resulting mixture was stirred at room temperature for 62 hours. Water and ethyl acetate were added to the reaction mixture, and the resulting mixture was subjected to separation. The thus obtained organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=90:1→80:1). The purified product was concentrated under reduced pressure to recrystallization of the residue from a mixture of ethyl acetate-n-hexaneobtaining a pale grey powder 2-furan-3-yl-4-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (130 mg, yield: 42%).

Melting point: 165-167°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.05 (3H, t, J=7,4 Hz), 1,83-1,2 (2H, m) of 4.12 (2H, t, J=6,4 Hz), 4,21 (3H, s), 7,07 (1H, s), 7,45-7,51 (2H, m), 7,54 (1H, s), of 7.70 (1H, s), 7,79-of 7.83 (1H, m), to 8.36 (1H, s) of 8.69 (1H, s), of 10.34-to 10.38 (1H, m).

Example 4

Getting 5 propoxy-2-thiophene-2-yl-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Pale brown powder (ethanol)

Melting point: 298-300°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.10 (3H, t, J=7,4 Hz), 1,87 is 2.01 (2H, m), of 4.27 (2H, t, J=6,5 Hz), 7,12 (1H, DD, J=3,9 Hz, 5.1 Hz), 7,47 (1H, d, J=4.7 Hz), 7,52 is 7.57 (2H, m), members, 7.59 (1H, s), with 7.66 (1H, d, J=3.7 Hz), 7.87 ft-7,91 (1H, m), and 8.50 (1H, s), 10,20-of 10.27 (1H, m), 11,95 (1H, br.C).

Example 5

Getting a 4-methyl-5-propoxy-2-thiophene-2-yl-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 3 using the appropriate starting material.

Pale yellow powder (ethyl acetate)

¹H-NMR (DMSO-d₆) δ M. D.: of 1.05 (3H, t, J=7,4 Hz), 1,84-of 1.92 (2H, m), of 4.12 (2H, t, J=6,4 Hz), 4,23 (3H, s), between 7.09-7.13 (1H, m), of 7.46 and 7.55 (4H, m), with 7.66 (1H, d, J=3.7 Hz), 7,80-7,84 (1H, m), 8,63 (1H, s), of 10.32-10,36 (1H, m).

Example 6

Getting 5 propoxy-2-thiophene-3-yl-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Pale brown�th powder

¹H-NMR (DMSO-d₆) δ M. D.: of 1.10 (3H, t, J=7.3 Hz), 1,90-of 1.98 (2H, m), of 4.27 (2H, t, J=6,5 Hz), 7,49-a 7.58 (4H, m), 7,63-with 7.66 (1H, m), the 7.85-8,00 (1H, m), USD 8.24 (1H, s) of 8.34-to 8.36 (1H, m), 10,23-10,29 (1H, m), 11,71 (1H, br.C).

Example 7

Getting a 4-methyl-5-propoxy-2-thiophene-3-yl-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 3 using the appropriate starting material.

White powder

¹H-NMR (DMSO-d₆) δ M. D.: of 1.05 (3H, t, J=7,4 Hz), 1,84-of 1.92 (2H, m), of 4.12 (2H, t, J=6,4 Hz), 4,19 (3H, s), 7,44 is 7.57 (4H, m), of 7.70 (1H, d, J=5.1 Hz), 7,80-7,84 (1H, m), to 8.38-8,40 (2H, br.C) 10,30-of 10.34 (1H, m).

Example 8

Obtaining 2-(4-methoxyphenyl)-3-methyl-5-propoxy-4H-benzo[f]quinolin-1-one

To a benzene solution (38 ml) containing 3-propoxylation-2-ylamine (600 mg, 2,98 mmol) and ethyl α-acetyl-4-methoxyphenylacetate (1.41 g, 5,96 mmol) was added 85 mg of Amberlyst 15 (Sigma-Aldrich). The resulting mixture was heated to reflux for 20 hours using a trap Dean stark. The reaction mixture was cooled to room temperature, filtered to remove the resin and then the filtrate was concentrated under reduced pressure. Diphenyl ether (2.8 ml) was added to the residue, and the mixture is then heated for a heating mantle and stirred for 70 minutes at boiling to reflux. The obtained reaction mixture was cooled�gave to room temperature, and then directly subjected to purification column chromatography on silica gel (dichloro methane:methanol=80:1→70:1). The purified product was concentrated under reduced pressure to obtain an oily substance (800 mg, yield: 72%). Ethyl acetate andn-hexanewas added to the thus obtained oily substance and then recrystallized from ethyl acetate to obtain a pale yellow powder of 2-(4-methoxyphenyl)-3-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (290 mg).

Melting point: 204-206°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.05 (3H, t, J=7,4 Hz), 1,90-of 1.98 (2H, m), was 2.31 (3H, s), with a score of 3.77 (3H, s) to 4.27 (2H, t, J=6.8 Hz), to 6.95 (2H, d, J=8.6 Hz), up 7.17 (2H, d, J=8.6 Hz), 7,39-7,50 (2H, m), 7,56 (1H, s), 7,84 (1H, DD, J=2.2 Hz, 6.5 Hz), of 10.09-10,13 (1H, m), 10,79 (1H, br.C).

Example 9

Obtain 3-methyl-5-propoxy-2-thiophene-3-yl-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 8 using the appropriate starting material.

Light gray powder (ethyl acetate)

Melting point: 186-188°C

¹H-NMR (DMSO-d₆) δ M. D.: the 1.04 (3H, t, J=7.3 Hz), 1,88 of 1.97 (2H, m), is 2.40 (3H, s), to 4.26 (2H, t, J=6,7 Hz), of 7.14 (1H, d, J=4,9 Hz), 7,41-7,54 (5H, m), of 7.83 (1H, d, J=6.6 Hz), 10,07-10,11 (1H, m), 10,84 (1H, br.C).

Example 10

Getting 5 propoxy-8-thiophene-2-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above with�the unity was obtained in the same way, described in example 1, using appropriate starting materials.

Yellow powder

¹H-NMR (DMSO-d₆) δ M. D.: the 1.04 (3H, t, J=7,4 Hz), 1,77-of 1.88 (2H, m), 1,97-of 2.08 (2H, m) to 2.86 (2H, t, J=7.5 Hz), 3,45 (2H, t, J=7.0 Hz), 4,10 (2H, t, J=6,5 Hz), 7,05 (1H, t, J=3.8 Hz), 7,13 (1H, s) of 7.36 (1H, d, J=5.1 Hz), 7,53 (1H, d, J=3,6 Hz), 8,31 (1H, s), is 11.39 (1H, br.C).

Example 11

Getting 6-methyl-5-propoxy-8-thiophene-2-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 3 using the appropriate starting materials.

Powder orange

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7,4 Hz), 1,77 is 1.85 (2H, m), 1,97-of 2.03 (2H, m), of 2.84 (2H, t, J=7,6 Hz), 3,49 (2H, t, J=7,1 Hz), of 4.00 (2H, t, J=6,4 Hz), 4.13 in (3H, s), 7,05 (1H, t, J=3.8 Hz), 7,18 (1H, s), of 7.35 (1H, d, J=4.7 Hz), 7,54 (1H, d, J=3.3 Hz), 8.48 to (1H, s).

Example 12

Getting 5 propoxy-8-thiophene-3-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 1, using appropriate starting materials.

Light brown powder

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 (3H, t, J=7,4 Hz), and 1.76-to 1.87 (2H, m), 1,95-of 2.07 (2H, m), 2,85 (2H, t, J=7.5 Hz), 3,30-3,55 (2H, m), of 4.09 (2H, t, J=6,5 Hz), 7,11 (1H, s) of 7.48 was 7.56 (2H, m), 8,11 (1H, d, J=6.2 Hz), 8,21-at 8.23 (1H, m), 11,18 (1H, d, J=5.8 Hz).

Example 13

Get�of 6-methyl-5-propoxy-8-thiophene-3-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 3 using the appropriate starting materials.

Light yellow powder

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7,4 Hz), 1,76 is 1.85 (2H, m), 1,95-of 2.01 (2H, m), USD 2.83 (2H, t, J=7,6 Hz), 3,49 (2H, t, J=7,4 Hz), of 3.99 (2H, t, J=6,5 Hz), of 4.09 (3H, s), 7,15 (1H, s) of 7.48-7,52 (1H, m), 7,63-7,65 (1H, m), 8,26-8,28 (2H, m).

Example 14

8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 1, using appropriate starting materials.

Light brown powder (ethyl acetate)

Melting point: 206-208°C

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7,4 Hz), 1,78-to 1.86 (2H, m), 1,96-2,02 (2H, m), USD 2.83 (2H, t, J=7.5 Hz), 3,40 (2H, t, J=7.3 Hz), 3,74 (3H, s) 4,07 (2H, t, J=6,4 Hz) 6,91 (2H, d, J=8,8 Hz), to 7.09 (1H, s), to 7.55 (2H, d, J=8,8 Hz), 7,78 (1H, d, J=5,9 Hz), 11,06 (1H, d, J=5.8 Hz).

Example 15

8-(4-methoxyphenyl)-7-methyl-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 8 using the appropriate starting material.

Light yellow powder (ethyl acetate)

Melting point: 223-225°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7,4 Hz), 1,79-to 1.87 (2H, m), 1.93 and is 1.99 (2H, m), or 2.21 (3H, s), 2,82 2H, t, J=7,4 Hz) and 3.31 (2H, t, J=7,1 Hz), of 3.75 (3H, s), 4,10 (2H, t, J=6,7 Hz), 6,90 (2H, d, J=8,7 Hz), to 7.08 (2H, d, J=8,5 Hz), 7,10 (1H, s), 10,30 (1H, br.C).

Example 16

Obtain 7-methyl-5-propoxy-8-thiophene-3-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 8, using the appropriate starting materials.

Light brown powder (ethyl acetate)

Melting point: 260-262°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), 1,79-to 1.87 (2H, m), 1,90-of 1.99 (2H, m), was 2.31 (3H, s), at 2.82 (2H, t, J=7.5 Hz), 3,32 (2H, t, J=7.3 Hz), of 4.09 (2H, t, J=6,7 Hz), 7,04-7,10 (2H, m), 7,31-7,32 (1H, m), 7,44-7,47 (1H, m), of 10.35 (1H, br.C).

Example 17

Getting 6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

To a solution of 8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-she (1.26 g, of 3.60 mmol) in DMF (6 ml) was added sodium hydride (60% oil basis, 189 mg of 4.33 mmol). The mixture was stirred at room temperature for 10 minutes. To the resulting mixture was added 1-bromo-3-chloropropane (1.70 g, 10.8 mmol) followed by stirring at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture and the obtained reaction mixture was subjected to separation. The thus obtained organic layer industrial�Ali aqueous saturated solution of sodium chloride twice. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=20:1→12:1). The purified product was concentrated under reduced pressure to obtain a yellow oily substance 6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-she (365 mg, yield: 92%).

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, m), 1,90 is 2.24 (6H, m) or 2.91 (2H, t, J=7,6 Hz) to 3.45 (2H, t, J=5.7 Hz), to 3.67 (2H, t, J=7.5 Hz), 3,83 (3H, s), of 4.04 (2H, t, J=6,7 Hz), 4,71 (2H, t, J=6,4 Hz), at 6.92-to 7.04 (3H, m), a 7.58-7.62 mm (3H, m).

Example 18

8-(4-methoxyphenyl)-6-(3-morpholine-4-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

A mixture containing 6-(3-chloropropyl)-8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-he (700 mg, of 1.64 mmol), morpholine (165 mg, of 1.90 mmol), potassium carbonate (341 mg, 2,47 mmol), sodium iodide (295 mg, 1.97 mmol) and dimethylformamide (3 ml), stirred at 60°C for 7 hours. Water and ethyl acetate were added to the reaction mixture followed by separation of the mixture. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride twice, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:IU�anal=70:1→50:1). The purified product was concentrated under reduced pressure to recrystallization of the residue from a mixture of ethyl acetate-n-hexaneto give a white powder 8-(4-methoxyphenyl)-6-(3-morpholine-4-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-she (295 mg, yield: 38%).

Melting point: 135-137°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,75 is 1.85 (4H, m) of 1.96 (2H, t, J=7.5 Hz), 2,04-of 2.15 (6H, m), USD 2.83 (2H, t, J=7.5 Hz), 3,38-to 3.41 (6H, m), 3,74 (3H, s), 4,02 (2H, t, J=6,5 Hz), 4,55 (2H, t, J=6.2 Hz), 6,90 (2H, d, J=8,7 Hz), 7,18 (1H, s), and 7.60 (2H, d, J=8,7 Hz), of 7.93 (1H, s).

Example 19

8-(4-methoxyphenyl)-6-(3-piperidine-1-ylpropyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting material.

Light yellow powder (ethyl acetate-n-hexane)

Melting point: 99-101°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,20-1,50 (6H, m), 1,74-to 1.86 (4H, m) of 1.96 (2H, t, J=7,4 Hz), 2,02-of 2.20 (6H, m), USD 2.83 (2H, t, J=7.3 Hz), 3,30 is 3.40 (2H, m), 3,74 (3H, s), 4,02 (2H, t, J=6,4 Hz), a 4.53 (2H, t, J=5.8 Hz), 6,90 (2H, d, J=8,7 Hz), 7,18 (1H, s), and 7.60 (2H, d, J=8,7 Hz), 7,91 (1H, s).

Example 20

Getting 6-(3-chloropropyl)-5-propoxy-8-thiophene-3-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same way that the op�San in example 17, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, m), 1,88, to 2.25 (6H, m) or 2.91 (2H, t, J=7,6 Hz) to 3.45 (2H, t, J=5.8 Hz), of 3.69 (2H, t, J=7.5 Hz), 4,01-of 4.04 (2H, m), 4.74 in (2H, t, J=6,4 Hz), 7,05 (1H, s), 7,32-of 7.35 (1H, m), 7,43-7,47 (1H, m), of 7.83 (1H, s), 8,08-8,10 (1H, m).

Example 21

Getting 6-(3-morpholine-4-ylpropyl)-5-propoxy-8-thiophene-3-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Light yellow powder (ethyl acetate)

Melting point: 163-165°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,76-to 1.86 (4H, m), 1.98 m (2H, t, J=7.5 Hz), 2,03-of 2.20 (6H, m), of 2.84 (2H, t, J=7.5 Hz), 3,41-3,52 (6H, m), 4,02 (2H, t, J=6,5 Hz), 4,60 (2H, t, J=6.3 Hz), 7,18 (1H, s), 7,49-7,52 (1H, m), 7,62-of 7.64 (1H, m), the 8.25-8,27 (1H, m), is 8.30 (1H, s).

Example 22

Getting 6-(3-[1,4]oxazepan-4-ylpropyl)-5-propoxy-8-thiophene-3-yl-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Light brown powder (ethyl acetate)

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,60-of 1.64 (2H, m), 1,74-to 1.86 (4H, m), 1.98 m (2H, t, J=7,4 Hz) to 2.19 (2H, t, J=6.3 Hz), is 2.40 to 2.45 (4H, m), of 2.84 (2H, t, J=7,4 Hz), 3,51 is 3.59 (6H, m), is 4.03 (2H, t, J=6,4 Hz), 4,60 (2H, t, J=6.0 Hz), of 7.19 (1H, s) of 7.48-7,51 (1H, m), 7,61 1H, d, J=4,9 Hz), at 8.23 (1H, d, J=1,8 Hz), 8,27 (1H, s).

Example 23

Obtaining di-tert-butyl 8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-elmerpost

To a solution of 8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-azacyclopenta[a]naphthalene-9-she (400 mg, 1.15 mmol) and sodium iodide (343 mg, 2,29 mmol) in DMF (10 ml) was added sodium hydride (60% oil basis, 74,9 mg, 1,72 mmol) and the mixture is then stirred for 10 minutes at room temperature. To the resulting mixture was added a solution of di-tert-butylchloroformate (888 mg, of 3.43 mmol) in DMF (20 ml) and the mixture is then stirred at 40°C for 4 hours. The reaction mixture was cooled on ice, was added ice water, and then the reaction mixture was subjected to extraction with ethyl acetate. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by liquid chromatography at medium pressure (NH silica gel,n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated under reduced pressure to give a white powder di-tert-butyl 8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-elmerpost (263 mg, yield: 40%).

¹H-NMR (CDCl₃) δ MD: 108-1 in accordance with,14 (3H, t, J=7,4 Hz), and 1.35 (18H, s), 1,88 is 2.16 (4H, m), 2,88 and 2.95 (2H, t, J=7,7 Hz), 3,60-a 3.66 (2H, t, J=7.5 Hz), 3,82 (3H, s), 4,05-4,10 (2H, t, J=6,7 Hz), between 6.30-6.35 mm (2H, d, J=12.4 Hz), 6,90-6,97 (2H, d, J=8,8 Hz), to 7.09 (1H, s), 7.57 the-7,63 (2H, d, J=8,8 Hz), 7,76 (1H, s).

Example 24

Obtaining [8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-ylmethyl]monophosphate

Dichlormethane solution (4 ml) di-tert-butyl 8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-Eletropaulo ester (263 mg, 0.46 mmol) was cooled on ice, trifluoroacetic acid (1.2 ml) and dichloro methane (4 ml) was added to the solution in a nitrogen atmosphere and the resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was subjected to vacuum drying to obtain a light yellow powder [8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-ylmethyl]monophosphate (147 mg, yield: 56%).

¹H-NMR (DMSO-d₆) δ MD: 1,01-of 1.04 (3H, t, J=7,4 Hz), 1,78-to 1.86 (2H, m), 1,96-2,02 (2H, m), USD 2.83 (2H, t, J=7.5 Hz), 3,40 (2H, t, J=7.3 Hz), 3,74 (3H, s) 4,07 (2H, t, J=6,4 Hz), 6,25-between 6.30 (2H, d, J=10,42 Hz), at 6.92-to 6.95 (2H, m), 7,13 (1H, s), members, 7.59-7,63 (2H, d, J=8,8 Hz), 7,76-7,79 (1H, d, J=5,9 Hz).

Example 25

Obtaining [8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-ylmethyl]monophosphate disodium salt

[8-(4-Methoxyphenyl)-9-oxo-5-Pro�hydroxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-ylmethyl]monophosphate (147 mg, 0,32 mmol) was suspended in isopropyl alcohol (20 ml) and then to the suspension was added 1N aqueous sodium hydroxide solution (of 0.64 ml, 0.64 mmol) in a nitrogen atmosphere at 0°C. the resulting mixture was stirred for 1 hour at 0°C. the Resulting insoluble substance was separated and washed with acetone and dried to give a white powder [8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-azacyclopenta[a]naphthalene-6-ylmethyl]monophosphate disodium salt (42 mg, yield: 26%).

¹H-NMR (D₂O) δ MD: 0,91-of 0.98 (3H, t, J=7,8 Hz), 1,74-of 1.83 (2H, m), 1,92-of 1.98 (2H, m), 2,75-of 2.81 (2H, t, J=7,6 Hz), 3,30-is 3.36 (2H, t, J=7,2 Hz), of 3.75 (3H, s), 3,90-3,95 (2H, t, J=6,7 Hz), 5,94-5,99 (2H, d, J=9.5 Hz), 6,89-6,93 (2H, d, J=8,8 Hz), 7,15 (1H, s), 7.87 ft-is 7.94 (2H, d, J=8,8 Hz), 8,58 (1H, s).

Example 26

Obtaining 2-(4-methoxyphenyl)-5-propoxy-7,8,9,10-tetrahydro-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Light yellow powder (ethyl acetate)

Melting point: 186-187°C

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7,4 Hz), 1,60-1,70 (4H, m), 1,78-to 1.86 (2H, m), 2,70 is 2.80 (2H, m), 3.30 x is 3.40 (2H, m), 3,74 (3H, s) to 4.05 (2H, t, J=6,4 Hz), of 6.85 (1H, s), 6,90 (2H, d, J=8,7 Hz), of 7.50 (2H, d, J=8,7 Hz), 7,72 (1H, d, J=5.1 Hz), of 10.95 (1H, d, J=4.7 Hz).

Example 27

Getting 5 propoxy-2-thiophene-3-yl-7,8,9,10-tetrahydro-4H-benzo[f]quinolin-1-one

UK�mentioned above compound was obtained in the same way, described in example 1 using the appropriate starting material.

Light korichnevyj powder (ethyl acetate)

Melting point: 213 to 215°C

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7,4 Hz), 1,60-1,70 (4H, m), 1,75-to 1.86 (2H, m), 2,70 is 2.80 (2H, m), 3.30 x is 3.40 (2H, m) to 4.05 (2H, t, J=6,4 Hz), of 6.85 (1H, s) of 7.46-7,52 (2H, m), 8,06 (1H, s), 8,14-8,15 (1H, m), 11,10 (1H, br.C).

Example 28

Obtaining 2-(4-methoxyphenyl)-3-methyl-5-propoxy-7,8,9,10-tetrahydro-4H-benzo[f]quinolin-1-one

The above compound was obtained in the same manner as described in example 8 using the appropriate starting material.

Light yellow powder (ethyl acetate)

Melting point: 199-201°C

¹H-NMR (DMSO-d₆) ∆ MD is 0.98 (3H, t, J=7.3 Hz), 1,60-1,70 (4H, m), 1,78-to 1.87 (2H, m), of 2.17 (3H, s), 2,70 is 2.80 (2H, m), 3,20 to 3.30 (2H, m), 3,74 (3H, s) 4,07 (2H, t, J=6,7 Hz), at 6.84 (1H, s), to 6.88 (2H, d, J=8,7 Hz), 7,06 (2H, d, J=8,5 Hz), 10,17 (1H, br.C).

Example 29

Obtain 3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-ox-1-azaphenanthrene-4-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Melting point: 222-223°C

¹H-NMR (DMSO-d₆) δ M. D.: from 1.00 to 1.06 (3H, t, J=7.5 Hz), 1,74 and 1.95 (4H, m), 2,72-of 2.75 (2H, t, J=6,5 Hz), of 3.75 (3H, s), 4,00-4,10 (4H, m), 6,87-6,93 (3H, m), of 7.46-7,52 (2H, d, J=9,0 Hz), 7,65 (1H, s), 10,70-10,90 (1H, br.C).

Example 30

Getting 1-{3-[4-(2-methoxyethyl)piperazine-1-yl]propyl}-3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-ox-1-azaphenanthrene-4-she dihydrochloride

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Melting point: 145-147°C

¹H-NMR (DMSO-d₆) δ MD: 1,01 was 1.06 (3H, t, J=7,4 Hz), 1.85 to 2,02 (4H, m), 2,12-of 2.33 (2H, m), 2,84-2,89 (2H, t, J=6.3 Hz), 3,02-3,20 (2H, m), or 3.28-3,80 (15H, m), 4.08 interest to 4.13 (2H, t, J=6.8 Hz), 4,28-4,31 (2H, t, J=4,6 Hz), 4,75-of 4.95 (2H, m), 7.00 and of 7.03 (2H, d, J=8.9 Hz), 7,30 (1H, s), 7,63-with 7.66 (2H, d, J=8.9 Hz), 8.48 to (1H, s).

Example 31

Obtain ethyl [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]acetate

The sodium hydride (60% oil basis, 80 mg, 2.0 mmol) was added to a solution of 3-(4-methoxyphenyl)-10-propoxy-1,6,7,8-tetrahydro-5-ox-1-azaphenanthrene-4-it (600 mg, of 1.64 mmol) in DMF (10 ml), then the resulting mixture was stirred at room temperature for 5 minutes. Ethylbromoacetate (330 mg, 2.0 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture followed by separation of the mixture. The thus obtained organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified liquid� chromatography at medium pressure (NH silica gel, n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated under reduced pressure to give a colorless oily substance ethyl [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]acetate (700 mg, yield: 95%).

¹H-NMR (CDCl₃) δ MD: 1,00-1,10 (3H, t, J=7.5 Hz), a 1.25 and 1.28 (3H, t, J=6,0), 1,75-of 1.90 (2H, m), 2,02 was 2.43 (2H, m), 2,80-2,90 (2H, m), 3,85 (3H, s), 3,86-3,88 (2H, m), 4,10 to 4.13 (4H, m) to 5.10 (2H, s), the 6.75 (1H, s), of 6.85-6,90 (2H, d, J=9,0), from 7.24 (1H, s), and 7.60-the 7.75 (2H, d, J=9,0).

Example 32

Obtain [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]acetic acid

5N Aqueous solution of sodium hydroxide (10 ml) was added to an ethanol solution (30 ml) of ethyl [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]acetate (700 mg, at 1.55 mmol) and heated for 2 hours to reflux. The mixture was cooled to room temperature and concentrated under reduced pressure. Upon cooling of the concentrate with ice, water and concentrated hydrochloric acid was added to the residue to acidification. Further, formed nerastvorim substance was separated and dried to obtain yellow powder [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]acetic acid (580 mg, yield: 88%).

¹H-NMR (DMSO-d₆) δ MD: 0,94-1,00 (3H, t, J=7.5 Hz), 1,74-of 1.82 (2H, m), 1,94-1,98 (2, m), 2,78 is 2.83 (2H, t, J=6.2 Hz), with a score of 3.77 (3H, s), 3,92-of 3.98 (2H, t, J=6,7 Hz), 4,21 of-4.25 (2H, t, J=4,8 Hz), USD 5.35 (2H, s), 6,96-7,00 (2H, d, J=8,8 Hz), made 7.16 interest (1H, s), 7,56-members, 7.59 (2H, d, J=8,8 Hz), to 8.29 (1H, s).

Example 33

Obtaining 2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]-N(2-morpholine-4-retil)acetamide

4-(2-Aminoethyl)morpholine (217 mg, 1.7 mmol) was added to a solution of [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]acetic acid (580 mg, of 1.39 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea of hexaflurophosphate (HATU, 790 mg, 2.1 mmol) and triethylamine (5 ml) in DMF (10 ml). The mixture was stirred over night at room temperature and then concentrated under reduced pressure. Water and ethyl acetate were added to the residue, followed by separation of the mixture. The thus obtained organic layer was washed with water and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=10:1). The purified product was concentrated under reduced pressure and the residue recrystallized from ethyl acetate to obtain a light brown powder of 2-[3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-yl]-N(2-morpholine-4-retil)acetamide (115 mg, yield: 16%).

Melting point: 201-203°C

¹H-NMR (DMSO-d₆) δ MD: 0,94-1,00 (3H, t, J7,5 Hz), 1,71-a 1.77 (2H, m), 1.91 a-to 1.93 (2H, m), 2,29-2,34 (4H, m), 2,72-of 2.75 (2H, t, J=6.2 Hz), 3,15-is 3.19 (2H, m), to 3.25 to 3.30 (2H, m), 3,33-was 3.54 (4H, m) to 3.76 (3H, s), 3,85 to 3.90 (2H, t, J=6,7 Hz), 4,07-4,11 (2H, m), of 5.06 (2H, s), 6,90-6,93 (3H, m), 7,54-a 7.58 (2H, m), 7,72 (1H, s), 7,80-of 7.82 (1H, m).

Example 34

Obtaining di-tert-butyl 3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 1,06-of 1.12 (3H, t, J=7,4 Hz) to 1.36 (18H, s), 1,88-of 1.96 (2H, m), 2,01-and 2.10 (2H, m), 3,82 (3H, s), 3,98 is 4.03 (2H, t, J=6,7 Hz), 4,28-4,32 (2H, t, J=5.1 Hz), 6,25 of 6.31 (2H, d, J=12.2 Hz), of 6.85-6,93 (3H, m), and 7.60-with 7.66 (3H, m).

Example 35

Obtain [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 0,99-of 1.04 (3H, t, J=7,4 Hz), 1,74 and 1.95 (4H, m), 2,72-of 2.75 (2H, t, J=6,5 Hz), of 3.75 (3H, s), 4,00-4,10 (4H, m), 6,20-for 6.24 (2H, d, J=10.3 Hz), at 6.92-7,10 (3H, m), 7,53 is 7.57 (2H, m), of 7.86 (1H, s).

Example 36

Obtain [3-(4-methoxyphenyl)-4-oxo-10-propoxy-7,8-dihydro-4H,6H-5-ox-1-azaphenanthrene-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same way, which� described in example 25, using the appropriate starting material.

¹H-NMR (D₂O) δ MD: 0,91-0,97 (3H, t, J=7,4 Hz), 1,72-to 1.86 (2H, m), 1,90-to 1.94 (2H, m), 2,70-of 2.75 (2H, t, J=6,4 Hz), 3,74 (3H, s), of 3.91-at 3.97 (3H, t, J=6.8 Hz), 4,11-4,15 (3H, t, J=4,8 Hz), 5,94 is 5.98 (2H, d, J=8,8 Hz), 6,89-6,93 (2H, d, J=8,8 Hz), 7,03 (1H, s), value of 7, 37-7,41 (2H, d, J=8,8 Hz), compared to 7.97 (1H, s).

Example 37

Obtain 9-(4-methoxyphenyl)-6-propoxy-2,3-dihydro-1H,7H-pyrano[3,2-f]quinolin-10-she

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Melting point: 171-173°C

¹H-NMR (CDCl₃) δ M. D.: of 1.03 and 1.10 (3H, t, J=7.5 Hz), 1,84-2,02 (4H, m), 3,52-3,58 (2H, t, J=6,5 Hz), of 3.81 (3H, s), 4,02 is 4.07 (2H, t, J=6.6 Hz), 4,16 is 4.19 (2H, t, J=5.1 Hz), to 6.58 (1H, s) 6,91 is 6.95 (2H, d, J=9,0 Hz), 7,51 and 7.55 (2H, d, J=9,0 Hz), 7,61-of 7.64 (1H, d, J=6.2 Hz), 8,86-the 8.88 (1H, d, J=5,45 Hz).

Example 38

Obtain ethyl [9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-yl]acetate

The above compound was obtained in the same manner as described in example 31, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 1,01-of 1.07 (3H, t, J=7.5 Hz), 1,23-of 1.29 (3H, t, J=7.5 Hz), 1,79 is 1.85 (2H, m), 1,95-of 1.98 (2H, m), 3,49-was 3.54 (2H, t, J=6,5 Hz), 3,83 (3H, s), of 3.91-to 3.96 (2H, t, 6.8 Hz), 4,11-of 4.27 (6H, m), to 5.05 (2H, s), to 6.62 (1H, s), at 6.92-to 6.95 (2H, d, J=8,8 Hz), 7,29 (1H, s), 7,54 is 7.57 (2H, d, J-8.8 Hz).

Example 39

Obtaining [9-(4-methoxide�yl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-yl]acetic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 0,94-1,00 (3H, t, J=7.5 Hz), 1,72-to 1.86 (4H, m), 3,11-of 3.33 (2H, m) to 3.76 (3H, s), 3,90-3,95 (2H, t, J=6,5 Hz), 4.08 interest-4,11 (2H, m), of 5.17 (2H, s), of 6.70 (1H, s), 6,90 is 6.95 (2H, d, J=8,8 Hz), 7,53 and 7.60 (2H, d, J=8,8 Hz), 8,54 (1H, s), its 12.6 to 12.9 (1H, br.C).

Example 40

Obtaining 2-[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-yl]-N(2-morpholine-4-retil)acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting material.

Melting point: 206-208°C

¹H-NMR (DMSO-d₆) δ MD: 0,93-0,98 (3H, t, J=7.3 Hz), 1,66-of 1.90 (4H, m) 3,00-3,20 (4H, m), 3,50 ranging from 3.62 (2H, m) to 3.76 (3H, s), 3,90-to 3.96 (4H, m), 4,04 at 4.12 (2H, m), 5,07 (2H, s), of 6.70 (1H, s) 6,91 is 6.95 (2H, d, J=8,8 Hz), 7,56-members, 7.59 (2H, d, J=8,8 Hz), of 7.77 (1H, s), 8,10 to 8.25 (1H, m).

Example 41

Obtaining 2-[9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-yl]-N(3-morpholine-4-ylpropyl)acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

Melting point: 185-187°C

¹H-NMR (DMSO-d₆) δ MD: 0,94-1,00 (3H, t, J=7,4 Hz), 1,66-of 1.96 (6H, m), 2,90-of 3.21 (6H, m), 3,25-of 3.43 (4H, m), 3,56-a 3.66 (2H, t, J=11.9 Hz), with a score of 3.77 (3H, s), 85-4,04 (4H, m), 4,05-4,18 (2H, m), 5,09 (2H, s) 6,71 (1H, s), at 6.92-of 6.96 (2H, d, J=8,8 Hz), 7.57 the-7,61 (2H, d, J=8,8 Hz), 7,79 (1H, s), 8,09-to 8.14 (1H, t, J=5,5 Hz).

Example 42

Getting 7-{3-[4-(2-methoxyethyl)piperazine-1-yl]propyl}-9-(4-methoxyphenyl)-6-propoxy-2,3-dihydro-1H,7H-pyrano[3,2-f]quinolin-10-she dihydrochloride

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Melting point: 180-182°C

¹H-NMR (DMSO-d₆) δ MD: 1,00-1,05 (3H, t, J=7,4 Hz), 1,83-of 1.91 (4H, m) of 2.00-2.20 (2H, m) 3,00-4,50 (20H, m), 4,50-4,70 (2H, m), was 6.77 (1H, s), 6,90 is 6.95 (2H, d, J=8,8 Hz) and 7.60-7,65 (2H, d, J=8,8 Hz), is 7.94 (1H, s).

Example 43

Obtaining di-tert-butyl 9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, t, J=7,4 Hz), and 1.35 (18H,s), 1,89-of 1.98 (4H, m), 3.46 in-3,51 (2H, t, J=6,5 Hz), 3,82 (3H, s), 4,01-4,06 (2H, t, J=6.6 Hz), 4,16-of 4.21 (2H, t, J=5.0 Hz), 6,25-between 6.30 (2H, d, J=12.3 Hz), of 6.70 (1H, s) 6,91 is 6.95 (2H, d, J=8,8 Hz), 7,55-members, 7.59 (2H, d, J=8,8 Hz), 7,68 (1H, s).

Example 44

Obtaining [9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-ylmethyl]monophosphate

The above compound was obtained in the same way, to�which is described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 and 1.10 (3H, t, J=7.5 Hz), 1,84-2,02 (4H, m), 3,52-3,58 (2H, t, J=6,5 Hz), of 3.81 (3H, s), 4,02 is 4.07 (2H, t, J=6.6 Hz), 4,16 is 4.19 (2H, t, J=5.1 Hz), 6,15-6,19 (2H, d, J=10.8 Hz), 6,80 (1H, s), 6,94-of 6.96 (2H, d, J=9,0 Hz), 7,52 was 7.56 (2H, d, J=9,0 Hz), 7,69-7,72 (1H, d, J=6.2 Hz).

Example 45

Obtaining [9-(4-methoxyphenyl)-10-oxo-6-propoxy-1,2,3,10-tetrahydropyrido[3,2-f]quinolin-7-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

¹H-NMR (D₂O) δ M. D.: of 0.94 to 0.99 (2H, t, J=7,4 Hz), 1,81-of 1.88 (2H, m), 3,21 is 3.23 (2H, m) to 3.78 (3H, s), 3,99-to 4.05 (2H, m), 4,13-is 4.15 (2H, m), 6,04-6,14 (2H, d, J=8,8 Hz), 6,78 (1H, s), 6,96 of 6.99 (2H, d, J=8,8 Hz), 7,39 of 7.45 (2H, m), 8,08 (1H, s).

Example 46

8-(4-methoxyphenyl)-5-propoxy-3,6-dihydro-2H-Flo[2,3-f]quinoline-9-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Light brown powder (ethyl acetate)

Melting point: 218-220°C

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7,4 Hz), 1,75-of 1.83 (2H, m), 3,13 (2H, t, J=8,8 Hz), 3,74 (3H, s), 4,02 (2H, t, J=6,5 Hz), of 4.54 (2H, t, J=8.9 Hz), 6,91 (2H, d, J=8,7 Hz), 7,15 (1H, s), 7,51 (2H, d, J=8,7 Hz), the 7.75 (1H, d, J=5,9 Hz), 10,99 (1H, d, J=5,9 Hz).

Example 47

Receive a 5 Ministers�si-8-thiophene-3-yl-3,6-dihydro-2H-Flo[2,3-f]quinoline-9-it

The above compound was obtained in the same manner as described in example 1, using appropriate starting materials.

Light brown powder (ethanol)

Melting point: 275-277°C

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7,4 Hz), 1,72-of 1.84 (2H, m), 3,14 (2H, t, J=8.9 Hz), 4,02 (2H, t, J=6,5 Hz), 4,55 (2H, t, J=8.9 Hz), 7,15 (1H, s), 7,47-7,54 (2H, m), 8,08 (1H, d, J=6.3 Hz), 8,16-8,17 (1H, m), 11,10 (1H, d, J=6.1 Hz).

Example 48

8-(4-methoxyphenyl)-7-methyl-5-propoxy-3,6-dihydro-2H-Flo[2,3-f]quinoline-9-it

The above compound was obtained in the same manner as described in example 8 using the appropriate starting material.

Light brown powder (ethyl acetate-n-hexane)

Melting point: 216-218°C

¹H-NMR (DMSO-d₆) δ MD: or = 0.97 (3H, t, J=7,4 Hz), and 1.76-of 1.84 (2H, m) of 2.18 (3H, s), 3,11 (2H, t, J=8.9 Hz), 3,74 (3H, s), of 4.04 (2H, t, J=6.8 Hz), 4,50 (2H, t, J=8.9 Hz), 6,90 (2H, d, J=8,7 Hz), 7,06 (2H, d, J=8.6 Hz), 7,15 (1H, s), 10,19 (1H, br.C).

Example 49

Obtain ethyl [8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-Flo[2,3-f]quinolin-6-yl]acetate

The above compound was obtained in the same manner as described in example 31, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: the 1.04 (3H, t, J=7.3 Hz), 1.26 in (3H, t, J=7,2 Hz), 1,78-to 1.86 (2H, m), is 3.19 (2H, t, J=8,8 Hz), 3,82 (3H, s), of 3.91 (2H, t, J=6.9 Hz), 4,22 (2H, sq, J=7,2 Hz), and 4.5 (2H, t, J=8.9 Hz), to 5.05 (2H, s), 6,90 (2H, d, J=8,8 Hz), 7,01 (1H, s), 7,31 (1H, s), 7,63 (2H, d, J=8,8 Hz).

Example 50

Obtaining [8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-Flo[2,3-f]quinolin-6-yl]acetic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: the 1.04 (3H, t, J=7.3 Hz), 1.26 in (3H, t, J=7,2 Hz), 1,78-to 1.86 (2H, m), is 3.19 (2H, t, J=8,8 Hz), 3,82 (3H, s), of 3.91 (2H, t, J=6.9 Hz), 4,22 (2H, sq, J=7,2 Hz), to 4.75 (2H, t, J=8.9 Hz), to 5.05 (2H, s), 6,90 (2H, d, J=8,8 Hz), 7,01 (1H, s), 7,31 (1H, s), 7,63 (2H, d, J=8,8 Hz).

Example 51

Obtaining 2-[8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-Flo[2,3-f]quinolin-6-yl]-N(2-morpholine-4-retil)acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: from 0.92 (3H, t, J=7.3 Hz), 1,67-of 1.76 (2H, m), 2,28-of 2.33 (6H, m), 3,08 is 3.17 (4H, m), 3,47-3,51 (4H, m), of 3.75 (3H, s), 3,86 (2H, t, J=6,7 Hz), a 4.53 (2H, t, J=8.9 Hz), of 5.06 (2H, s), 6,90 (2H, d, J=8,8 Hz) of 7.19 (1H, s), 7,54 (2H, d, J=8,8 Hz), 7,74 (1H, s), of 7.83 (1H, t, J=5.4 Hz).

Example 52

8-(4-methoxyphenyl)-6-(2-morpholine-4-retil)-5-propoxy-3,6-dihydro-2H-Flo[2,3-f]quinoline-9-it

The above compound was obtained in the same manner as described in example 18, using the appropriate factory�e materials.

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), 1,74-of 1.82 (2H, m), 2,30-of 2.33 (4H, m) to 2.54 (2H, t, J=5,5 Hz), 3,14 (2H, t, J=8,8 Hz), 3,42 is-3.45 (4H, m), 3,74 (3H, s), at 3.97 (2H, t, J=6,5 Hz), 4,50-USD 4.61 (4H, m), at 6.92 (2H, d, J=8,8 Hz), with 7.25 (1H, s), 7,56 (2H, d, J=8,8 Hz), 7,81 (1H, s).

Example 53

Obtaining di-tert-butyl 8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-Flo[2,3-f]quinoline-6-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 1,06-of 1.12 (3H, t, J=7,4 Hz) to 1.36 (18H, s), 1,85 of 1.97(2H, m), 3,19-about 3.26 (2H, t, J=9,0 Hz), 3,82 (3H, s), 4,00-to 4.05 (2H, t, J=6,7 Hz), 4,73-of 4.80 (2H, t, J=9,0 Hz), 6,28-system 6.34 (2H, d, J=12.6 Hz), to 6.88-6.94 per (2H, d, J=8,8 Hz), 7,11 (1H, s), 7,63-of 7.70 (2H, d, J=8,8 Hz), 7,74 (1H, s).

Example 54

Obtaining [8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-Flo[2,3-f]quinoline-6-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 1,00-1,05 (3H, t, J=7,4 Hz), 1,79-of 1.90 (2H, m), 3,15-to 3.22 (2H, m), 4,00-4,06 (2H, t, J=6,7 Hz), a 4.53-4,62 (2H, m), 6,21-of 6.25 (2H, d, J=10.6 Hz), at 6.92-6.97 in (2H, m), of 7.36 (1H, s), 7,56-members, 7.59 (2H, m), 7,90 (1H, s).

Example 55

Obtaining [8-(4-methoxyphenyl)-9-oxo-5-propoxy-2,3-dihydro-9H-Flo[2,3-f]quinoline-6-ylmethyl]monophosphate disodium salt

Specified above� compound was obtained in the same way, described in example 25, using the appropriate starting material.

¹H-NMR (D₂O) δ M. D.: from 0.92 to 0.97 (3H, t, J=7,4 Hz), and 1.76-of 1.84 (2H, m), 3,12-is 3.19 (2H, t, J=8.9 Hz), of 3.75 (3H, s), 3,93-of 3.99 (2H, t, J=6.8 Hz), 4,56-4,59 (2H, m), 5,95-5,99 (2H, d, J=8.9 Hz), 6,90-6,94 (2H, d, J=8,8 Hz), 7,27 (1H, s), 7,39-the 7.43 (2H, d, J=8,8 Hz), 8,01 (1H, s).

Example 56

Obtain 7-(4-methoxyphenyl)-5-methyl-9H-Flo[3,2-h]quinoline-6-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

White powder (ethyl acetate)

¹H-NMR (DMSO-d₆) δ MD: 2,84 (3H, s) to 3.76 (3H, s), 6,89-7,02 (3H, m), 7,22 (1H, s), 7,52-a 7.58 (2H, d, J=8,8 Hz), of 7.77 (1H, s), 8,21 (1H, s), 12,06 (1H, br.C).

Example 57

Obtain 7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-9H-Flo[3,2-h]quinoline-6-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

White powder

¹H-NMR (DMSO-d₆) δ MD: 2,73 (3H, s), 3,26-of 3.33 (2H, t, J=8,8 Hz), of 3.75 (3H, s), 4,69-to 4.76 (2H, t, J=8,8 Hz), 6,87-6,93 (3H, m), 7.50 to 7,53 (2H, d, J=8.9 Hz), of 7.64 (1H, s), 11,30 (1H, br.C).

Example 58

Obtaining di-tert-butyl 7-(4-methoxyphenyl)-5-methyl-6-oxo-3,6-dihydro-2H-Flo[3,2-h]quinoline-9-elmerpost

The above compound was obtained in the same manner as described in example 23, employed�I corresponding to the source material.

¹H-NMR (CDCl₃) δ M. D.: of 1.39 (18H, s) to 2.86 (3H, s), 3,26-of 3.33 (2H, t, J=8,8 Hz), 3,83 (3H, s), 4,66-4,73 (2H, t, J=8.9 Hz), 6,21-of 6.26 (2H, d, J=11.3 Hz), at 6.92 of 6.99 (3H, m), 7,52 was 7.56 (2H, d, J=8.9 Hz), with 7.66 (1H, s).

Example 59

Obtain [7-(4-methoxyphenyl)-5-methyl-6-oxo-3,6-dihydro-2H-Flo[3,2-h]quinoline-9-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 2.75 (3H, s), 3,26-of 3.33 (2H, t, J=8,8 Hz), of 3.75 (3H, s), 4,69-to 4.76 (2H, t, J=8,8 Hz), 6,15-6,19 (2H, d, J=10.8 Hz), 6,90-6,97 (3H, m), 7,52-a 7.58 (2H, d, J=8.9 Hz), of 7.64 (1H, s).

Example 60

Obtain [7-(4-methoxyphenyl)-5-methyl-6-oxo-3,6-dihydro-2H-Flo[3,2-h]quinoline-9-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

¹H-NMR (D₂O) δ M. D.: of 2.57 (3H, s), 3,06 was 3.13 (2H, t, J=8,8 Hz), and 3.72 (3H, s), 4,50-4,58 (2H, m), 5,84-is 5.88 (2H, d, J=8,8 Hz), 6,84-of 6.87 (2H, d, J=8,8 Hz), 6,93 (1H, s), 7,27-7,31 (2H, d, J=8,8 Hz), the 7.75 (1H, s).

Example 61

Obtaining 2-(4-methoxyphenyl)-5-propoxy-4,7,9,10-tetrahydro-[4,7]phenanthroline-1,8-dione

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Yellow powder (ethyl acetate-IU�anal)

Melting point: 132-133°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 and 1.10 (3H, t, J=7,4 Hz), to 1.80-2.00 (2H, m), 2,33-2,39 (2H, t, J=7,4 Hz), 3.70 to of 3.80 (5H, m), 4,04 of 4.09 (2H, t, J=6,5 Hz), of 6.85 (1H, s) 6,91 is 6.95 (2H, d, J=8,8 Hz), 7,53 was 7.56 (2H, d, J=8,8 Hz), 7,72-the 7.75 (1H, d, J=6,4 Hz), 9,94 (1H, s), of 11.02-of 11.25 (1H, m).

Example 62

Obtaining 2-(4-methoxyphenyl)-7-methyl-5-propoxy-4,7,9,10-tetrahydro-[4,7]phenanthroline-1,8-dione

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Yellow powder

Melting point: 89-91°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 and 1.10 (3H, t, J=7,4 Hz), 1,82 is 2.00 (2H, m), 2,37 was 2.43 (2H, t, J=7,4 Hz), 3,32 (3H, s), 3,65-3,95 (5H, m), 4,17-of 4.22 (2H, t, J=6,5 Hz), 6,90 is 6.95 (2H, d, J=8,8 Hz), 7,05 (1H, s), of 7.50 and 7.55 (2H, d, J=8,8 Hz), 7,76 (1H, s), 11,14 (1H, br.C).

Example 63

Obtain 5-methoxy-3-(4-methoxyphenyl)-1H-[1,10]phenanthrolin-4-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Yellow powder (ethanol)

Melting point: 118-120°C

¹H-NMR (DMSO-d₆) δ M. D.: of 3.75 (3H, s), 3.89 points (3H, s), 6,93 (2H, d, J=8.6 Hz), 7,00 (1H, s), EUR 7.57 (2H, d, J=8.6 Hz), 7,63-to 7.68 (1H, m), 7,91 (1H, s) of 8.26 (1H, d, J=8,2 Hz), 8,78 (1H, d, J=4.2 Hz), 12,23 (1H, br.C).

Example 64

Obtain 5-methoxy-3-thiophene-3-yl-1H-[1,10]phenanthrolin-4-it is hydrochlor�Yes

The above compound was obtained in the same manner as described in example 1, using appropriate starting materials.

Light brown powder (ethanol)

Melting point: 143-145°C

¹H-NMR (DMSO-d₆) δ M. D.: of 3.98 (3H, s), 7,17 (1H, s), members, 7.59 (1H, s), and 7.60 (1H, s), 7,70-the 7.75 (1H, m), 8,20 (1H, br.C) of 8.33 (1H, d, J=8,3 Hz) and 8.50 (1H, s), 8,81-8,83 (1H, m).

Example 65

Obtain 5-methoxy-3-thiophene-2-yl-1H-[1,10]phenanthrolin-4-it

The above compound was obtained in the same manner as described in example 1, using appropriate starting materials.

Light brown powder (ethanol)

Melting point: 265-267°C

¹H-NMR (DMSO-d₆) δ MD: 3,94 (3H, s), 7,07-7,10 (2H, m), 7,44 (1H, d, J=6,0 Hz) and 7.60 (1H, d, J=3.7 Hz), 7,61-7,71 (1H, m), to 8.29 (1H, d, J=8,3 Hz) of 8.47 (1H, s), 8,80-8,83 (1H, m), 12,60 (1H, br.C).

Example 66

Obtain 5-methoxy-1-methyl-3-thiophene-2-yl-1H-[1,10]phenanthrolin-4-it

The above compound was obtained in the same manner as described in example 3 using the appropriate starting material.

Brown powder (ethyl acetate-n-hexane)

Melting point: 216-218°C

¹H-NMR (DMSO-d₆) δ MD: 3,90 (3H, s), of 4.54 (3H, s), 7,08-7,13 (2H, m), 7,44 (1H, d, J=5.1 Hz), 7,56-7,61 (1H, m), 7,65 (1H, d, J=3.7 Hz), USD 8.24 (1H, d, J=8,2 Hz), 8,64 (1H, s), the 8.75-8,77 (1H, m).

Example 67

/p>

Obtain 9-(4-methoxyphenyl)-6-propoxy-7H-[3,7]phenanthrolin-10-she

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

Melting point: 250-251°C

1H-NMR (CDCl₃) δ MD: 1,14-of 1.19 (3H, t, J=7,4 Hz), 1,98-of 2.07 (2H, m), of 3.87 (3H, s), 4,26-4,32 (2H, t, J=6.6 Hz), 6,98-7,02 (2H, d, J=8,7 Hz), 7,30(1H, s), 7,61-of 7.64 (2H, d, J=6.6 Hz), 8,64-8.66 roubles (1H, d, J=6.0 Hz), 9,10 (1H, s), at 9.38-of 9.40 (1H, d, J=4,8 Hz), 9,97-9,99 (1H, d, J=5,9 Hz).

Example 68

Obtaining [9-(4-methoxyphenyl)-10-oxo-6-propoxy-10H-[3,7]phenanthrolin-7-yl]acetic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 1,14-of 1.19 (3H, t, J=7,4 Hz), 1,98-of 2.07 (2H, m), of 3.87 (3H, s), 4,26-4,32 (2H, t, J=6.6 Hz), were 5.47 (2H, s), 6,98-7,02 (2H, d, J=8,7 Hz), 7,30 (1H, s), 7,61-of 7.64 (2H, d, J=6.6 Hz), 8,64-8.66 roubles (1H, d, J=6.0 Hz), 9,10 (1H, s), at 9.38-of 9.40 (1H, d, J=4,8 Hz).

Example 69

Obtaining 2-[9-(4-methoxyphenyl)-10-oxo-6-propoxy-10H-[3,7]phenanthrolin-7-yl]-N(2-morpholine-4-retil)acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting material.

Melting point: 189-192°C

¹H-NMR (DMSO-d₆) δ M. D.: from 1.00 to 1.06 (3H, t, J=7,4 Hz), 1,82-of 1.91 (2H, m), 2,82-3,12 (8H, m), 3,60-of 3.80 (4H, m), of 3.81 (3H, s), 4,14-4,20 (2H, t, J=6,8 Hz), 32 (2H, C) 7,00-of 7.03 (2H, d, J=7,8 Hz), 7,69-7,72 (2H, d, J=7,8 Hz), 7,78 (1H, s), 8,11 (1H, s), 8,20 of 8.30 (1H, m), 8,51-8,53 (1H, d, J=6.1 Hz) at 9.19 (1H, s), 9,99 of 10.0 (1H, d, J=6.1 Hz).

Example 70

Obtain ethyl [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate

The above compound was obtained in the same manner as described in example 31, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 0,96-to 1.02 (3H, t, J=7,4 Hz), 1,18-to 1.24 (3H, t, J=7,1 Hz), 1,69-of 1.80 (2H, m) to 3.78 (3H, s), 3,94 to 4.00 (2H, t, J=6,7 Hz), 4,12-of 4.21 (2H, sq, J=7,1 Hz) of 5.32 (2H, s), 6.94 per-to 7.04 (3H, m), 7,21-7,26 (1H, m), a 7.58-7.62 mm (2H, d, J=8,7 Hz), 8,02 (1H, s).

Example 71

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 0,97-1,03 (3H, t, J=7,4 Hz), 1,72-to 1.87 (2H, m), 3,82 (3H, s), 3,95 to 4.00 (2H, t, J=6,7 Hz), 5,24 (2H, s), 6.94 per-of 7.03 (3H, m), 7,20-7,26 (1H, m), members, 7.59-7.62 mm (2H, d, J=8,7 Hz), 8,02 (1H, s), of 12.5 and 13.3 (1H, br.).

Example 72

GettingNbutyl-2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

White powder

¹H-NMR (DMSO-d₆

Example 73

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(2-morpholine-4-retil)acetamide

To a solution of [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid (800 mg, 2.07 mmol) in DMF (2 ml) were successively added a DMF solution (1 ml) of 4-(2-aminoethyl)morpholine (273 mg), triethylamine (506 mg, 5.0 mmol), diethylphosphonoacetate (DEPC, 405 mg, 2.48 mmol) and DMF (1 ml) under cooling with ice, followed by stirring at room temperature for 23 hours. Water was added to the reaction mixture, and then the mixture was subjected to extraction with ethyl acetate. The thus obtained organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, and the residue recrystallized from ethyl acetate to give a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(2-morpholine-4-retil)acetamide (789 mg, yield: 77%).

Tempera�cheers melting point: 139-141°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.95 (3H, t, J=7.3 Hz), 1,71-of 1.80 (2H, m), 2,30-2,34 (6H, m), of 3.18 (2H, sq, J=6,5 Hz), 3,49-of 3.53 (4H, m) to 3.76 (3H, s), 3,93 (2H, t, J=6.8 Hz), of 5.14 (2H, s), at 6.92 of 6.99 (3H, m), 7,18 (1H, DD, J=4.5 Hz, 9,0 Hz), a 7.58 (2H, d, J=8,8 Hz), 7,90-to 7.95 (2H, m).

Example 74

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-Nmethyl-N(2-morpholine-4-retil)acetamide

The sodium hydride (60% oil basis, 61 mg, 1.4 mmol) was added to a solution of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(2-morpholine-4-retil)acetamide (580 mg, of 1.16 mmol) in DMF (2 ml), and the resulting mixture was stirred at room temperature for 5 minutes. The methyl iodide (230 mg, was 1.62 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction mixture followed by separation of the mixture. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=30:1→>15:1). The purified product was concentrated under reduced pressure, and the residue recrystallized from ethyl acetate to give a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-Nmethyl-N(2-morpholine-4-retil)�of cetamide (440 mg, yield: 74%).

Melting point: 218-220°C

¹H-NMR (DMSO-d₆) δ MD: or 0.94 (3H, t, J=7.3 Hz), 1,64 is 1.72 (2H, m), 2,33-of 2.38 (4H, m), 2,43-of 2.50 (2H, m), 2,85 (1H, s) to 2.99 (2H, s) of 3.37 (2H, t, J=6.8 Hz), 3,44-3,48 (4H, m), of 3.75 (3H, s), 3.89 points (2H, t, J=6,7 Hz), of 5.43 (2H, s), 6,89-6,97 (3H, m), 7,12-up 7.17 (1H, m), 7,53 is 7.57 (2H, m), of 7.83 (1H, s).

Example 75

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(3-morpholine-4-ylpropyl)acetamide

The above compound was obtained in the same manner as described in example 73, using the appropriate starting material.

White powder (ethyl acetate-n-hexane)

Melting point: 117-119°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.95 (3H, t, J=7.3 Hz), of 1.52 and 1.57 (2H, m), 1,71-to 1.79 (2H, m), 2,21-to 2.29 (6H, m), of 3.09 (2H, sq, J=5.8 Hz), 3,49-was 3.54 (4H, m) to 3.76 (3H, s), 3,93 (2H, t, J=6.8 Hz), 5,12 (2H, s), at 6.92 of 6.99 (3H, m), to 7.18 (1H, DD, J=4.5 Hz, 9,0 Hz), a 7.58 (2H, d, J=8,8 Hz), 7,90 (1H, s), 8,00 (1H, t, J=5.4 Hz).

Example 76

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-Nmethyl-N(3-morpholine-4-ylpropyl)acetamide

The above compound was obtained in the same manner as described in example 74, using the appropriate starting material.

White powder (ethyl acetate-n-hexane)

Melting point: 166-168°C

¹H-NMR (DMSO-d₆) δ M. D.: from 0.92 to 0.98 (3H, m), 1.65 V is 1.71 (4H, m), 2,21-a 2.36 (6H, m), 2,82 (1H, s), 2,98 (2H, s), 3,20 to 3.30 (2H, m), 3,48-3,58(4H, m) to 3.76 (3H, s), 3,90 (2H, t, J=6.8 Hz), 5,43-of 5.45 (2H, m), 6,90-6,98 (3H, m), 7,13-to 7.18 (1H, m), 7,54-members, 7.59 (2H, m), of 7.86 (1H, s).

Example 77

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(1-demerol-4-yl)acetamide

The above compound was obtained in the same manner as described in example 73, using the appropriate starting material.

Light yellow powder (ethyl acetate-n-hexane)

Melting point: 201-203°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.95 (3H, t, J=7.3 Hz), 1,40 was 1.49 (2H, m), 1,67-of 1.84 (4H, m), of 1.91 to 2.00 (2H, m) to 2.14 (3H, s), 2,69-to 2.73 (2H, m), 3,55 of 3.75 (1H, m), of 3.75 (3H, s), 3,93 (2H, t, J=6,7 Hz), of 5.14 (2H, s), 6,90-6,98 (3H, m), made 7.16 interest (1H, DD, J=4.4 Hz, 9,0 Hz), a 7.58 (2H, d, J=8.6 Hz), 7,90 (1H, s), 8,03 (1H, d, J=7,3 Hz).

Example 78

Obtain tert-butyl 4-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetylamino}piperidine-1-carboxylate

The above compound was obtained in the same manner as described in example 73, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.03 (3H, t, J=7.3 Hz), 1,31-of 1.38 (2H, m) of 1.41 (9H, s), 1.80 to to 1.86 (4H, m), 2.70 m to 3.00 (2H, m), with 3.79 (3H, s), 3,88 to 4.13 (5H, m), 4,94 (2H, s), 6,55 (1H, br.C) was 6.77-at 6.92 (4H, m), 7,31 (1H, s) of 7.46 (2H, d, J=8,8 Hz).

Example 79

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-Nthe piperidine-4-ylacetamide

4N Solution of�hydrochloric acid in ethyl acetate (25 ml) was added to a solution of tert-butyl 4-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetylamino}piperidine-1-carboxylate (820 mg, 1.44 mmol) in ethanol (12 ml), followed by stirring at room temperature for 28 hours. The resulting mixture was concentrated under reduced pressure. After adding an aqueous solution of sodium bicarbonate to the residue to bring the pH to 8, the residue was washed with ethyl acetate. To the aqueous layer was added 2N aqueous solution of sodium hydroxide to bring the pH to 11, followed by extraction with dichloromethane. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is recrystallized from ethanol-ethyl acetate to give a white powder of 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-Nthe piperidine-4-ylacetamide (185 mg, yield: 27%).

Melting point: 226-228°C

¹H-NMR (DMSO-d₆) δ MD: or 0.94 (3H, t, J=7.3 Hz), 1.22 m and 1.33 (2H, m), 1,62 at 1.81 (4H, m), 2,36-of 2.45 (2H, m), 2,84-2,89 (2H, m), 3,55 of 3.75 (2H, m), of 3.75 (3H, s), 3,92 (2H, t, J=6,7 Hz), 5,13 (2H, s), 6,90-6,98 (3H, m), made 7.16 interest (1H, DD, J=4.5 Hz, 9,0 Hz), 7,56 (2H, d, J=8,6 Hz) of 7.88 (1H, s), 8,01 (1H, d, J=7.5 Hz).

Example 80

Obtain ethyl 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butyrate

The above compound was obtained in the same manner as described in example 31, using the appropriate starting materials.

¹H-NMR (D�WITH-d ₆) δ M. D.: from 1.00 to 1.06 (3H, t, J=7,4 Hz), 1,06-of 1.12 (3H, t, J=7,13), 1,80-2,02 (4H, m), 2,24-of 2.30 (2H, t, J=7,4 Hz), with a score of 3.77 (3H, s), 3,92 to 4.00 (2H, sq, J=7,1 Hz), 4,03 of 4.09 (2H, t, J=6.6 Hz), of 4.54-4,60 (2H, t, J=6,87 Hz), 6,93-to 7.04 (3H, m), 7.24 to 7,29 (1H, m), and 7.60-7,63 (2H, d, J=8.6 Hz), compared to 7.97 (1H, s).

Example 81

Obtaining 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butyric acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: from 1.00 to 1.06 (3H, t, J=7,4 Hz), 1,78 is 2.00 (4H, m), of 2.16-2.22 (2H, t, J=7,4 Hz) to 3.78 (3H, s), 4,04 of 4.09 (2H, t, J=6.6 Hz), of 4.54-4,60 (2H, t, J=7.0 Hz), 6,93-to 7.04 (3H, m), 7.24 to is 7.30 (1H, m), 7,60-of 7.64 (2H, d, J=8,8 Hz), compared to 7.97 (1H, s) 11,80-12,20 (1H, br.).

Example 82

GettingNbutyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butylamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

¹H-NMR (DMSO-d₆) δ MD: 0,78 is 0.84 (3H, t, J=7,1 Hz) of 0.99 and 1.05 (3H, t, J=7,4 Hz), 1,10-of 1.42 (4H, m), 1.75 of which is 2.01 (6H, m), 2,92-of 2.97 (2H, m), with a score of 3.77 (3H, s), 4.03 us-to 4.08 (2H, t, J=6.6 Hz), a 4.53-4,58 (2H, t, J=6.2 Hz), at 6.92-of 7.03 (3H, m), 7.23 percent-to 7.28 (1H, m), and 7.60-7,63 (2H, t, J=8,6 Hz), 7,70-the 7.75 (1H, m), of 7.93 (1H, s).

Example 83

Obtaining 1-(3-bromopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same way�m, which is described in example 17 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: 1,05-of 1.12 (3H, m), 1.85 to to 1.96 (2H, m), 2,30 of 2.35 (2H, m), of 3.33 (2H, t, J=6.1 Hz), 3,83 (3H, s), 3,96-to 4.05 (2H, m), or 4.69 (2H, t, J=6,5 Hz), of 6.85-of 7.03 (4H, m), members, 7.59-of 7.64 (3H, m).

Example 84

Obtaining 1-(3-chloropropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 17 using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: the 1.05 and 1.13 (3H, m), 1,87-of 1.96 (2H, m), 2,22-of 2.27 (2H, m), 3,49 (2H, t, J=5.8 Hz), 3,83 (3H, s), 3,96-to 4.05 (2H, m), 4,70 (2H, t, J=6,5 Hz), 6,86-7,02 (4H, m), members, 7.59-of 7.64 (3H, m).

Example 85

Getting 5-fluoro-3-(4-methoxyphenyl)-1-(3-morpholine-4-ylpropyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting material.

White powder (ethyl acetate-n-hexane)

Melting point: 130-132°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), 1,73-to 1.87 (4H, m), 2.07 to 2.20 m (6H, m), 3,36-3,39 (4H, m), 3,74 (3H, s) 4,01 (2H, t, J=6,5 Hz) to 4.56 (2H, t, J=6.3 Hz), 6,90-7,00 (3H, m), 7,21 (1H, DD, J=4.5 Hz, 9,0 Hz), EUR 7.57 (2H, d, J=8,7 Hz) of 7.98 (1H, s).

Example 86

Obtaining 1-(3-diethylaminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound yielding�and in the same manner, which is described in example 18, using the appropriate starting materials.

White powder (diethyl ether)

Melting point: 80-82°C

¹H-NMR (DMSO-d₆) δ MD: 0,81 (6H, t, J=7,0 Hz) of 1.01 (3H, t, J=7.3 Hz), 1,75-to 1.87 (4H, m), 2,22-of 2.38 (6H, m), of 3.75 (3H, s), is 4.03 (2H, t, J=6.6 Hz), of 4.54 (2H, t, J=6,7 Hz), 6,91-7,01 (3H, m), 7.23 percent (1H, DD, J=4.5 Hz, 9,0 Hz), members, 7.59 (2H, d, J=8,8 Hz), 7,96 (1H, s).

Example 87

Getting 5-fluoro-3-(4-methoxyphenyl)-1-[3-(4-methylpiperazin-1-yl)propyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

White powder (ethyl acetate-n-hexane)

Melting point: 152 to 154°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,78-to 1.86 (4H, m) of 1.96 (3H, s), 2,04-2,14 (10H, m), of 3.75 (3H, s), 4,02 (2H, t, J=6,5 Hz), 4,55 (2H, t, J=6.2 Hz), 6,90-7,01 (3H, m), 7.23 percent (1H, DD, J=4.5 Hz, 9,0 Hz), a 7.58 (2H, d, J=8,8 Hz), compared to 7.97 (1H, s).

Example 88

Getting 5-fluoro-3-(4-methoxyphenyl)-1-(3-piperidine-1-ylpropyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

White powder (ethyl acetate-n-hexane)

Melting point: 132-134°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), measuring 1.20-1.40 (6H, m), 1,73-of 1.84 (4H, m), 2,02-and 2.10 (6H, m), 3,74 (3H, s), of 4.00 (2H, t, J6,4 Hz), a 4.53 (2H, t, J=6.2 Hz), 6,89-7,00 (3H, m), 7,20 (1H, DD, J=4.5 Hz, 9,0 Hz), EUR 7.57 (2H, d, J=8.6 Hz), 7,95 (1H, s).

Example 89

Obtaining 1-[3-(4-ethylpiperazin-1-yl)propyl]-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Light yellow powder (ethyl acetate-n-hexane)

Melting point: 147-149°C

¹H-NMR (DMSO-d₆) δ MD: 0,80-1,00 (6H, m), 1,70-1,80 (4H, m) of 2.00-2.20 (12H, m), of 3.75 (3H, s), 4,00-4,06 (2H, m), of 4.54-4,59 (2H, m), 6,90-7,00 (3H, m), 7,20-7,26 (1H, m), 7,55 and 7.60 (2H, m), of 7.98 (1H, s).

Example 90

Getting 5-fluoro-1-[3-(3-hydroxyazetidine-1-yl)propyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she hydrochloride

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Light yellow powder (ethyl acetate)

Melting point: 183-185°C

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7.3 Hz), 1,79-to 1.94 (4H, m), 3,08-3,14 (2H, m), 3,68-3,83 (5H, m) to 4.05 (2H, t, J=6,7 Hz), 4,19-to 4.43 (3H, m), of 4.54-4,60 (2H, m), a 6.23 (1H, br.C) at 6.92-to 7.04 (3H, m), 7,27 (1H, DD, J=4.5 Hz, 9,0 Hz), 7,61 (2H, d, J=8.6 Hz), 8,00 (1H, s), 10,30 (1H, br.C).

Example 91

Getting 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-[3-(4-pyridin-2-reparation-1-yl)propyl]-1H-quinolin-4-it

Shown� above compound was obtained in the same way, which is described in example 18, using the appropriate starting materials.

White powder (ethyl acetate-n-hexane)

Melting point: 123-125°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,79-of 1.89 (4H, m), 2,14-of 2.27 (6H, m), 3,20 to 3.30 (4H, m), 3,74 (3H, s), is 4.03 (2H, t, J=6,5 Hz), 4,60 (2H, t, J=6.0 Hz), to 6.58 (1H, DD, J=5.0 Hz, 6.9 Hz), was 6.69 (1H, d, J=8,6 Hz), 6,90-7,02 (3H, m), 7.23 percent (1H, DD, J=4.4 Hz, 9,0 Hz), 7,40-7,50 (1H, m), 7,58-7,61 (2H, m), 8,02-8,06 (2H, m).

Example 92

Getting 5-fluoro-3-(4-methoxyphenyl)-1-[3-(4-the morpholine-4-reparacin-1-yl)propyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Light brown powder (ethyl acetate)

Melting point: 168-170°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,12-1,20 (2H, m), 1.50 to 1.55 (2H, m), 1,68-to 1.86 (6H, m), 1,90 was 2.11 (3H, m), 2,30-of 2.33 (4H, m), 2,62-of 2.67 (2H, m), 3,48-3,51 (4H, m), of 3.75 (3H, s), is 4.03 (2H, t, J=6.5 Hz), to 4.56 (2H, t, J=5,9 Hz), 6,90-7,01 (3H, m), 7.23 percent (1H, DD, J=4.5 Hz, 9,0 Hz) and 7.60 (2H, d, J=8,8 Hz), is 7.99 (1H, s).

Example 93

Getting 5-fluoro-1-{3-[4-(2-methoxyethyl)piperazine-1-yl]propyl}-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she dihydrochloride

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Powder light beige (utilized�t)

Melting point: 184-186°C

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,81-of 1.89 (2H, m), 2,00-2,25 (2H, m), 2,80-of 2.97 (2H, m), 3,25 (3H, s), 3,20-3,40 (4H, m), 3,60-in 3.65 (8H, m), of 3.75 (3H, s) 4,06 (2H, t, J=6,7 Hz), 4,60 (2H, t, J=6.3 Hz), 6,91-to 7.04 (3H, m), 7,26 (1H, DD, J=4.5 Hz, 9,0 Hz), 7,61 (2H, d, J=8,8 Hz), 8,03 (1H, s).

Example 94

Obtain 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindol-1,3-Dion

The sodium hydride (60% oil basis, 800 mg, or 18.3 mmol) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (5.0 g, 15.2 mmol) in DMF (25 ml). The mixture was stirred for 30 minutes at room temperature.N-Bromopropylamine (4.48 g, 16.7 mmol) was added to the mixture and stirred at room temperature for 30 minutes and at 50°C for 5 hours. The reaction mixture was cooled with ice and water (20 ml) and ethyl acetate was added to the mixture, followed by stirring for 2 hours. The resulting insoluble substance was separated, washed with water and then dried to obtain a light yellow powder of 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindole-1,3-dione (4,63 g, yield: 59%).

¹H-NMR (DMSO-d₆) δ MD: or 0.94 (3H, t, J=7.3 Hz), 1,74-of 1.83 (2H, m) to 2.03 (2H, t, J=7,4 Hz), is 3.62 (2H, t, J=6,6 Hz) to 3.76 (3H, s) 4,01 (2H, t, J=6,7 Hz), USD 4.61 (2H, t, J=7.5 Hz), 6,91-7,02 (3H, m), with 7.25 (1H, DD, J=4.5 Hz, 9,0 Hz), a 7.58 (2H, d, J=8,8 Hz), 7,78-of 7.86 (4H, m), 8,06 (1H, s).

Example 95

Obtaining 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

Hydrazine hydrate (0,62 ml, 12.8 mmol) was added to a solution of 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}isoindole-1,3-dione (2.0 g, 3.88 mmol) in ethanol (60 ml) and heated to reflux for 4 hours. The resulting mixture was concentrated under reduced pressure, 5N aqueous solution of sodium hydroxide was added to the thus obtained residue and then the resulting mixture was subjected to extraction with dichloromethane. The thus obtained organic layer was successively washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a yellow oily compound 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (1.4 g, yield: 94%).

¹H-NMR (CDCl₃) δ M. D.: of 1.09 (3H, t, J=7.3 Hz), 1,23 (2H, br.C) 1,84 and 1.95 (4H, m), of 2.69 (2H, t, J=6.8 Hz), 3,82 (3H, s) 4,01 (2H, t, J=6,7 Hz), USD 4.61 (2H, t, J=6.9 Hz), 6,83-7,02 (4H, m), members, 7.59-7,65 (3H, m).

Example 96

Obtain 2-chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide

A solution of 1-(3-aminopropyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it (645 mg, 1.67 mmol) in dichloromethane (6 ml) was cooled on ice. Triethylamine (253 mg, 2.5 MMO�ü) and chlorocatechol (207 mg, of 1.83 mmol) was added to the solution and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The thus obtained organic layer was condensible and then the residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=4:1→2:1). The purified product was concentrated to dryness under reduced pressure to give a white powder of 2-chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide (372 mg, yield: 48%).

¹H-NMR (CDCl₃) δ M. D.: of 1.10 (3H, t, J=7.3 Hz), 1,86 of 2.09 (4H, m), of 3.33 (2H, sq, J=6,9 Hz), 3,83 (3H, s) 4,01 (2H, s), of 4.04 (2H, t, J=6,8 Hz) to 4.56 (2H, t, J=6.9 Hz), to 6.66 (1H, br.C) 6,86-of 6.96 (3H, m), 7,03 (1H, DD, J=4.5 Hz, 9,0 Hz), 7,52 (1H, s), 7,61 (2H, d, J=8,8 Hz).

Example 97

GettingN{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}-2-[4-(2-methoxyethyl)piperazine-1-yl]acetamide hydrochloride

2-Chloro-N-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}acetamide (370 mg, 0.8 mmol) was suspended in acetonitrile (12 ml). 1-(2-Methoxyethyl)piperazine (138 mg, 0.96 mmol), triethylamine (162 mg, 1.6 mmol) and acetonitrile (2 ml) was added to the suspension and stirred at a temperature of from 70 to 80°C for 6 hours. The resulting mixture was concentrated under reduced pressure and the residue was subjected to extraction with ethyl�the top. Then the extract is then washed with water, aqueous saturated solution of sodium chloride and saturated aqueous sodium bicarbonate solution. The product is subjected to washing, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (dichloro methane:methanol=30:1→10:1). The purified product was concentrated under reduced pressure and then the residue was dissolved in ethyl acetate (5 ml). To the solution was added 4N solution of hydrogen chloride in ethyl acetate (0.19 ml) and stirred, and the mixture is then concentrated to dryness under reduced pressure to obtain a pale yellow solid substance in the amorphous stateN{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propyl}-2-[4-(2-methoxyethyl)piperazine-1-yl]acetamide hydrochloride (200 mg).

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7.3 Hz), 1,78-of 1.89 (4H, m), from 2.50 to 3.00 (4H, m), 2,96-3,20 (8H, m), 3,25 (3H, s), is 3.62-3.66 m (4H, m), of 3.75 (3H, s), 3,98-of 4.04 (2H, m) to 4.56 (2H, t, J=6,4 Hz), 6,91-7,02 (3H, m), of 7.24 (1H, DD, J=4.5 Hz, 9.1 Hz), and 7.60 (2H, d, J=8,8 Hz), 8,00 (1H, s) of 8.07 (1H, br.C).

Example 98

Obtaining 1-(4-bromobutyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 17 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ MD to 1.06 and 1.13 (3H, m), of 1.70 to 2.00 (6H, m), is 3.39 (2H, t, J=6.3 Hz), 3,83 (3H, s), 4,03 (H, t, J=6,7 Hz), a 4.53 (2H, t, J=6.8 Hz), 6,86-of 7.03 (4H, m), 7,49 (1H, s), 7.57 the-7,63 (2H, m).

Example 99

Getting 5-fluoro-3-(4-methoxyphenyl)-1-(4-morpholine-4-libutil)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting material.

White powder (ethyl acetate-n-hexane)

Melting point: 118-120°C

¹H-NMR (DMSO-d₆) ∆ MD is 0.98 (3H, t, J=7.3 Hz), 1.27 mm was 1.35 (2H, m), 1.62 V-to 1.82 (4H, m), 2,13-to 2.19 (6H, m), 3,44-3,47 (4H, m), 3,73 (3H, s), of 3.98 (2H, t, J=6,5 Hz), 4.49 in (2H, t, J=6.8 Hz), 6,89 of 6.99 (3H, m), of 7.19 (1H, DD, J=4.5 Hz, 9,0 Hz), EUR 7.57 (2H, d, J=8.6 Hz), 7,95 (1H, s).

Example 100

Getting 5-fluoro-3-(4-methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)butyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 18, using the appropriate starting materials.

Pale yellow amorphous

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), 1.27 mm is 1.32 (2H, m), 1.62 V-of 1.65 (2H, m) to 1.79 (2H, sq, J=6,9 Hz), of 2.07 (3H, s), 2,11-2,21 (10H, m), 3,74 (3H, s), of 4.00 (2H, t, J=6,5 Hz), 4.49 in (2H, t, J=6.8 Hz), 6,90-7,00 (3H, m), 7,21 (1H, DD, J=4.5 Hz, 9,0 Hz), a 7.58 (2H, d, J=8.6 Hz), 7,96 (1H, s).

Example 101

Obtain 2-{4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]butyl}isoindol-1,3-Dion

The above compound was obtained in the same way, which� described in example 94, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: is 0.96 (3H, t, J=7.3 Hz), 1,50-1,80 (6H, m), 3,57 (2H, t, J=6.3 Hz), to 3.76 (3H, s), at 3.97 (2H, t, J=6,7 Hz), 4.49 in (2H, t, J=6.8 Hz), to 6.88-to 6.95 (3H, m), 7,18 (1H, DD, J=4.5 Hz, 9.1 Hz), and 7.60 (2H, d, J=8,7 Hz), 7,80-7,90 (4H, m), 8,01 (1H, s).

Example 102

Obtaining 1-(4-aminobutyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 95, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.10 (3H, t, J=7.3 Hz), of 1.36 to 1.60 (4H, m) of 1.75 and 1.95 (4H, m), of 2.69 (2H, t, J=6.9 Hz), 3,82 (3H, s) 4,01 (2H, t, J=6.6 Hz), 4,50 (2H, t, J=7.3 Hz), 6,83-7,02 (4H, m), of 7.50 (1H, s), and 7.60 (2H, d, J=8,5 Hz).

Example 103

Obtain 2-{6-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]hexyl}isoindol-1,3-Dion

The above compound was obtained in the same manner as described in example 94, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.08 (3H, t, J=7.3 Hz), 1,20-a 1.77 (8H, m), 1,83-to 1.94 (2H, m), 3,65 (2H, t, J=6.9 Hz), 3,82 (3H, s) 4,01 (2H, t, J=6,5 Hz), 4,46 (2H, t, J=7.3 Hz), 6,83-to 7.04 (4H, m), 7,49 (1H, s), 7,61 (2H, d, J=8,7 Hz), 7,68-of 7.83 (4H, m).

Example 104

Obtaining 1-(6-aminohexyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 95,using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.10 (3H, t, J=7.3 Hz), 1,30-of 1.80 (10H, m), 1.87 a and 1.95 (2H, m), 2,65 (2H, t, J=6,4 Hz), 3,83 (3H, s) 4,01 (2H, t, J=6.6 Hz), 4,47 (2H, t, J=7.5 Hz), to 6.88-of 7.03 (4H, m), of 7.50 (1H, s), a 7.62 (2H, d, J=8,7 Hz).

Example 105

Obtaining 1-(2-chloroethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 17 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, t, J=7,4 Hz), 1,81 is 2.01 (2H, m), 3,83 (3H, s), 3,84-3,89 (2H, t, J=6.3 Hz), 4,00-to 4.05 (2H, t, J=6,7 Hz), 4.74 in-4,79 (2H, t, J=6.3 Hz), 6,89-to 7.04 (4H, m), 7,54 (1H, s), members, 7.59-7.62 mm (2H, d, J=8,8 Hz).

Example 106

Getting 5-fluoro-3-(4-methoxyphenyl)-1-(2-morpholine-4-retil)-8-propoxy-1H-quinolin-4-it

Potassium carbonate (2.1 g, 15.2 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1,36 g, 7.31 mmol) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (1.0 g, of 3.05 mmol) inN-methylpyrrolidone (NMP) (5 ml) and then stirred at a temperature of from 50 to 60°C for 45 hours. Water and ethyl acetate were added to the reaction mixture, with subsequent separation. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride twice, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=50:1→30:1). Ocianydataset concentrated under reduced pressure and the residue recrystallized from ethyl acetate to give a white powder of 5-fluoro-3-(4-methoxyphenyl)-1-(2-morpholine-4-retil)-8-propoxy-1H-quinolin-4-she (1.01 g, yield: 75%).

Melting point: 206-208°C

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7.3 Hz), 1,78-to 1.87 (2H, m), 2,33-a 2.36 (4H, m) to 2.59 (2H, t, J=5.6 Hz), 3,43-3,47 (4H, m), with a score of 3.77 (3H, s) to 4.05 (2H, t, J=6,5 Hz), of 4.66 (2H, t, J=5.7 Hz), 6.94 per-7,02 (3H, m), with 7.25 (1H, DD, J=4.5 Hz, 9,0 Hz) and 7.60 (2H, d, J=8,8 Hz), 7,95 (1H, s).

Example 107

Obtain 2-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}isoindol-1,3-Dion

The above compound was obtained in the same manner as described in example 94, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7.3 Hz), 1.85 to a 2.01 (2H, m) to 3.76 (3H, s), 4.03 us at 4.12 (4H, m), 4,84 (2H, t, J=5.6 Hz), 6,84-6,89 (3H, m), at 6.92-7,00 (1H, m), 7,56 (2H, d, J=8.6 Hz), 7,68-7,79 (5H, m).

Example 108

Obtaining 1-(2-aminoethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 95, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.10 (3H, t, J=7.3 Hz), of 1.36 (2H, br.C) 1,84 and 1.95 (2H, m), 3,10 (2H, t, J=6.0 Hz), 3,82 (3H, s) 4,01 (2H, t, J=6,7 Hz), of 4.54 (2H, t, J=6.1 Hz), 6,84-7,02 (4H, m), and 7.60-of 7.64 (3H, m).

Example 109

Obtain tert-butyl ((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamate}-2-hydroxyethyl)carbamate

SolutionN-(tert-butoxycarbonyl)-L-serine (174 mg, 0.85 mmol), Treaty�amine (198 mg, of 1.96 mmol), diethylphosphonoacetate (DEPC, 176 mg, 0.97 mmol) in DMF (0.5 ml) and DMF (0.5 ml) were successively added to a solution of 1-(2-aminoethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it (300 mg, 0.81 mmol) in DMF (1 ml) under cooling with ice and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and then subjected to extraction with ethyl acetate. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride twice. The product is subjected to washing, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=40:1→30:1). The purified product was concentrated to dryness under reduced pressure to give a white solid substance in the amorphous state of tert-butyl ((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamate}-2-hydroxyethyl)carbamate (338 mg, yield: 75%).

¹H-NMR (CDCl₃) δ M. D.: of 1.09 (3H, t, J=7.3 Hz), of 1.38 (9H, s), 1,87-of 1.95 (2H, m), 3,08 (1H, br.C), 3,45-of 3.60 (3H, m), 3,69 was 3.79 (1H, m) to 3.76 (3H, s), of 3.99 (2H, t, J=6.8 Hz), 4,34 (1H, br.C) a 4.64 (2H, br.C) 5,87 (1H, d, J=7,9 Hz), 6,56 (1H, DD, J=8.9 Hz, 11.7 Hz), 6,73 (2H, d, J=8,7 Hz) 6,91 (1H, DD, J=4.5 Hz, 9,0 Hz), of 7.36 (2H, d, J=8,7 Hz) of 7.46 (1H, s) of 8.26 (1H, br.C).

Example 110

Obtain tert-butyl ((S)-5-tert-butoxycarbonylamino-5-{2-[5-fluoro-3-(4-�ethoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamate}pentyl)carbamate

The above compound was obtained in the same manner as described in example 109, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 0.90 and 1.05 (4H, m) of 1.12 (3H, t, J=7.3 Hz), and 1.37 (9H, s) of 1.41 (9H, s) of 1.48 to 1.60 (2H, m), 1,87-of 1.99 (2H, m), 2,80-2,90 (2H, m), 3,40-of 3.50 (1H, m), 3,80 (3H, s), of 3.91-a 4.24 (5H, m), a 4.53 (1H, br.C), 5,27-is 5.33 (1H, m), 5,75-5.78% was established (1H, m), 6,43-of 6.52 (1H, m), 6,84-6,90 (3H, m), 7,39-of 7.48 (3H, m), 8,09 (1H, br.C).

Example 111

Obtain tert-butyl [(S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamate}-2-(1H-imidazol-4-yl)ethyl]carbamate

The above compound was obtained in the same manner as described in example 109, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.10 (3H, t, J=7.3 Hz), of 1.39 (9H, s), 1.85 to a 2.01 (2H, m), 2,72-2,90 (2H, m), 3,50-3,60 (1H, m) to 3.76 (3H, s), 3,77-of 3.86 (1H, m), 4,02 (2H, t, J=6,7 Hz), 4,30-to 4.43 (2H, m), 4,82-of 4.88 (1H, m), 5,82 (1H, br.C) to 6.57 (1H, s), 6,72-6,84 (3H, m), 6.94 per of 6.99 (1H, m), to 7.08 (1H, s), value of 7, 37 of 7.45 (3H, m), with 8.05 (1H, br.C).

Example 112

Obtain 2-chloro-N{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}acetamide

The above compound was obtained in the same manner as described in example 96, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.12 (3H, t, J=7.3 Hz), 1,90-of 1.98 (2H, m), 3,64-of 3.70 (2H, m), 3,83 (3H, s), of 3.98 (2H, s), is 4.03 (2H, t, J=6.6 Hz), 4.72 in-4,76 (2H, m), is 6.51 (1H, DD, J=9,0 Hz, 11.7 Hz), 6,78 (2H, q, j =8,8 Hz), 6,89 (1H, DD, J=4.5 Hz, 9,0 Hz), the 7.25-7,32 (3H, m), 8,54 (1H, br.C).

Example 113

GettingN-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-2-(4-morpholine-4-reparacin-1-yl)acetamide dihydrochloride

The above compound was obtained in the same manner as described in example 97 using the appropriate starting materials.

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7.3 Hz), 1,75-of 1.96 (7H, m), 2.50 to the 2.80 (2H, m), 2,85-3,25 (10H, m) to 3.76 (3H, s), 3,80-3,95 (4H, m), of 4.04 (2H, t, J=6,5 Hz), or 4.69 (2H, br.C) 6,93-7,02 (3H, m), with 7.25 (1H, DD, J=4.5 Hz, 9.1 Hz), of 7.64 (2H, d, J=8,8 Hz), a 7.87 (1H, s) of 8.69 (1H, br.C).

Example 114

Obtain N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-2-[4-(2-methoxyethyl)piperazine-1-yl]acetamide dihydrochloride

The above compound was obtained in the same manner as described in example 97 using the appropriate starting materials.

¹H-NMR (DMSO-d₆) ∆ MD is 0.98 (3H, t, J=7.3 Hz), 1,76 is 1.85 (2H, m), 2,95-of 3.05 (4H, m), 3,25 (3H, s) of 3.10 to 3.30 (2H, m), 3,39-3,64 (10H, m), of 3.75 (3H, s), 4,02 (2H, t, J=6,5 Hz), to 4.68 (2H, br.C) 6,91-7,01 (3H, m), 7.23 percent (1H, DD, J=4.5 Hz, 9.1 Hz), members, 7.59 (2H, d, J=8,7 Hz), of 7.86 (1H, s), to 8.57 (1H, t, J=5.4 Hz).

Example 115

Preparation of (S)-2-amino-N{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-hydroxypropionate hydrochloride

4N Solution of hydrogen chloride in the e�racette (5 ml) was added to an ethanol solution (5 ml) of tert-butyl ((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamate}-2-hydroxyethyl)carbamate (330 mg, 0.6 mmol) and stirred at room temperature for 14 hours. The resulting mixture was concentrated under reduced pressure. Water was added to the residue, which was then washed with ethyl acetate. 2N Aqueous sodium hydroxide solution (6 ml) was added to the aqueous layer to bring its pH to 11, followed by extraction with dichloromethane. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=20:1→15:1). The purified product was concentrated under reduced pressure, the residue was dissolved in ethanol (3 ml) and ethyl acetate (3 ml) and then a 4N solution of hydrogen chloride in ethyl acetate (0.1 ml) was added to the solution. The mixture was stirred and concentrated to dryness under reduced pressure and recrystallized from ethyl acetate to give a white powder of (S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-hydroxypropionate hydrochloride (145 mg, yield: 50%).

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7.3 Hz), 1,76-of 1.88 (2H, m), 3,23-of 3.50 (5H, m), of 3.75 (3H, s) to 4.05 (2H, t, J=6,5 Hz), a 4.53-4,73 (2H, m), 5.40 to-5,42 (1H, m), 6,91-of 7.03 (3H, m), 7,26 (1H, DD, J=4.5 Hz, 9,0 Hz), a 7.58 (2H, d, J=8,7 Hz), 7,80 (1H, s), 8,00 (2H, br.C) 8,58 (1H, t, J=5,2 Hz).

Example 116

The above compound was obtained in the same manner as described in example 115 using an appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), 1,00-1,50 (6H, m), 1,77-to 1.86 (2H, m), 2,57 (2H, t, J=7,2 Hz), 3,32-3,44 (3H, m), 3,50-of 3.70 (4H, m), 3,74 (3H, s), 4,00-to 4.05 (2H, m), a 4.53-and 4.82 (2H, m), 6,91-of 7.03 (3H, m), of 7.24 (1H, DD, J=4.5 Hz, 9.1 Hz), and 7.60 (2H, d, J=8,7 Hz), of 7.86 (1H, s), 8,61 (1H, br.C).

Example 117

Preparation of (S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-(1H-imidazol-4-yl)propionamide

The above compound was obtained in the same manner as described in example 115 using an appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7.3 Hz), 1,78-to 1.86 (2H, m), and 2.26 (1H, DD, J=9,3 Hz, 14.5 Hz), 2,65 (1H, DD, J=3.8 Hz, 14.5 Hz), about 3.26 (1H, DD, J=3.8 Hz, 9.3 Hz), 3,30-3,55 (4H, m), 3,73 (3H, s), 3,98-to 4.05 (2H, m), a 4.64 (2H, the Shire.C) 6,61 (1H, s), 6,87-7,01 (3H, m), 7,22 (1H, DD, J=4.5 Hz, 9,0 Hz) of 7.48 (1H, s), EUR 7.57 (2H, d, J=8,7 Hz), 7,79 (1H, s), 8,13 (1H, br.C).

Example 118

Getting 1-but-3-enyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 3 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ �.etc.: 1,09 were 1.15 (3H, t, J=7,4 Hz), 1,82-of 2.03 (2H, m), 2,38-of 2.64 (2H, m), 3,85 (3H, s), 4,02 is 4.07 (2H, t, J=6,7 Hz), 4,55-USD 4.61 (2H, t, J=7,2 Hz), 4,96-of 5.15 (2H, m), 5,60-to 5.89 (1H, m), of 6.79-to 7.08 (4H, m), 7,49 (1H, s), 7,61-of 7.64 (2H, d, J=8,8 Hz).

Example 119

Obtain 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]Propionaldehyde

Prepare a solution of 1-but-3-enyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (1.2 g, 3,15 mmol) in a mixture of dioxane (30 ml)-water (10 ml). To the solution was added 2,6-lutidine (0,674 g, 6,29 mmol), 4% solution of osmium acid (1 ml) and sodium periodate (2,69 g, 12.6 mmol) and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, then the mixture was extracted with dichloromethane, washed with water and then dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure and then the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated to dryness under reduced pressure to obtain a pale yellow powder of 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]Propionaldehyde (1.0 g, yield: 83%).

¹H-NMR (CDCl₃) δ MD: 1.05 and 1.10 (3H, t, J=7,4 Hz), 1,75-to 1.94 (2H, m), 3,04 was 3.92 (2H, t, J=6.6 Hz), 3,83 (3H, s), 3,99-of 4.04 (2H, t, J=6.8 Hz), 4,76-to 4.81 (2H, t, J=6.6 Hz), about 6,82-7,06 (4H, m), 7,49-to 7.68 (3H, m), to 9.81 (1H, C).

Example 120

Obtain 3-[5-fluoro-3-(4-methoxide�l)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionic acid

3-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]Propionaldehyde (1.0 g, 2,61 mmol) was dissolved in water (10 ml), tert-butyl alcohol (20 ml) and dichloromethane (20 ml). Sodium chlorite (3.2 g, of 35.4 mmol), 2-methyl-2-butene (19,86 mg, 283 mmol) and dehydrate dihydrogenphosphate sodium (2 g, 2,61 mmol) was added to the resulting solution and the solution was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with dichloromethane and then washed with water and dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=50:50→0:100). The purified product was concentrated to dryness under reduced pressure to obtain a pale yellow powder of 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionic acid (710 mg, yield: 68%).

¹H-NMR (DMSO-d₆) δ MD: 0,96-to 1.02 (3H, t, J=7,4 Hz), 1,62-of 1.91 (2H, m), 2,75 is 2.80 (2H, t, J=6,9 Hz) to 3.76 (3H, s), 4,01 is 4.07 (2H, t, J=6.6 Hz), 4,69-of 4.75 (2H, t, J=7.0 Hz), 6,90-of 7.03 (3H, m), 7,22-7,29 (1H, m), members, 7.59-7,63 (2H, d, J=8,8 Hz), 8,03 (1H, s).

Example 121

Obtain 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-[3-(4-methylpiperazin-1-yl)propyl]propionamide

The above compound was obtained in the same manner as described in example 33, using the corresponding�following source materials.

Melting point: 191-192°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 and 1.05 (3H, t, J=7,4 Hz), 1,25-1,50 (2H, m), 1,75-of 1.90 (2H, m), 2,20-of 2.45 (2H, m), 2,50-3,00 (15H, m) to 3.78 (3H, s), 3,98-to 4.05 (2H, m), of 4.75 to 5.00 (2H, m), 6.94 per-7,05 (3H, m), 7,26-7,40 (1H, m), a 7.58-7.62 mm (2H, d, J=8,7 Hz) of 7.88-a 7.92 (2H, m).

Example 122

Obtaining 2-(4-methylpiperazin-1-yl)ethyl 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionate dihydrochloride

1-(2-Hydroxyethyl)-4-methylpiperazine (199 mg, 1.38 mmol), dicyclohexylcarbodiimide (310 mg, of 1.50 mmol) and 4-dimethylaminopyridine (168 mg, 1.38 mmol) was added to a solution of 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionic acid (500 mg, 1.25 mmol) in DMF (10 ml) and stirred over night at room temperature. Water was added to the reaction mixture, the mixture was extracted with dichloromethane and washed with water and then dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (ethyl acetate→dichloro methane:methanol=10:1). The residue was dissolved in ethyl acetate and 4N solution of hydrogen chloride in ethyl acetate was added and stirred. The mixture was concentrated to dryness under reduced pressure to obtain a pale yellow powder of 2-(4-methyl piperazine-1-yl)ethyl 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionate Digi�of rochloride (110 mg, yield: 17%).

Melting point:150-152°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 and 1.05 (3H, t, J=7,4 Hz), 1,69-of 1.88 (2H, m), 2,78 (3H, s), 2,87-of 3.04 (2H, m), 3,10-of 3.60 (10H, m), with a score of 3.77 (3H, s), 4,01-of 4.11 (2H, t, J=6.8 Hz), 4,27-of 4.44 (2H, m), 4,67-4,94 (2H, m), 6,76-to 7.09 (3H, m)that made 7.16 interest is 7.33 (1H, m), 7,58-7,63 (2H, d, J=8,8 Hz) of 8.07 (1H, s).

Example 123

Receiving S-(2-dimethylaminoethyl) 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]thiopropionate hydrochloride

The above compound was obtained in the same manner as described in example 122 using the appropriate starting material.

Melting point: 50-52°C

¹H-NMR (DMSO-d₆) δ MD: 0,97-1,03 (3H, t, J=7,4 Hz), 1,65-of 1.88 (2H, m), 2,68 (3H, s) to 2.70 (3H, s), 2,93 is 3.10 (2H, m), 3,11-of 3.29 (4H, m) to 3.76 (3H, s), 4,04 of 4.09 (2H, t, J=6.6 Hz), 4,68-4,94 (2H, m), 6,90-7,06 (3H, m), 7,26-7,31 (1H, m), 7,61-of 7.64 (2H, d, J=8,7 Hz), 8,00 (1H, s), 10,41-10,92 (1H, br.).

Example 124

Obtaining 1-(2-bromacil)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 17 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: 1,09 were 1.15 (3H, t, J=7,4 Hz), 1,82-of 2.03 (2H, m), 3,67-and 3.72 (2H, t, J=6.8 Hz), 3,84 (3H, s), 4,01 is 4.07 (2H, t, J=6.8 Hz), 4,79 is 4.85 (2H, t, J=6.8 Hz), to 6.88-7,06 (4H, m), 7,53 (1H, s), 7,58-7,63 (2H, m).

Example 125

Obtain methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinoline-yl]ethylsulfanyl}propionate

1-(2-Chloroethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-he (3.5 g, 8,98 mmol), methyl 3-mercaptopropionate (1.19 g, for 9.88 mmol) and sodium iodide (1,48 g, for 9.88 mmol) was added to DMF (30 ml) and stirred at 80°C for 5 hours. Water and ethyl acetate were added to the reaction mixture followed by separation of the mixture. The thus obtained organic layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane). The purified product was concentrated to dryness under reduced pressure to obtain a pale yellow powder of methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate (3.2 g, yield: 75%).

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 and 1.05 (3H, t, J=7,4 Hz), 2.65 or the 2.80 (2H, m), 2,54 is 2.60 (2H, t, J=7,2 Hz), 2,70 is 2.76 (2H, t, J=7,2 Hz), 2,88-of 2.93 (2H, t, J=6,9 Hz) to 3.56 (3H, s) to 3.78 (3H, s), 4,03 of 4.09 (2H, t, J=6.6 Hz), to 4.68-4.74 in (2H, t, J=6.9 Hz), of 6.85-to 7.08 (3H, m), the 7.25-is 7.30 (1H, m), 7,52-7,67 (2H, m), 8,06 (1H, s).

Example 126

Obtain 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionic acid

The lithium hydroxide monohydrate (31 mg, 0.74 mmol) and water (5 ml) was added to a solution of methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate (175 mg, of 0.37 mmol) in acetonitrile (10 ml) and the mixture shuffle�Wali at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate, and then 2N hydrochloric acid was added to the aqueous layer to acidify the mixture. The resulting insoluble substance was separated, washed with water and then dried to give a white powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionic acid (140 mg, yield: 82%).

¹H-NMR (DMSO-d₆) δ MD: 0,96-to 1.02 (3H, t, J=7,4 Hz), 1,70-1,90 (2H, m), 2,42 was 2.47 (2H, t, J=7.0 Hz), 2,64-to 2.70 (2H, t, J=7.0 Hz), 2,85-2,90 (2H, t, J=6.8 Hz), 3,74 (3H, s), 3,99-of 4.04 (2H, t, J=6.6 Hz), a 4.65 at 4.70 (2H, t, J=6.8 Hz), 6,91-7,02 (3H, m), 7,20-7,26 (1H, m), 7,55 and 7.60 (2H, m), 8,01 (1H, s) to 11.35-12.84 per (1H, br.).

Example 127

Obtain 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]econsultancy}propionic acid

3-{2-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionic acid (2,26 g, to 4.92 mmol) was dissolved in a mixture solvent of dichloromethane (100 ml) and methanol (20 ml), m-chlormadinone acid (mCPBA, purity:70%, 2.55 g, 10,33 mmol) was added to the solution and the mixture is then stirred at room temperature for 1 hour. The obtained reaction mixture was cooled with ice. Aqueous saturated solution of sodium hydrosulfite (50 ml) was added to the reaction mixture, followed by extraction with dichloromethane. The thus obtained organic layer was washed with water and then concentrated p�and reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=100:0→100:10). The purified product was concentrated under reduced pressure and subjected to recrystallization from a mixture of ethyl acetate-n-hexaneobtaining a pale yellow powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]econsultancy}propionic acid (2.2 g, yield: 91%).

¹H-NMR (DMSO-d₆) δ MD: 0,97-1,03 (3H, t, J=7,4 Hz), 1,73-of 1.96 (2H, m), 2,64-to 2.70 (2H, t, J=7,7 Hz), 3,37-of 3.43 (2H, t, J=7,7 Hz), 3,66-and 3.72 (2H, t, J=6,7 Hz), with a score of 3.77 (3H, s), 4,05-of 4.11 (2H, t, J=6.8 Hz), 4,94-4,99 (2H, t, J=6,7 Hz), 6,93-7,06 (3H, m), 7,27-is 7.30 (1H, m), members, 7.59-7,63 (2H, m), 8,02 (1H, s).

Example 128

Obtain methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]econsultancy}propionate

The above compound was obtained in the same manner as that described in example 127, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, t, J=7,4 Hz), 1,84-of 2.03 (2H, m), 2,84-2,89 (2H, t, J=7.0 Hz), 3,27-of 3.33 (2H, t, J=7.0 Hz), 3,51 is 3.57 (2H, t, J=6.9 Hz), 3,70 (3H, s), 3,83 (3H, s), 4,05 of 4.09 (2H, t, J=6.8 Hz), 4,95 to 5.00 (2H, t, J=6.9 Hz), 6,86-6,94 (3H, m), 7,01-to 7.08 (1H, m), 7,58-of 7.64 (2H, m), with 7.66 (1H, s).

Example 129

Getting 5-fluoro-1-[2-(3-hydroxypropanesulfonic)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 125 using suitable�sponding to the source material.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, t, J=7,4 Hz), 1,60-1,75 (2H, m), 1,84-of 2.03 (2H, m), 2,40-2,60 (2H, m), 2,84-2,89 (2H, m), 3,60 of 3.75 (2H, m), 3,70 (3H, s), 4,05 of 4.09 (2H, t, J=6.8 Hz), 4,62-of 4.80 (2H, m), 6,86-6,94 (3H, m), 7,01-to 7.08 (1H, m), 7,58-of 7.64 (2H, m), with 7.66 (1H, s).

Example 130

Getting 5-fluoro-1-[2-(3-hydroxypropan-1-sulfonyl)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as that described in example 127, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 0,97-1,03 (3H, t, J=7,4 Hz), 1,66-to 1.94 (4H, m), 3,38-of 3.53 (2H, m), 3,56-of 3.71 (2H, m), with a score of 3.77 (3H, s), 4.03 us-4,14 (4H, m), 4,67-at 4.70 (1H, t, J=5.1 Hz), 4,93-4,99 (2H, t, J=6,7 Hz), 6,93-7,06 (3H, m), 7,26 is 7.33 (1H, m), members, 7.59-7.62 mm (2H, m), 8,01 (1H, s).

Example 131

Obtain 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]econsultancy}Propionaldehyde

o-Iodoxybenzoic acid (IBX, 1.9 g, 6,78 mmol) was added to a solution of 5-fluoro-1-[2-(3-hydroxypropan-1-sulfonyl)ethyl]-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (2.7 g, 5,65 mmol) in dimethyl sulfoxide (DMSO) (3 ml) and the mixture was stirred over night at room temperature. Water and ethyl acetate were added to the reaction mixture. Further, nerastvorimaya substance was filtered and then the filtrate was separated. The thus obtained organic layer was washed with water and concentrated under reduced pressure. The residue PTS�kept separated by column chromatography on silica gel ( n-hexane:ethyl acetate=2:1→0:1). The purified material was concentrated to dryness under reduced pressure to give a white powder of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]econsultancy}Propionaldehyde (1.8 g, yield: 67%).

¹H-NMR (DMSO-d₆) δ MD: 0,97-1,03 (3H, t, J=7,4 Hz), 1,82-of 2.03 (2H, m), 2,80-of 3.01 (2H, m), 3,45-of 3.50 (2H, m), 3,60-of 3.70 (2H, m) to 3.78 (3H, s), 4,03 of 4.09 (2H, t, J=6.8 Hz), 4,90-5,10 (2H, m), 6,93-7,06 (3H, m), 7,26-to 7.33 (1H, m), members, 7.59-7.62 mm (2H, m), 8,01 (1H, s), to 9.67 (1H, s).

Example 132

Obtaining 1-[2-(2-dimethylaminoethanol)ethyl]-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she hydrochloride

The above compound was obtained in the same manner as described in example 125 using the appropriate starting material.

Melting point: 93-95°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 and 1.05 (3H, t, J=7,4 Hz), 1,69-to 1.94 (2H, m), of 2.69 (3H, s), 2,71 (3H, s), 2,85-of 3.04 (4H, m), 3,11 -, or 3.28 (2H, m) to 3.76 (3H, s), 4.03 us-to 4.08 (2H, t, J=6.8 Hz), a 4.64-of 4.87 (2H, m), 6,73-to 7.09 (3H, m), 7,12-7,34 (1H, m), 7,63-7,67 (2H, d, J=8,8 Hz) to 8.14 (1H, s), 10,62-the 11.04 (1H, br.).

Example 133

Getting 5-fluoro-3-(4-methoxyphenyl)-1-{2-[3-(4-methylpiperazin-1-yl)-3-oxoprop-1-sulfonyl]ethyl}-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

Melting point: 85-88°C

¹H-NMR (DMSO-d ) δ MD: 0,97-1,03 (3H, t, J=7,4 Hz), 1,78-of 1.96 (2H, m), of 2.25 (3H, s), 2,29-of 2.45 (4H, m), 2,75 is 2.80 (2H, t, J=7,4 Hz), 3,30-of 3.50 (6H, m), 3,65-of 3.70 (2H, t, J=6,7 Hz), 4,05-of 4.11 (2H, t, J=6,7 Hz), 4,95 to 5.00 (2H, t, J=6,7 Hz), 6,91-7,06 (3H, m), 7,27-7,32 (1H, m), and 7.60-of 7.64 (2H, d, J=8,8 Hz), 8,03 (1H, s).

Example 134

Getting 5-fluoro-3-(4-methoxyphenyl)-1-{2-[3-(4-methylpiperazin-1-yl)propane-1-sulfonyl]ethyl}-8-propoxy-1H-quinolin-4-she dihydrochloride

Nmethylpiperazin (0,455 mg of 4.54 mmol) was added to a solution of 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]econsultancy}Propionaldehyde (1.8 g, with 3.79 mmol) in methanol (20 ml) under cooling with ice and then the resulting mixture was stirred at room temperature for 1 hour. Cyanoborohydride sodium (0,238 g, with 3.79 mmol) and acetic acid (2 ml) was added to the resulting mixture and stirred at room temperature for 3 hours. Water was added to the reaction mixture, then the mixture was subjected to extraction with ethyl acetate. The extract was washed with aqueous saturated sodium bicarbonate solution and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=100:0→10:1). The purified product was concentrated under reduced pressure and 4N solution of hydrogen chloride in ethyl acetate was added to ethylacetate solution residue. The resulting insoluble substance was separated by Poluchenie yellow powder of 5-fluoro-3-(4-methoxyphenyl)-1-{2-[3-(4-methylpiperazin-1-yl)propane-1-sulfonyl]ethyl}-8-propoxy-1H-quinolin-4-she dihydrochloride (360 mg, yield: 15%).

Melting point: 72-74°C

¹H-NMR (DMSO-d₆) δ MD: 0,98-of 1.04 (3H, t, J=7,4 Hz), 1,78-of 1.96 (2H, m), 2,12-2,34 (2H, m), the 2.80 (3H, s), 3.00 fee of 3.75 (14H, m), with a score of 3.77 (3H, s), 4,06 at 4.12 (2H, t, J=6,7 Hz), 4,98-of 5.03 (2H, t, J=6,4 Hz), 6.94 per amounted to 7.07 (3H, m), 7,28 is 7.33 (1H, m), 7,61-of 7.64 (2H, d, J=8,8 Hz), with 8.05 (1H, s).

Example 135

Obtaining 8-(2-benzyloxyethyl)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: a score of 3.77 (3H, s), 3,87 to 3.90 (2H, t, J=4.3 Hz), 4,35-of 4.38 (2H, t, J=4.3 Hz), 4,58 (2H, s), 6.80 per-7,00 (3H, m), 7,10-7,32 (6H, m), 7,54 is 7.57 (2H, m), 7,79-of 7.82 (1H, d, J=6.2 Hz), 11,49 (1H, d, J=5,2 Hz).

Example 136

Getting 5-fluoro-8-(2-hydroxyethoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-it

20% palladium Hydroxide/on charcoal (5.0 g) was added to an ethanol solution (50 ml) of 8-(2-benzyloxyethyl)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-she (6.3 g, 15.0 mmol) followed by substitution of hydrogen. The mixture was stirred at room temperature for 4 hours. After the reaction, the catalyst was removed and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=100:0→20:1). The purified material was concentrated to dryness under reduced pressure to obtain a pale yellow powder of 5-fluoro-8-(2-g�doxetaxel)-3-(4-methoxyphenyl)-1H-quinolin-4-she (5.2 g, yield: 99%).

¹H-NMR (DMSO-d₆) δ M. D.: a score of 3.77 (3H, s), 3,79-3,83 (2H, t, J=4.7 Hz), 4,12-of 4.16 (2H, t, J=4.7 Hz), 6,84-of 6.96 (3H, m), 7,12-up 7.17 (1H, m), 7,53 is 7.57 (2H, d, J=8,8 Hz), the 7.85 (1H, s).

Example 137

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]acetic acid

The above compound was obtained in the same manner as described in example 120, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 3.80 (3H, s) to 4.92 (2H, s), of 6.85-at 6.92 (3H, m), 7,11-made 7.16 interest (1H, m), 7,53 is 7.57 (2H, d, J=8,8 Hz), 7,80-of 7.82 (1H, d, J=6.2 Hz), 11,46-11,49 (1H, d, J=6.0 Hz), 13,10-13,30 (1H, br.).

Example 138

GettingNbutyl-2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

Light brown powder

¹H-NMR (DMSO-d₆) δ MD: 0,84-0,90 (7,2 Hz), of 1.10 to 1.60 (4H, m), 3,15-to 3.23 (2H, sq, J=6,5 Hz) to 3.76 (3H, s), of 4.66 (2H, s), 6,87-of 6.96 (3H, m), 7,11-made 7.16 interest (1H, m), 7,55-members, 7.59 (2H, d, J=8,5 Hz), 8,31 to 8.35 (1H, t, 5.8 Hz), 11,68 (1H, br.C).

Example 139

Obtain 2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]-N(2-morpholine-4-retil)acetamide

The above compound was obtained in the same manner as described in example 33, using appropriate source �the material.

Melting point: 180-182°C

¹H-NMR (DMSO-d₆) δ MD: 2,40-of 2.50 (2H, m), 3,10-3,14 (2H, m), of 4.45 (2H, s), or 3.28-was 3.54 (4H, m), of 3.75 (3H, s), 3,80-of 4.21 (4H, m), 6,84 is 6.95 (3H, m), 7,10-7,15 (1H, m), 7,51-7,54 (2H, d, J=8,8 Hz), 8,20-and 8.50 (1H, m).

Example 140

Obtain ethyl 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]butyrate

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: between 1.22 and 1.27 (3H, t, J=7,1 Hz), of 2.16 and 2.26 (2H, m), 2,54 at 2.59 (2H, t, J=6.6 Hz), of 3.81 (3H, s), 4,10-4,20 (4H, m), 6.75 to-6,94 (4H, m), 7,55-7,72 (2H, m), 7,72-the 7.75 (1H, d, J=6.1 Hz), 9,49 ones, 9.51 (1H, d, J=5,2 Hz).

Example 141

Obtaining 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]butyric acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 1,89-of 2.01 (2H, m), of 2.42 to 2.45 (2H, m), of 3.69 (3H, s), 4,05-4,10 (2H, t, J=6.1 Hz), 6,76-6,89 (3H, m), 7,02 amounted to 7.07 (1H, m), 7,45-7,49 (2H, d, J=8,5 Hz), 7,71-7,73 (1H, d, J=5.4 Hz), 11,21-at 11.23 (1H, d, J=4,9 Hz), 11,6 to 12.5 (1H, br.).

Example 142

GettingNbutyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]butylamide

The above compound was obtained in the same manner as described in example 33, using suitable� source materials.

White amorphous

¹H-NMR (DMSO-d₆) δ MD: 0,79 is 0.86 (3H, t, J=7,1 Hz), 1,15-of 1.40 (4H, m), 2.00 to-2,10 (2H, m), 2,29 of 2.35 (2H, t, J=7.3 Hz), 2,99 is 3.10 (2H, m) to 3.76 (3H, s), 4,10-is 4.15 (2H, t, J=6.2 Hz), 6,84 is 6.95 (3H, m), 7,10-made 7.16 interest (1H, m), 7,52 was 7.56 (2H, t, J=8,6 Hz), 7,70-a 7.85 (2H, m), 11,27 (1H, br.C).

Example 143

Obtaining 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-8 yloxy]-N(2-morpholine-4-retil)butylamide hydrochloride

The above compound was obtained in the same manner as described in example 33, using the appropriate starting material.

Melting point: 180-182°C

¹H-NMR (DMSO-d₆) δ MD: 2,02-of 2.07 (2H, m), 2,40 was 2.43 (2H, m), 2,94-about 3.26 (6H, m), or 3.28-was 3.54 (4H, m), of 3.75 (3H, s), 3,80-of 4.21 (4H, m), 6,84 is 6.95 (3H, m), 7,10-7,15 (1H, m), 7,51-7,54 (2H, d, J=8,8 Hz), 8,20-and 8.50 (1H, m), 10,60-11,10 (1H, br.).

Example 144

Obtain 3-[4-(2-benzyloxyethyl)phenyl]-5-fluoro-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 1, using appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: 1,03-of 1.09 (3H, t, J=7,4 Hz), and 1.80-of 1.91 (2H, m), 3,81 to 3.85 (2H, m), 4,03-of 4.08 (2H, t, J=6.6 Hz), 4,63 (2H, s) of 6.79-6,93 (4H, m), 7,30-value of 7, 37 (5H, m), 7,53 is 7.57 (2H, m), 7,69-7,72 (1H, d, J=6.1 Hz), 9,05 remaining 9.08 (1H, d, J=5.7 Hz).

Example 145

Getting 5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained that�them the same way, which is described in example 136 using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 1,06-of 1.09 (3H, t, J=7,4 Hz), 1,81-of 1.90 (2H, m), 3.70 to of 3.75 (2H, m), 3,99 is 4.03 (2H, m), of 4.09-to 4.14 (2H, t, J=6,4 Hz), 4.80 to-the 4.93 (1H, m), 6,86-6,97 (3H, m), 7,13-to 7.18 (1H, m), 7,53 is 7.57 (2H, d, J=8,7 Hz), 7,79-a 7.87 (1H, m), 11,0-11,5 (1H, m).

Example 146

Obtain ethyl [5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate

Ethyl [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate (4.0 g, 9.6 mmol) was dissolved in dichloromethane (20 ml). 1 M Solution trichromate boron in dichloromethane (35 ml, 35 mmol) was added dropwise to the prepared solution of the above compound at -10°C. After stirring at the same temperature for 2 hours water was added to the reaction mixture, followed by extraction with dichloromethane. The thus obtained organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=50:1→15:1). The purified product was concentrated to dryness under reduced pressure to obtain yellow powder [5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate (2.7 g, yield: 57%).

¹H-NMR (DMSO-d₆) δ MD: or = 0.97 (3H, t, J=7.3 Hz), of 1.19 (3H, t, J=7,1 Hz), 1,69-a 1.77 (2H, m), 3,95 (2H, t, J=6.6 Hz), 4,14 (2H, sq, J=7,1 Hz) of 5.29 (2H, s) 6,76 (2H, d, J=8,7 Hz), 6,97 (1H, DD, J=9,0 Hz, 11.7 Hz), 7,21 (1H, DD, J=4.5 Hz, 9,0 Hz), 7,45 (H, d, J=8,7 Hz), 7,95 (1H, s), 9,41 (1H, s).

Example 147

Obtain [5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) ∆ MD is 0.98 (3H, t, J=7,4 Hz), 1,73-of 1.82 (2H, m), 3,95 (2H, t, J=6.6 Hz), to 5.21 (2H, s) 6,76 (2H, d, J=8,7 Hz) of 6.96 (1H, DD, J=9,0 Hz, 11.6 Hz), 7,20 (1H, DD, J=4.5 Hz, 9,0 Hz), USD 7.45 (2H, d, J=8,7 Hz), to 7.95 (1H, s), of 9.40 (1H, s), 12,50 (1H, br.C).

Example 148

Obtain 2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(2-morpholine-4-retil)acetamide

4-(2-Aminoethyl)morpholine (184 mg, 1.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC, 295 mg, 1.54 mmol) and 1-hydroxy-benzotriazole (HOBT, 215 mg, 1.41 mmol) was added to a solution of [5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid (500 mg, of 1.34 mmol) in DMF (7 ml) and then the mixture was stirred at room temperature for 23 hours. Water and triethylamine were added to the reaction mixture to alkalize the reaction mixture, followed by extraction with ethyl acetate. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by column chromatography�her on silica gel (dichloro methane:methanol=30:1→10:1). The purified product was concentrated under reduced pressure and the residue recrystallized from ethyl acetate to give a white powder of 2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(2-morpholine-4-retil)acetamide (157 mg, yield: 24%).

¹H-NMR (DMSO-d₆) δ MD: or 0.94 (3H, t, J=7.3 Hz), 1,70 is 1.78 (2H, m), 2,29-of 2.33 (6H, m), 3,17 (2H, sq, J=6.3 Hz), 3,44-3,52 (4H, m), 3,92 (2H, t, J=6.8 Hz), 5,12 (2H, s), the 6.75 (2H, d, J=8,7 Hz) 6,94 (1H, DD, J=8.9 Hz, the 11.6 Hz), made 7.16 interest (1H, DD, J=4.5 Hz, 9,0 Hz), 7,44 (2H, d, J=8.6 Hz), of 7.83 (1H, s), 7,91 (1H, t, J=5.4 Hz), 9,50 (1H, s).

Example 149

Obtain ethyl (4-{5-fluoro-1-[(2-morpholine-4-iletileri)methyl]-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl}phenoxy)acetate

Potassium carbonate (129 mg, 0.93 mmol) and ethylbromoacetate (114 mg, of 0.68 mmol) was added to a solution of 2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N(2-morpholine-4-retil)acetamide (300 mg, of 0.62 mmol) in DMF (4 ml) followed by stirring at room temperature for 87 hours. Water and ethyl acetate were added to the reaction mixture and then the reaction mixture was subjected to separation. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=50:1→>20:1). The purified product was concentrated under reduced� pressure to obtain a pale yellow oily substance ethyl [(4-{5-fluoro-1-[(2-morpholine-4-iletileri)methyl]-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl}phenoxy)acetate (306 mg, yield: 87%).

¹H-NMR (CDCl₃) δ MD: to 1.02 (3H, t, J=7.3 Hz), at 1.30 (3H, t, J=7,1 Hz), 1,79-of 1.88 (2H, m), 2,30 was 2.43 (6H, m) a 3.35 (2H, sq, J=6.0 Hz), 3,48-3,52 (4H, m), of 3.91 (2H, t, J=6.9 Hz), to 4.26 (2H, sq, J=7,1 Hz), 4,59 (2H, s), 5,00 (2H, s), 6,76-of 6.96 (5H, m), value of 7, 37 (1H, s), 7,51 (2H, d, J=8,8 Hz).

Example 150

Obtaining 2-(4-{5-fluoro-1-[(2-morpholine-4-iletileri)methyl]-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl}phenoxy)acetamide

Ethyl (4-{5-fluoro-1-[(2-morpholine-4-yl-ethylcarbamate)methyl]-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl}phenoxy)acetate (300 mg) was added to a 7N solution of ammonia in methanol (15 ml) and the mixture is then stirred at 70°C for 43 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=50:1→9:1→ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure and the residue recrystallized from a mixture of ethyl acetate-n-hexaneobtaining a pale yellow powder of 2-(4-{5-fluoro-1-[(2-morpholine-4-iletileri)methyl]-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl}phenoxy)acetamide (100 mg, yield: 35%).

¹H-NMR (DMSO-d₆) δ M. D.: of 0.95 (3H, t, J=7.3 Hz), 1,72 at 1.81 (2H, m), 2,32-2,34 (6H, m), of 3.18 (2H, sq, J=6,5 Hz), 3,50-was 3.54 (4H, m), 3,94 (2H, t, J=6.8 Hz), 4,43 (2H, s), of 5.14 (2H, s), at 6.92-7,00 (3H, m), of 7.19 (1H, DD, J=4.5 Hz, 9,0 Hz), 7,39 (1H, s), 7,53 (1H, s), members, 7.59 (2H, d, J=8,8 Hz), 7,91-of 7.93 (2H, br.C).

Example 151

Obtain ethyl (5-fluoro-4-oxo-8-propoxy-3-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-quinolin-1-yl)acetate

The above compound was obtained in the same manner as described in example 149, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.05 (3H, t, J=7.3 Hz), of 1.27 (3H, t, J=7,1 Hz), 1,53-of 1.74 (6H, m), 1.80 to to 1.88 (2H, m), 3,50-3,60 (1H, m), 3,83-of 3.91 (2H, m), 3,95 (2H, t, J=6.8 Hz), 4,03-of 4.08 (1H, m), 4,16-to 4.28 (4H, m), 4.72 in (1H, the Shire.C) to 5.10 (2H, s), 6,84-7,00 (4H, m), 7,35 (1H, s), a 7.58 (2H, d, J=8,8 Hz).

Example 152

Getting ethyl {5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetate

2N Raster hydrochloric acid (6.3 ml) was added to a solution of ethyl (5-fluoro-4-oxo-8-propoxy-3-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-quinolin-1-yl)acetate (840 mg, 1,59 mmol) in ethanol (20 ml) and stirred at 50°C for 2 hours. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. Ethyl acetate and water were added to the residue, followed by separation of the mixture. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure to obtain BL�bottom-yellow oily substance ethyl {5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetate (627 mg, yield: 89%).

¹H-NMR (CDCl₃) δ M. D.: of 1.05 (3H, t, J=7.3 Hz), of 1.27 (3H, t, J=7,1 Hz), 1,79-of 1.88 (3H, m), 3,92-of 3.98 (4H, m), 4.08 interest at 4.12 (2H, m), a 4.24 (2H, sq, J=7,1 Hz) to 5.10 (2H, s), 6,84-7,00 (4H, m), 7,35 (1H, s), a 7.58 (2H, d, J=8,8 Hz).

Example 153

Receive {5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) ∆ MD is 0.98 (3H, t, J=7.3 Hz), 1,71 is 1.85 (2H, m), and 3.72 (2H, m), 3,93-of 4.02 (4H, m), of 4.87 (1H, br.C), with 5.22 (2H, s), 6,93-7,02 (3H, m), 7,22 (1H, DD, J=4.5 Hz, 9,0 Hz), EUR 7.57 (2H, d, J=8,8 Hz), 8,00 (1H, s), 12,50 (1H, br.C).

Example 154

Obtain 2-{5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}-N(2-morpholine-4-retil)acetamide

The above compound was obtained in the same manner as described in example 148 using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 0.95 (3H, t, J=7.3 Hz), 1,72-to 1.79 (2H, m), 2,30-to 2.40 (6H, m), of 3.18 (2H, sq, J=5,9 Hz), 3,50-of 3.53 (4H, m), 3,69-to 3.74 (2H, m), of 3.91 to 4.00 (4H, m), of 4.91 (1H, t, J=5.4 Hz), of 5.14 (2H, s), at 6.92-6,98 (3H, m), 7,18 (1H, DD, J=4.4 Hz, 9,0 Hz), EUR 7.57 (2H, d, J=8.6 Hz), 7,90-of 7.93 (2H, br.C).

Example 155

Obtain ethyl 4-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydro-quinolin-3-yl)phenoxy]butyrate

The above compound was obtained in the same SP�the FDS, described in example 1, using appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, t, J=7,4 Hz), 1,25-of 1.31 (3H, t, J=7,1 Hz), 1,87-of 1.98 (2H, m), 2,10-of 2.17 (2H, m), 2,51-of 2.57 (2H, t, J=7.3 Hz), 4,00-4,21 (6H, m), 6,83-6,93 (4H, m), 7,55-members, 7.59 (2H, d, J=8.4 Hz), 7,72-the 7.75 (1H, d, J=6.1 Hz), means 8.93 (1H, br.C).

Example 156

Obtaining 4-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)phenoxy]butyric acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 0.93 to 1.00 (3H, t, J=7,4 Hz), 1,69-of 1.91 (4H, m), 2,28-2,34 (2H, t, J=7.3 Hz), 3,89-3,94 (2H, t, J=6,4 Hz), 4,00-to 4.05 (2H, t, J=6,4 Hz), 6.67 cm-of 6.87 (3H, m), 7,03-to 7.08 (1H, m), 7,43-7,47 (2H, d, J=8,7 Hz), 7,71-7,73 (1H, d, J=6.3 Hz), 11,18-11,20 (1H, d, J=6.0 Hz), of 11.5 to 12.2 (1H, br.).

Example 157

GettingNbutyl-4-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)phenoxy]butylamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

White amorphous

¹H-NMR (DMSO-d₆) δ MD: 0,81-of 0.87 (3H, t, J=7.3 Hz), 1,01 for 1.08 (3H, t, J=7,4 Hz), measuring 1.20-1.40 (4H, m), of 1.80 and 1.95 (4H, m), 2,19-of 2.25 (2H, t, J=7,4 Hz), 3.00-which is 3.40 (2H, m), 3,93-of 3.99 (2H, t, J=6.3 Hz), 4,07 to 4.13 (2H, t, J=6,4 Hz), 6,84-6,93 (3H, m), 7,11-made 7.16 interest (1H, m), 7,51-7,54 (2H, d, J=8,5 Hz), 7,82 (2H, m), 11,24 (1H, br.C).

Example 158

Obtaining 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)phenoxy]acetic acid

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

¹H-NMR (DMSO-d₆) δ MD: 1,03-of 1.09 (3H, t, J=7,4 Hz), 1,78-of 1.92 (2H, m), of 4.09-to 4.14 (2H, t, J=6,4 Hz), 4,70 (2H, s), 6,86-6,97 (3H, m), 7,13-to 7.18 (1H, m), 7,51 was 7.56 (2H, m), 7,80-of 7.83 (1H, d, J=6.3 Hz), 11,27-of 11.29 (1H, d, J=6.0 Hz), 12,99 (1H, br.C).

Example 159

GettingNbutyl-2-[4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)phenoxy]acetamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

White powder

¹H-NMR (DMSO-d₆) δ MD: 0,83-of 0.88 (3H, t, J=7,2 Hz), and 1.02 for 1.08 (3H, t, J=7,4 Hz), 1,23-of 1.50 (4H, m), 1.80 to to 1.88 (2H, m), 3,08-3,16 (2H, m), 4.08 interest to 4.13 (2H, t, J=6,4 Hz), 4,47 (2H, s), of 6.85-6.97 in (3H, m), 7,12-up 7.17 (1H, m), 7,53 was 7.56 (2H, d, J=8,8 Hz), 7,80 (1H, s), 8,03-8,08 (1H, t, J=5,5 Hz), 11,24 (1H, br.C).

Example 160;

Obtaining 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)benzaldehyde

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7.3 Hz), of 1.86 to 2.00 (2H, m), of 4.12 (2H, t, J=6.6 Hz), of 6.85-6,98 (2H, m), 7,84-of 7.93 (5H, m), of 8.90 (1H, br.(C), of 10.02 (1H, s).

Example 161

Getting 5-fluoro-3-[4-(4-morpholine-4-reparacin-1-carbonyl)phenyl]-8-ProPak�and-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 106, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 1.01 (3H, t, J=7.3 Hz), 1,74-to 1.86 (2H, m), 2,32 of 2.35 (4H, m) to 2.59 (2H, t, J=5.4 Hz), 3,51-was 3.54 (4H, m), of 4.04 (2H, t, J=6,5 Hz), 4,50 (2H, d, J=4.5 Hz), of 4.66 (2H, d, J=5.4 Hz), with 5.22 (1H, br.C) of 6.99 (1H, DD, J=8.9 Hz, 11.6 Hz), 7,22-to 7.33 (3H, m), 7,61 (2H, d, J=8,2 Hz), compared to 7.97 (1H, s).

Example 162

Obtaining 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinoline-3-yl)-N(2-morpholine-4-retil)benzamide derivative

The above compound was obtained in the same manner as described in example 73, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7.3 Hz), 1,75-of 1.89 (2H, m), 2,38-of 2.50 (6H, m), 3,38 (2H, sq, J=6.3 Hz), 3,53-3,61 (4H, m), up 4.08 (2H, t, J=6,4 Hz), at 6.92 (1H, DD, J=8,7 Hz, 12.0 Hz), 7,15 (1H, DD, J=3,9 Hz and 8.8 Hz), 7,71 (2H, d, J=8,5 Hz), to 7.89 (2H, d, J=8,5 Hz), is 7.94 (1H, s) to 8.41 (1H, t, J=5,5 Hz), 11,46 (1H, br.C).

Example 163

Getting 5-fluoro-3-[4-(4-morpholine-4-reparacin-1-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 73, using the appropriate starting materials.

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7.3 Hz), 1,30-of 1.38 (2H, m), 1,75-of 1.89 (4H, m), 2.34 point-of 2.49 (4H, m), 2,79-3,02 (2H, m), 3,61-of 3.69 (6H, m), up 4.08 (2H, t, J=6,4 Hz), 4,42 (1H, br.C) at 6.92 (1H, DD, J=8,8 Hz, 12.0 Hz), 7,15 (1H, DD, J=3,9 Hz and 8.8 Hz), value of 7, 37 (2H, q, j =8,2 Hz), 7,67 (2H, d, J=8,2 Hz), 7,92 (1H, s), of 11.45 (1H, br.C).

Example 164

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbaldehyde

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: 1,10-of 1.16 (3H, t, J=7,4 Hz), of 1.86 to 2.00 (2H, m), of 3.86 (3H, s), 4,02 is 4.07 (2H, t, J=6,5 Hz), 6,72-6,91 (1H, m), at 6.92-7,05 (3H, m), 7,31-the 7.43 (2H, m), the 9.25 (1H, br.C) 9,77 (1H, s).

Example 165

Obtain methyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylic acid

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: 1,10-of 1.16 (3H, t, J=7,4 Hz), 1.85 to of 2.05 (2H, m), 3,70 (3H, s), 3,85 (3H, s), 4,10-is 4.15 (2H, t, J=6,5 Hz), 6,75 of 6.99 (4H, m), 7,12-7,22 (2H, m), 9,36 (1H, br.C).

Example 166

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylic acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: from 1.00 to 1.06 (3H, t, J=7,4 Hz), 1,69-of 1.92 (2H, m) to 3.76 (3H, s), 4,10-is 4.15 (2H, t, J=6,5 Hz), to 6.88-6.97 in (3H, m), 7,12-7.23 percent (3H, m), 10,78 (1H, br.C) 13,00-15,00 (1H, br.).

Example 167

Obtaining 2-hydroxyethyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbamide

Ethanolamine (10 ml) was added to methyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylic acid (3.2 g, 7,78 mmol) and stirred at 100°C for 3 hours. The mixture was cooled to room temperature and was purified by column chromatography on silica gel (dichloro methane:methanol=100:0→20:1). Treated material was concentrated to dryness under reduced pressure to obtain a pale yellow solid substance in the amorphous state 2-hydroxyethyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-urea (3.0 g, yield: 93%).

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 and 1.05 (3H, t, J=7,4 Hz), 1,69-of 1.95 (2H, m), 2,92 is 3.17 (4H, m) to 3.76 (3H, s), 4.08 interest to 4.13 (2H, t, J=6.6 Hz), 4,32-up 4.57 (1H, m), 6,86-6,93 (3H, m), 7,15-7,21 (3H, m), 8,13-of 8.33 (1H, m), written: 11.09 (1H, br.C).

Example 168

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide

Triphenylphosphine (2,47 g, 9.8 mmol) and carbon tetrachloride (1.4 g, 9.1 mmol) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-hydroxyethyl)amide (3.0 g, of 7.24 mmol) in THF (30 ml) and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and then water was added, followed extras�the Ktsia dichloromethane. The thus obtained organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=100:0→20:1). Treated material was concentrated to dryness under reduced pressure to give a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide (1.8 g, yield: 58%).

¹H-NMR (DMSO-d₆) δ MD: 0,99-of 1.04 (3H, t, J=7,4 Hz), 1,75-of 1.89 (2H, m), 3,20 to 3.30 (4H, m), of 3.75 (3H, s), 4.08 interest to 4.13 (2H, t, J=6.6 Hz), 6,86 is 6.95 (3H, m), made 7.16 interest-7,21 (3H, m), 8,64-of 8.69 (1H, t, J=5.4 Hz), 11,14 (1H, s).

Example 169

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-hydroxyethyl)methylamine

The above compound was obtained in the same manner as described in example 167 using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 100-1,10 (3H, m), 1,83 and 1.95 (2H, m), 3,42-was 3.54 (5H, m), 3,60-in 3.65 (2H, m), 3,80 (1,2 H, C), 3,82 (1,8 H, C), 3,99-4,00 (0,8 H, t, J=6.6 Hz), 4,06-4,12 (1,2 H, t, J=6.6 Hz), the 6.75-of 6.96 (4H, m), 7,32 of 7.45 (2H, m), 8,89 (0,6 H, br.C) 9,31 (0,4 H, br.C).

Example 170

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxymethyl-[2-(4-methylpiperazin-1-yl)ethyl]amide

Nmethylpiperazin (276 mg, to 2.76 mmol), sodium iodide (440 mg, 2.9 mmol) and�rbonate potassium (572 mg, to 4.14 mmol) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxy-(2-chloroethyl)amide (600 mg, 1.38 mmol) in DMF (8 ml) and the mixture was stirred over night at 80°C. the Mixture was cooled to room temperature and then water was added, followed by extraction with chloroform. The thus obtained organic layer was concentrated under reduced pressure and then the residue was purified by liquid chromatography at medium pressure (NH silica gel, dichloro methane:methanol=100:0→10:1). The purified product was concentrated under reduced pressure to give a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxymethyl-[2-(4-methylpiperazin-1-yl)ethyl]amide (100 mg, yield: 14%).

Melting point: 106-107°C

¹H-NMR (CDCl₃) δ MD: 1,10-of 1.16 (3H, t, J=7,4 Hz), 1,90-of 1.99 (2H, m), 2,21-2,80 (13H, m), or 3.28-a 3.35 (2H, m), 3,85 (3H, s), 4.08 interest-to 4.14 (2H, t, J=6,5 Hz), 6,25-6,50 (1H, br.C) of 6.79-7,05 (4H, m), 7,28-7,32 (2H, m), 9,77 to 10.1 (1H, br.).

Example 171

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxymethyl-[2-(morpholine-4-yl)ethyl]amide

The above compound was obtained in the same manner as described in example 170, using the appropriate starting material.

Melting point: 111-112°C

¹H-NMR (CDCl₃) δ MD: 1,10-of 1.16 (3H, t, J=7,4 Hz), 1,88 is 2.00 (2H, m), 2,17-of 2.25 (6H,m), 3,29-a 3.35 (2H, m), 3,54-3,58 (4H, �), 3,84 (3H, s), 4.08 interest-to 4.14 (2H, t, J=6,4 Hz), 6.35 mm-6,50 (1H, m), of 6.79-7,05 (4H, m), 7,28-7,34 (2H, m), to 9.96 (1H, s).

Example 172

Getting 5-fluoro-2-{[(2-hydroxyethyl)methylamino]methyl}-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 134 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: up to 1.07 and 1.13 (3H, t, J=7,4 Hz), 1,83-of 1.92 (2H, m) to 2.32 (3H, s), 2,61-to 2.65 (2H, t, J=5,5 Hz), 3.75 to of 3.80 (2H, m), 3,82 (3H, s), 4,04 at 4.12 (3H, m), 6,72-6,94 (4H, m), 7,13-up 7.17 (2H, m), 10,03 (1H, br.C).

Example 173

Getting 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-2-reparation-1-ylmethyl)-1H-quinolin-4-it

1-(2-Pyridyl)piperazine (551 mg, of 3.38 mmol) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carbaldehyde (800 mg, of 2.25 mmol) in 1,2-dichloromethane (20 ml) and stirred at room temperature for 1 hour. Triacetoxyborohydride sodium (670 mg, 3,16 mmol) was added to the resulting mixture and stirred at room temperature for 4 hours. Dichloro methane was added to the obtained reaction mixture, washed with water and then the mixture was dried over sodium sulfate. Then the solvent was removed under reduced pressure. The residue is then subjected to cleaning NH-separated by column chromatography on silica gel (dichloro methane:ethyl acetate=1:1). The solvent in�of alali under reduced pressure and the residue recrystallized from a mixture of ethyl acetate- n-hexaneto give a white powder of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-2-reparation-1-ylmethyl)-1H-quinolin-4-she (400 mg, yield: 35%).

Melting point: 211-212°C

¹H-NMR (CDCl₃) δ MD to 1.06 and 1.13 (3H, t, J=7,4 Hz), 1,84-to 1.93 (2H, m), 2,63-of 2.67 (4H, m), 3,50-in 3.65 (6H, m), 3.89 points (3H, s), 4,06-of 4.11 (2H, t, J=6.3 Hz), 6,93-6,68 (2H, m), 6,76-6,98 (4H, m), made 7.16 interest-7,20 (2H, d, J=8,8 Hz), 7,45 was 7.56 (1H, m), 8,18-8,21 (1H, m) of 10.0 to 10.2 (1H, br.C).

Example 174

Getting 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-2-(4-pyridin-4-reparation-1-ylmethyl)-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 210-211°C

¹H-NMR (CDCl₃) δ MD: 1,05-of 1.11 (3H, t, J=7,4 Hz), 1,81-of 1.95 (2H, m), 2,66-2,70 (4H, m), 3,38 was 3.42 (4H, m) to 3.56 (2H, s), 3,83 (3H, s), 4,06-of 4.11 (2H, t, J=6.3 Hz), 6,66 was 6.69 (2H, d, J=5.3 Hz), 6,76-6,97 (4H, m), 7,15-of 7.19 (2H, d, J=7.5 Hz), 8,28 of 8.30 (2H, d, J=5.3 Hz), 9,90 is 10.2 (1H, br.C).

Example 175

Getting 5-fluoro-3-(4-methoxyphenyl)-2-[4-(6-methylpyridine-2-yl)piperazine-1-ylmethyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 205-206°C

¹H-NMR (CDCl₃) δ MD: 1,06-of 1.12 (3H, t, J=7.3 Hz), 1.85 to to 1.93 (2H, m), 2,39 (3H, s), 2,62-of 2.64 (4H, m), 3,53 (2H, s), 3,55-of 3.70 (4H, m), 3,83 (3H, s), 4,05-4,10 (2H,t, J=6,4 Hz), 6,41-is 6.44 (1H, d, J=8.4 Hz), 6,50-a 6.53 (1H, d, J=7.3 Hz), the 6.75-of 6.96 (4H, m), made 7.16 interest-7,20 (2H, d, J=8,8 Hz), value of 7, 37-7,41 (1H, m), 10,2 (1H, s).

Example 176

Getting 5-fluoro-3-(4-methoxyphenyl)-2-[4-(2-methylpyridine-4-yl)piperazine-1-ylmethyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 205-207°C

¹H-NMR (CDCl3) δ MD: 1,05-of 1.11 (3H, t, J=7,4 Hz), 1,81-of 1.95 (2H, m), of 2.46 (3H, s), 2,60-2,70 (4H, m), 3.30 x is 3.40 (4H, m), was 3.54 (2H, s), 3,82 (3H, s), 4,05-4,10 (2H, t, J=6.3 Hz), 6,45-6,55 (2H, m), 6,74 is 6.95 (4H, m), 7,13-up 7.17 (2H, d, J=8,7 Hz), 8.17-a to 8.19 (1H, d, J=5,9 Hz), there is a 10.04 (1H, s).

Example 177

Getting 5-fluoro-3-(4-methoxyphenyl)-2-(4-methyl-[1,4]diazepam-1-ylmethyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 243-244°C

¹H-NMR (CDCl₃) δ MD: 1,13-of 1.20 (3H, t, J=7,4 Hz), 1,50-1,70 (2H, m), 2,30 is 2.60 (3H, m), 2.70 to-2,90 (6H, m), 3,40-of 3.77 (4H, m), 3,83 (3H, s), 4,11-of 4.16 (2H, t, J=6.3 Hz), 6,76-of 6.96 (4H, m), 7,08-7,12 (2H, d, J=8,7 Hz), 9,60 (1H, s).

Example 178

Getting 5-fluoro-3-(4-methoxyphenyl)-2-[(2-morpholine-4-ylethylamine)methyl]-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using� appropriate source material.

Melting point: 135-137°C

¹H-NMR (CDCl₃) δ MD: 1,11-of 1.17 (3H, t, J=7,4 Hz), 1,87-of 2.15 (3H, m), 2.39 and was 2.42 (4H, m), 2,46-2,51 (2H, t, J=5.7 Hz), 2,64-of 2.68 (2H, t, J=5.7 Hz), 3,65-to 3.68 (4H, t, J=4,6 Hz), 3,74 (2H, s), 3,83 (3H, s), 4,07 at 4.12 (2H, t, J=6.3 Hz), 6,74-of 6.96 (4H, m), made 7.16 interest-7,20 (2H, m), of 10.35 (1H, s).

Example 179

Getting 5-fluoro-3-(4-methoxyphenyl)-2-{[methyl-(2-morpholine-4-retil)amino]methyl}-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 127-128°C

¹H-NMR (CDCl3) δ MD: 1,10-of 1.17 (3H, t, J=7,4 Hz), of 1.86 to 2.00 (2H, m), 2,30 of 2.42 (7H, m), 2,46-to 2.52 (2H, m), 2,58-of 2.64 (2H, m), 3,52 (2H, s), 3,52-3,63 (4H, t, J=4,6 Hz), 3,83 (3H, s), 4.08 interest to 4.13 (2H, t, J=6.3 Hz), the 6.75-of 6.96 (4H, m), 7,13-to 7.18 (2H, d, J=8,7 Hz), 10,11 (1H, s).

Example 180

Obtaining 2-{[(2-chloroethyl)methylamino]methyl}-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 168, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 100-1,10 (3H, m), 1,83 and 1.95 (2H, m), and 2.26 (3H, s) of 2.64 (2H, m), 3,03 (2H, s), 3,48 2H, m), 3,82 (3H, s), 4.08 interest to 4.13 (2H, t, J=6.6 Hz), the 6.75-of 6.96 (4H, m), 7,32 of 7.45 (2H, m), 8,89 (0,6 H, br.C) 9,31 (0,4 H, br.C).

Example 181

Getting 5-fluoro-2-gidroximetil-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

A solution of methyl 5-�top-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-carboxylate (5.0 g, 13 mmol) in dichloromethane (30 ml) was cooled to -78°C and diisobutylaluminium (DIBAL-H, 1M in toluene solution, 30 ml) was added dropwise in a nitrogen atmosphere. Upon completion of the addition the mixture was stirred at the same temperature for 3 hours. The reaction mixture was warmed to room temperature and the 5N sodium hydroxide solution was added to the mixture, followed by extraction with dichloromethane. The thus obtained organic layer was washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=10:1). Treated material was concentrated to dryness under reduced pressure to obtain yellow solids in the amorphous state 5-fluoro-2-gidroximetil-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (4.8 g, yield: 85%).

¹H-NMR (CDCl₃) δ M. D.: the 1.04 and 1.10 (3H, t, J=7,4 Hz), 1,83-of 1.92 (2H, m), of 3.75 (3H, s), 4,02 is 4.07 (2H, t, J=6,5 Hz) to 4.39 (2H, s), the 4.67 (1H, br.C) 6,71-6,83 (4H, m), 6,95-6,98 (2H, m), 9,82 (1H, s).

Example 182

Getting 5-fluoro-3-(4-methoxyphenyl)-2-morpholine-4-ylmethyl-8 propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 175-176°C

¹H-NMR (DMSO-d₆) δ MD: 1,09 of 1.14 (3H, t, J=7,4 Hz),1,78-1,94 (2H, m), 2,32 was 2.47 (4H, m), 3,47 (2H, s), 3,55-to 3.68 (4H, m), with a score of 3.77 (3H, s), 4,12-of 4.16 (2H, t, J=6.2 Hz), of 6.79-7,00 (3H, m), 7,06-of 7.14 (2H, m), 7,15-the 7.25 (1H, m), 10,21 (1H, br.C).

Example 183

Getting 5-fluoro-3-(4-methoxyphenyl)-2-(4-methylpiperazin-1-ylmethyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 173, using the appropriate starting material.

Melting point: 204-205°C

¹H-NMR (CDCl₃) δ MD: 1,18-to 1.24 (3H, t, J=7,4 Hz), 1,86-of 2.08 (2H, m), was 2.31 (3H, s), 2,36-2,79 (8H, m), 3,49 (2H, s), 3,84 (3H, s), 4.08 interest to 4.13 (2H, t, J=6.2 Hz), 6,68-7,00 (4H, m), 7,11-7,22 (2H, m), 10,21 (1H, br.C).

Example 184

Obtaining 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-yl]butyric acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

Melting point: 154-156°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.99 (3H, t, J=7.3 Hz), 1.65 V is 1.71 (2H, m), 1,79-to 1.87 (2H, m), of 2.09 (2H, t, J=7,4 Hz), 2,57 (2H, t, J=7,0 Hz) to 3.76 (3H, s), of 4.13 (2H, t, J=6.6 Hz), 6,81-6,94 (3H, m), 7,06 (2H, d, J=8,7 Hz), of 7.14 (1H, DD, J=4.0 Hz and 8.8 Hz), 10,40 (1H, br.C).

Example 185

GettingN-butyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-yl]butylamide

The above compound was obtained in the same manner as described in example 33, ispolzuyutsya source materials.

Pale yellow powder (diethyl ether)

Melting point: 134-136°C

¹H-NMR (DMSO-d₆) δ M. D.: of 0.82 (3H, t, J=6,9 Hz), and 1.00 (3H, t, J=7.3 Hz), 1.19 and of 1.30 (4H, m), 1,64-of 1.70 (2H, m) of 1.84 (2H, sq, J=6,9 Hz), 1,98-of 2.03 (2H, m), 2,48-2,56 (2H, m), 2,94 of 2.99 (2H, m), of 3.75 (3H, s), 4,10 (2H, t, J=6,4 Hz), 6,81-6,93 (3H, m), 7,05-7,15 (3H, m), 7,82 (1H, t, J=5.0 Hz), representation stands at 10.97 (1H, br.C).

Example 186

Getting 5-fluoro-8-propoxy-3-pyrimidine-5-yl-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

Melting point: >250°C

¹H-NMR (DMSO-d₆) δ MD to 1.06 (3H, t, J=7,4 Hz), 1,75-2,00 (2H, m), 4,14 (2H, t, J=6,4 Hz), of 6.99 (1H, DD, J=8,8, and 12.0 Hz), 7.23 percent (1H, DD, J=3,9, 8,8 Hz), 8,12 (1H, s), remaining 9.08 (2H, s), 9,10 (1H, s), 11,68 (1H, s).

Example 187

Getting 5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

Melting point: 223-225°C

¹H-NMR (DMSO-d₆) δ MD to 1.06 (3H, t, J=7,4 Hz) of 1.75 and 1.95 (2H, m), of 3.87 (3H, s), 4,11 (2H, t, J=6,4 Hz), 6,90 (1H, DD, J=8,7, and 12.0 Hz), 7,13 (1H, DD, J=3,9, to 8.7 Hz), 7,95 (1H, s), 8,08 (1H, d, J=5.4 Hz), 8,37 (1H, s), 11,36 (1H, d, J=5.4 Hz).

Example 188

Obtaining di-tert-butyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ilmatila�veil

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7,4 Hz) to 1.36 (18H, s), 1.85 to of 2.05 (2H, m), 3,83 (3H, s) 4,07 (2H, t, J=6.6 Hz), 6.32 per (2H, d, J=13,0 Hz), 6,90-7,00 (3H, m), 7,07 (1H, DD, J=4,5, 9,0 Hz), 7,63 (2H, d, J=8.9 Hz), 7,79 (1H, s).

Example 189

Obtaining di-tert-butyl @3-(2,4-dichlorophenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7,4 Hz), and 1.37 (18H, s), 1.85 to of 2.05 (2H, m), up 4.08 (2H, t, J=6.6 Hz), between 6.30 (2H, d, J=12.6 Hz), of 6.99 (1H, DD, J=9,0, 10.7 Hz), 7,13 (1H, DD, J=4.4 and from 9.0 Hz), 7,27 (1H, DD, J=2,1, 8,3 Hz), value of 7, 37 (1H, d, J=8,3 Hz), 7,47 (1H, d, J=2.1 Hz), the 7.75 (1H, s).

Example 190

Obtaining di-tert-butyl 3-(2,4-dimethoxyphenyl)-8-ethoxy-5-fluoro-4-oxo-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: and 1.37 (18H, s) a 1.54 (3H, t, J=7,0 Hz) to 3.76 (3H, s), 3,83 (3H, s), 4,18 (2H, sq, J=7,0 Hz), 6,28 (2H, d, J=11.9 Hz), 6,50-of 6.60 (2H, m), 6,93 (1H, DD, J=9,0, to 10.9 Hz), 7,07 (1H, DD, J=4,5, 9,0 Hz), 7,34 (1H, d, J=9,0 Hz), 7,72 (1H, s).

Example 191

Obtaining di-tert-butyl 3-(4-atexit�Neal)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7.5 Hz), of 1.36 (18H, s) of 1.42 (3H, t, J=7.0 Hz), 1.85 to of 2.05 (2H, m), 4,00-4,15 (4H, m), 6.32 per (2H, d, J=13,0 Hz), 6.80 per-7,00 (3H, m), to 7.08 (1H, DD, J=4,5, 9,0 Hz), 7,61 (2H, t, J=8.9 Hz), 7,78 (1H, s).

Example 192

Obtaining di-tert-butyl 8-(cyclohexylethylamine)-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 1,02-1,90 (28H, m), 2,50-2,75 (1H, m), 2,78 (3H, s), 3,84 (3H, s), 5,97 (1H, DD, J=9,4, 10.7 Hz), 6.80 per-7,05 (3H, m), of 7.42 (1H, DD, J=5.1 m and 8.8 Hz), 7,51 (1H, DD, J=9,4, a 12.1 Hz), of 7.64 (2H, d, J=8,8 Hz), 7,71 (1H, s).

Example 193

Obtaining di-tert-butyl 5-fluoro-3-(2-fluoro-4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7.5 Hz), of 1.36 (18H, s), 1.85 to of 2.05 (2H, m), 3,82 (3H, s) 4,07 (2H, t, J=6.6 Hz), between 6.30 (2H, d, J=12.6 Hz), 6,60-of 6.80 (2H, m), of 6.96 (1H, DD, J=9,0, to 10.8 Hz), 7,10 (1H, DD, J=4,5, 9,0 Hz), 7,51 (1H, t, J=8.4 Hz), 7,79 (1H, s).

Example 194

Obtaining di-tert-butyl 8-cyclopropylmethyl�C-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 0,35-0,50 (2H, m), 0,60-0,75 (2H, m), 1,25-1,45 (19H, m), 3,83 (3H, s), 3,95 (2H, d, J=7,1 Hz), 6,40 (2H, d, J=13.1 per Hz) of 6.85-7,00 (3H, m) to 7.04 (1H, DD, J=4,6, 9,0 Hz), 7,63 (2H, d, J=8.9 Hz), 7,79 (1H, s).

Example 195

Obtaining di-tert-butyl 8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.36 (18H, s) a 1.55 (3H, t, J=7.0 Hz), 3,83 (3H, s), 4,19 (2H, sq, J=7,0 Hz), 6,33 (2H, d, J=12.8 Hz), 6,90-7,00 (3H, m), to 7.08 (1H, DD, J=4,5, 9,0 Hz), 7,63 (2H, d, J=8,8 Hz), of 7.77 (1H, s).

Example 196

Obtaining di-tert-butyl 8-cyclobutylmethyl-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.36 (18H, s), 1.85 to and 2.10 (4H, m), 2,15-of 2.30 (2H, m), of 2.85 to 3.00 (1H, m), 3,83 (3H, s) 4,07 (2H, d, J=7,0 Hz), between 6.30 (2H, d, J=13.2 Hz), 6,90-7,00 (3H, m), 7,07 (1H, DD, J=4,5, 9,0 Hz), 7,63 (2H, d, J=8.9 Hz), 7,79 (1H, s).

Example 197

Obtaining di-tert-butyl 5,6-debtor-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ileti�phosphate

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.12 (3H, t, J=7,4 Hz) to 1.36 (18H, s), 1,90-of 2.05 (2H, m), 3,83 (3H, s) 4,06 (2H, t, J=6.6 Hz), 6,28 (2H, d, J=13.2 Hz), 6.94 per (2H, d, J=8.9 Hz), 7,02 (1H, DD, J=6,8, an 11.6 Hz), a 7.62 (2H, d, J=8.9 Hz), 7,78 (1H, s).

Example 198

Obtaining di-tert-butyl 5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-8-propoxy-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.11 (3H, t, J=7.5 Hz), and 1.37 (18H, s), 1.85 to a 2.00 (2H, m), 3,93 (3H, s) 4,06 (2H, t, J=6.6 Hz), system 6.34 (2H, d, J=13.1 per Hz) 6,94 (1H, DD, J=9,0,, and 11.1 Hz), 7,06 (1H, DD, J=4,5, 9,0 Hz), 7,81 (1H, s), 8,01 (1H, s), to 8.38 (1H, s).

Example 199

Obtaining di-tert-butyl 5-fluoro-4-oxo-8-propoxy-3-pyrimidine-5-yl-4H-quinolin-1-elmerpost

The above compound was obtained in the same manner as described in example 23, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.13 (3H, t, J=7.5 Hz), of 1.36 (18H, s), 1,90-2,10 (2H, m), 4,10 (2H, t, J=6.6 Hz), 6,36 (2H, d, J=13.8 per Hz), 7,01 (1H, DD, J=9,0, to 10.9 Hz), made 7.16 interest (1H, DD, J=4,5, 9,0 Hz), 7,96 (1H, s), remaining 9.08 (2H, s), of 9.15 (1H, s).

Example 200

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-eletronorte

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: to 1.02 (3H, t, J=7,4 Hz), 1,75-of 1.90 (2H, m), with a score of 3.77 (3H, s) 4,07 (2H, t, J=6,5 Hz), a 6.26 (2H, d, J=11.2 Hz), of 6.96 (2H, d, J=8.9 Hz), 7,06 (1H, DD, J=9,1, the 11.6 Hz), to 7.33 (1H, DD, J=4.5 and 9.1 Hz), a 7.58 (2H, d, J=8.9 Hz), 8,00 (1H, s).

Example 201

Obtain [3-(2,4-dichlorophenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: the 1.04 (3H, t, J=7,4 Hz), and 1.80 and 1.95 (2H, m), 4,10 (2H, t, J=6,5 Hz), for 6.24 (2H, d, J=11.2 Hz), 7,13 (1H, DD, J=9,0, or 11.4 Hz), 7,40 (1H, DD, J=4,6, 9,0 Hz) of 7.42 (1H, d, J=8,2 Hz), 7,52 (1H, DD, J=2,1, 8,2 Hz), 7,69 (1H, d, J=2.1 Hz), compared to 7.97 (1H, s).

Example 202

Obtain [3-(2,4-dimethoxyphenyl)-8-ethoxy-5-fluoro-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: the 1.45 (3H, t, J=6.9 Hz), of 3.69 (3H, s), 3,80 (3H, s), 4,19 (2H, sq, J=6,9 Hz), 6,20 (2H, d, J=a 9.7 Hz), 6,56 (1H, DD, J=2,4, 8,2 Hz), 6,61 (1H, d, J=2.4 Hz), 7,07 (1H, DD, J=9,0, of 11.5 Hz), made 7.16 interest (1H, d, J=8,2 Hz), 7,35 (1H, DD, J=4,5, 9,0 Hz), 7,80 (1H, s).

Example 203

Obtain [3-(4-idoxifene�)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 1.05 (3H, t, J=7,4 Hz), and 1.35 (3H, t, J=7,0 Hz) of 1.75 and 1.95 (2H, m), 4,00-4,15 (4H, m), 6,28 (2H, d, J=11.2 Hz), of 6.96 (2H, d, J=8,8 Hz), to 7.08 (1H, DD, J=9,0, the 11.6 Hz), 7,35 (1H, DD, J=4,5, 9,0 Hz), members, 7.59 (2H, d, J=8,8 Hz), 8,03 (1H, s).

Example 204

Obtain [5-fluoro-3-(2-fluoro-4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: the 1.04 (3H, t, J=7,4 Hz) of 1.75 and 1.95 (2H, m), of 3.81 (3H, s), of 4.09 (2H, d, J=6,9 Hz), for 6.24 (2H, d, J=10,9 Hz), 6.75 to-7,00 (2H, m), 7,11 (1H, DD, J=9,0, or 11.4 Hz), 7.24 to 7,50 (2H, m), 7,95 (1H, s).

Example 205

Obtaining [8 cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ m d: 0.35 to 0.45 (2H, m), 0,55-0,70 (2H, m), 1,30-1,45 (1H, m), with 3.79 (3H, s), 3,99 (2H, d, J=7,2 Hz), 6,36 (2H, d, J=11.2 Hz), 6,98 (2H, d, J=8.9 Hz), 7,07 (1H, DD, J=9,0, the 11.6 Hz), to 7.33 (1H, DD, J=4,5, 9,0 Hz) and 7.60 (2H, d, J=8.9 Hz), 8,03 (1H, s).

Example 206

Obtaining [8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-hee�Olin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: the 1.45 (3H, t, J=6.9 Hz), with 3.79 (3H, s), 4,19 (2H, sq, J=6,9 Hz), 6,28 (2H, d, J=10.8 Hz), 6,98 (2H, d, J=8.9 Hz), to 7.08 (1H, DD, J=9,0, the 11.6 Hz), of 7.36 (1H, DD, J=4,5, 9,0 Hz) and 7.60 (2H, d, J=8.9 Hz), 8,03 (1H, s).

Example 207

Obtaining [8 cyclobutylmethyl-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 1,60-of 2.20 (6H, m), 2.70 m and 2.95 (1H, m), with 3.79 (3H, s), 4,11 (2H, d, J=6,9 Hz), the 6.25 (2H, d, J=11.5 Hz), 6,97 (2H, d, J=8.9 Hz), to 7.08 (1H, DD, J=9,0, of 11.5 Hz), 7,35 (1H, DD, J=4.5 and 9 Hz), and 7.60 (2H, d, J=8.9 Hz), 8,02 (1H, s).

Example 208

Obtaining [5,6-debtor-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: the 1.04 (3H, t, J=7,4 Hz), actually 1,705 is 2.00 (2H, m) to 3.78 (3H, s) of 4.12 (2H, t, J=6,5 Hz), the 6.25 (2H, d, J=11.5 Hz), 6,98 (2H, d, J=8,8 Hz), 7.50 to 7,70 (3H, m), of 8.07 (1H, s).

Example 209

Obtaining [8-(cyclohexylethylamine)-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monoposto�and

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 0.75 to 2.00 (10H, m), with 3.79 (3H, s), 3,83 (3H, s), 3,90-4,60 (1H, m), of 5.85 (1H, d, J=9.5 Hz), 6,48 (1H, d, J=9.5 Hz), 7,00 (2H, d, J=8.9 Hz), to 7.33 (1H, DD, J=8,6, the 11.6 Hz), 7,52 (2H, d, J=8.9 Hz), of 8.16 (1H, DD, J=3.2 and 8.6 Hz), 8,22 (1H, s).

Example 210

Obtain [5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: the 1.04 (3H, t, J=7,4 Hz) of 1.75 and 1.95 (2H, m), 3,80-4,15 (5H, m), 6,29 (2H, d, J=10.5 Hz), 7,07 (1H, DD, J=9,0, the 11.6 Hz), 7,32 (1H, DD, J=4,5, 9,0 Hz), a 7.87 (1H, s), 8,31 (1H, s), 8,32 (1H, s).

Example 211

Preparation of (5-fluoro-4-oxo-8-propoxy-3-pyrimidine-5-yl-4H-quinolin-1-ylmethyl)monophosphate

The above compound was obtained in the same manner as described in example 24, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 1.05 (3H, t, J=6.6 Hz), of 1.75 and 1.95 (2H, m), 4,11 (2H, t, J=6,5 Hz), 6.32 per (2H, d, J=12.0 Hz), up 7.17 (1H, DD, J=9,1, or 11.4 Hz), the 7.43 (1H, DD, J=4.5 and 9.1 Hz), of 8.39 (1H, s), 9,10 (2H, s), of 9.13 (1H, s).

Example 212

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate dynatree�Oh salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 204-206°C

¹H-NMR (D₂O) δ MD: or = 0.97 (3H, t, J=7,4 Hz), 1,75 is 1.85 (2H, m) to 3.76 (3H, s), of 4.00 (2H, t, J=6,7 Hz), 6,04 (2H, d, J=9.1 Hz), 6,90-7,05 (3H, m), 7,18 (1H, DD, J=4,6, or 9.1 Hz), of 7.42 (2H, d, J=8,7 Hz) to 8.14 (1H, s).

Example 213

Obtain [3-(2,4-dichlorophenyl)-5-fluoro-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt

Melting point: 208-210°C

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

¹H-NMR (D₂O) δ M. D.: is 0.96 (3H, t, J=7.5 Hz), of 1.75 and 1.95 (2H, m) 4,07 (2H, t, J=6,7 Hz), 6,08 (2H, d, J=8,8 Hz), 7,05 (1H, DD, J=9,1, 12.2 Hz), 7,30 (1H, DD, J=4,7, to 9.1 Hz), 7,32-7,40 (2H, m), of 7.50 and 7.55 (1H, m), 8,21 (1H, s).

Example 214

Obtain [3-(2,4-dimethoxyphenyl)-8-ethoxy-5-fluoro-4-oxo-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 205-207°C

¹H-NMR (D₂O) δ M. D.: of 1.40 (3H, t, J=7.0 Hz), 3,66 (3H, s), with a score of 3.77 (3H, s), of 4.16 (2H, sq, J=7,0 Hz), 6,03 (2H, d, J=8,2 Hz), 6,55-of 6.65 (2H, m), 7,02 (1H, DD, J=9,0, to 12.3 Hz), up 7.17 (1H, d, J=9,0 Hz), 7,28 (1H, DD, J=4,7, 9,0 Hz), 8,09 (1H, s).

Example 215

Obtain [5-fluoro-3-(4-ethoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 200-202°C

¹H-NMR (D₂O) δ M. D.: of 0.93 (3H, t, J=7.5 Hz), of 1.27 (3H, t, J=7.0 Hz), 1,70-1,90 (2H, m), 3,95-4,10 (4H, m), 6,03 (2H, d, J=8.9 Hz), 6,90-7,05 (3H, m), 7,20 (1H, DD, J=4,6, or 9.1 Hz), 7,40 (2H, d, J=8,7 Hz), 8,15 (1H, C).

Example 216

Obtain [5-fluoro-3-(2-fluoro-4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 208-210°C

¹H-NMR (D₂O) δ MD: 0,57 (3H, t, J=7,4 Hz), 1,70 is 1.85 (2H, m), of 3.69 (3H, s), with 3.96 (2H, d, J=6,7 Hz), 5,98 (2H, d, J=8.9 Hz), 6,65 to 6.75 (2H, m), to 6.95 (1H, DD, J=8,4, 12.2 Hz), 7,15-is 7.30 (2H, m), 8,12 (1H, s).

Example 217

Obtaining [8 cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 202-204°C

¹H-NMR (D₂O) δ MD: 0,20-0,35 (2H, m), 0,40-0,60 (2H, m) of 1.20 and 1.45 (1H, m), 3,73 (3H, s), 3,90 (2, d, J=7,3 Hz) 6,09 (2H, d, J=9,2 Hz), 6.80 per-7,05 (3H, m), 7,21 (1H, DD, J=4,7, 9,0 Hz), 7,40 (2H, d, J=8,8 Hz), 8,15 (1H, s).

Example 218

Obtaining [8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 206-208°C

¹H-NMR (D₂O) δ M. D.: of 1.38 (3H, t, J=7.0 Hz), 3,73 (3H, s), 4,10 (2H, sq, J=7,0 Hz), 6,01 (2H, d, J=8.4 Hz), 6,90-7,05 (3H, m), of 7.19 (1H, DD, J=4,6, and 8.9 Hz), 7,40 (2H, d, J=8,8 Hz), 8,13 (1H, s).

Example 219

Obtaining [8 cyclobutylmethyl-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 205-207°C

¹H-NMR (D₂O) δ MD: 1,63-and 2.10 (6H, m), 2,75-3,00 (1H, m), and 3.72 (3H, s) 4,00 (2H, d, J=7,2 Hz), 5,99 (2H, d, J=9.8 Hz), 6,90-7,05 (3H, m), up 7.17 (1H, DD, J=4,7, to 9.1 Hz), 7,40 (2H, d, J=8,7 Hz) to 8.14 (1H, s).

Example 220

Obtaining [5,6-debtor-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Those�the temperature of the melting point: 205-206°C

¹H-NMR (D₂O) δ MD: or 0.94 (3H, d, J=7.5 Hz), 1,70-of 1.95 (2H, m), 3,73 (3H, s) 4,01 (2H, t, J=6,5 Hz), is 6.02 (2H, d, J=9.1 Hz), 6,90-of 7.50 (5H, m), 8,16 (1H, s).

Example 221

Obtaining [8-(cyclohexylethylamine)-5-fluoro-3-(4-methoxyphenyl)-4-oxo-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 196-198°C

¹H-NMR (D₂O) δ MD: 0,60-1,75 (10H, m), 2,40-2,60 (1H, m), of 2.66 (3H, s) 3,73 (3H, s), by 5.80 (1H, DD, J=7,7, and 7.8 Hz), 6.80 per-7,05 (4H, m), 7,35 and 7.55 (3H, m), 8,18 (1H, s).

Example 222

Obtain [5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 212-214°C

¹H-NMR (D₂O) δ MD: or 0.94 (3H, d, J=7.5 Hz), 1,70-1,90 (2H, m), with 3.79 (3H, s), 3,93 (2H, t, J=6,7 Hz), 5,99 (2H, d, J=9.1 Hz), at 6.92 (1H, DD, J=9,0, to 12.3 Hz), to 7.08 (1H, DD, J=4,7, 9,0 Hz), of 7.86 (1H, s), 8,02 (1H, s), of 8.30 (1H, s).

Example 223

Preparation of (5-fluoro-4-oxo-8-propoxy-3-pyrimidine-5-yl-4H-quinolin-1-ylmethyl)monophosphate disodium salt

The above compound was obtained in the same manner as described in example 25 using with�testwuide the source material.

Melting point: 205-207°C

¹H-NMR (D₂O) δ M. D.: is 0.96 (3H, d, J=7,4 Hz), 1,70-of 1.95 (2H, m) 4,06 (2H, t, J=6,7 Hz), 6,10 (2H, d, J=9.6 Hz), 7,05 (1H, DD, J=8,9, a 12.1 Hz), 7,29 (1H, DD, J=4.4 and 8.9 Hz), to 8.41 (1H, s), quick 8.94 (2H, s), 8,96 (1H, s).

Example 224

Obtain ethyl 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-pyrrolidin-1-yl-4H-quinolin-1-yl]butyrate

The above compound was obtained in the same manner as described in example 31, using the appropriate starting materials.

¹H-NMR (CDCl₃) δ MD: 1,23-of 1.29 (3H, t, J=7,1 Hz), 1,70 is 1.78 (2H, m), 1,91-of 2.15 (6H, m), 2,52 is 2.87 (2H, m), 3,14-3,44 (2H, m), 4,00-of 4.08 (2H, sq, J=6.1 Hz), 4,59-a 4.64 (2H, t, J=6.9 Hz), 6,87-of 7.03 (3H, m), 7,14-value of 7, 37 (1H, m), 7,51 (1H, s), 7,55-7,73 (2H, m).

Example 225

Obtaining 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-pyrrolidin-1-yl-4H-quinolin-1-yl]butyric acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: 1,63-of 1.81 (2H, m), 1,87 to 2.14 (6H, m), 2,57-of 2.81 (2H, m), 3,14-is 3.39 (2H, m), of 3.81 (3H, s), 4,61-of 4.66 (2H, t, J=6.8 Hz), 6,84-7,01 (3H, m), the 7.25-is 7.30 (1H, m), 7,52-7,63 (3H, m).

Example 226

GettingNbutyl-4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-pyrrolidin-1-yl-4H-quinolin-1-yl]butylamide

The above compound was obtained in the same manner as described in example 33, using appropriate �similar materials.

Brown amorphous

¹H-NMR (CDCl₃) δ MD: 0,82-of 0.88 (3H, t, J=7,1 Hz), to 1.21 to 1.31 (4H, m), 1,74-a 1.77 (2H, m), 1,89-and 2.10 (2H, m), 2,60 is 2.80 (2H, m), 3,04-of 3.12 (2H, m), 3,20 is-3.45 (2H, m), 3,82 (3H, s), 4,58-4,63 (2H, m), 5,20-and 5.30 (1H, m), to 6.88-6.94 per (2H, m), 7.23 percent-to 7.28 (1H, m), 7,52 (1H, s), 7,61-7,67 (2H, m).

Example 227

Obtaining 4-[4-(5-fluoro-4-oxo-8-pyrrolidin-1-yl-1,4-dihydroquinoline-3-yl)phenoxy]butyric acid

The above compound was obtained in the same manner as described in example 32, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: to 1.80-2.00 (6H, m), 2,33-2,39 (2H, t, J=7,2 Hz), 3,00-of 3.05 (4H, m), USD 3.96-4,01 (2H, t, J=6,4 Hz), 6,84-6,93 (3H, m), 7,32-value of 7, 37 (1H, m), 7.50 to 7,53 (2H, d, J=8,7 Hz), 7,79 (1H, s), of 10.95 (1H, s), 11,80-12,20 (1H, br.C).

Example 228

GettingNbutyl-4-[4-(5-fluoro-4-oxo-8-pyrrolidin-1-yl-1,4-dihydroquinoline-3-yl)phenoxy]butylamide

The above compound was obtained in the same manner as described in example 33, using the appropriate starting materials.

Pale yellow powder

¹H-NMR (DMSO-d₆) δ MD: 0,81-of 0.87 (3H, t, J=7.0 Hz), 1.19 and of 1.40 (4H, m) of 1.85 and 1.95 (6H, m), 2,19-of 2.25 (2H, t, J=7,2 Hz), 2,97 is 3.10 (6H, m), 3,93-of 3.98 (2H, t, J=6.3 Hz), of 6.85-6,93 (3H, m), 7,34-7,39 (1H, m), 7,51-7,54 (2H, d, J=8,3 Hz), the 7.75-of 7.83 (2H, m), representation stands at 10.97 (1H, br.C).

Example 229

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (tert-butoxycarbonylmethylene)AC�Tata

Sodium iodide (1.4 g, 0.9 mmol) and sodium hydride (60% oil basis, 220 mg, 5.5 mmol) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (1.0 g, 3.0 mmol) in DMF (15 ml) and stirred at room temperature for 10 minutes. Chloromethyl (tert-butoxycarbonylmethylene)acetate (2,52 g, 10.6 mmol) was added to the reaction mixture while cooling with ice and the mixture is then stirred at room temperature for 3 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture and then the mixture was subjected to extraction with ethyl acetate. The thus obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1). Treated material was concentrated to dryness under reduced pressure to obtain a pale yellow solid substance in the amorphous state 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (tert-butoxycarbonylmethylene)acetate (290 mg, yield: 18%).

¹H-NMR (CDCl₃) δ MD: 100-1,15 (3H, m), 1,29-of 1.44 (9H, s), 1.85 to a 2.00 (2H, m), 2,88-2,90 (3H, s), 3,84 (3H, s), 3,90-4,15 (4H, m), of 6.46-is 6.51 (2H, s), 6,90-7,15 (4H, m), members, 7.59 (2H, d, J=8.6 Hz), 7,74-7,79 (1H, s).

Example 230

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl of methyliminodiacetic hydrochloride�

4N Solution of hydrogen chloride in ethyl acetate (1 ml) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (tert-butoxycarbonylmethylene)acetate (100 mg, 0,19 mmol) in ethyl acetate (2 ml) and stirred at room temperature for 3 hours. The precipitated insoluble substance was collected by filtration, washed with acetone and then dried to give a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl of methyliminodiacetic hydrochloride (78,3 mg, yield: 88%).

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 (3H, t, J=7,4 Hz) of 1.80-1.90 (2H, m), 2,45 is 2.60 (3H, m), with 3.79 (3H, s) 4,07 (2H, s), 4,10 (2H, t, J=6.6 Hz), 6,61 (2H, s), of 6.99 (2H, d, J=8.9 Hz), 7,11 (1H, DD, J=9,1 that 11.5 Hz), 7,39 (1H, DD, J=4.5 and 9.1 Hz), and 7.60 (2H, d, J=8.9 Hz), 8,17 (1H, s), 9,14 (2H, br.).

Example 231

Getting 5-fluoro-1-(2-morpholine-4-retil)-8-propoxy-3-[4-(pyrrolidin-1-carbonyl)phenyl]-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 106, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7,4 Hz), 1,77-of 1.88 (6H, m), 2,31-2,34 (4H, m), of 2.58 (2H, t, J=5.4 Hz), 3,37-3,44 (8H, m), of 4.04 (2H, t, J=6,5 Hz), the 4.67 (2H, d, J=5.4 Hz), 7,01 (1H, DD, J=9,0 Hz, 11.6 Hz), 7,27 (1H, DD, J=4.5 Hz, 9,0 Hz), 7,52 (2H, d, J=8,3 Hz), 7,72 (2H, d, J=8,3 Hz), with 8.05 (1H, s).

Example 232

Getting 1-chloromethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-chinolin-it

4N Solution of hydrogen chloride in ethyl acetate (2 ml) was added to a solution of di-tert-butyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-elmerpost (300 mg, 0.55 mmol) in ethyl acetate (3 ml) under cooling with ice and the mixture was stirred at room temperature for 2 hours. The precipitated insoluble substance was collected by filtration and dried to give a white powder of 1-chloromethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it (18 mg, yield: 92%).

¹H-NMR (CDCl₃) δ M. D.: of 1.13 (3H, t, J=7.5 Hz), 1,70-and 2.10 (2H, m), 3,84 (3H, s), 4,11 (2H, t, J=6.6 Hz), 6,40 (2H, s), 6,90-7,05 (3H, m), 7,12 (1H, DD, J=4,5, 9,0 Hz), 7,51 (1H, s), 8,59 (2H, d, J=8,8 Hz).

Example 233

Obtaining 1-(2-benzyloxyethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

Benzyloxyacetophenone (1.9 ml, 3 equivalent weight) was added to a solution of 4-(tert-butyldimethylsilyloxy)-5-fluoro-3-(4-methoxyphenyl)-8-propoxyimino (1.5 g, 3.4 mmol) in dichloromethane (50 ml) under cooling with ice and the mixture was stirred over night at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The thus obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=21). The product after purification was concentrated under reduced pressure to give a colorless oily substance, 1-(2-benzyloxyethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-she (250 mg, yield: 15%).

¹H-NMR (CDCl₃) δ M. D.: a 1.00 (3H, t, J=7,4 Hz), 1,70-1,90 (2H, m), 3,84 (3H, s), 3,95 (2H, t, J=6,4 Hz), of 4.38 (2H, s), 4,52 (2H, s) 6,94 (2H, d, J=8,8 Hz), 6,95-7,40 (7H, m), EUR 7.57 (2H, d, J=8,8 Hz), 7,92 (1H, s).

Example 234

Obtain 1-acetyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 233, using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.05 (3H, t, J=7.5 Hz), to 1.80-2.00 (2H, m), USD 2.41 (3H, s), 3,83 (3H, s), 4,02 (2H, t, J=5.7 Hz), to 6.95 (2H, d, J=8.9 Hz), 7.00 x-7,15 (2H, m), members, 7.59 (2H, d, J=8.9 Hz), 8,02 (1H, s).

Example 235

Obtaining 1-(2-bromoacetyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 233, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD: 0,95 were 1.15 (3H, m), 1,70-of 2.05 (2H, m), 3,80-4,20 (7H, m), 6,50 was 8.00 (7H, m).

Example 236

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-benzyloxybenzoate

The above compound was obtained in the same way, which is described in Primera, using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD to 1.06 (3H, t, J=7,4 Hz), to 1.80-2.00 (2H, m), 3,84 (3H, s), of 4.08 (2H, t, J=6,7 Hz), 5,11 (2H, s), to 6.62 (2H, s), 6,90-7,15 (6H, m), 7,30 of 7.45 (5H, m), a 7.62 (2H, d, J=8.9 Hz), 7,84 (1H, s), is 7.94 (2H, d, J=8.9 Hz).

Example 237

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-hydroxybenzoate

10% Palladium/charcoal (260 mg) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-benzyloxybenzoate (2.6 g, 4.6 mmol) in THF (30 ml) and ethanol (15 ml). The mixture was subjected to substitution reactions with hydrogen and stirred at room temperature for 3 hours. After the reaction, the catalyst was removed by filtration through celite and the mixture was concentrated to dryness under reduced pressure to obtain a pale yellow powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-hydroxybenzoate (2.22 g, yield: quantitative).

¹H-NMR (CDCl₃) δ MD to 1.06 (3H, t, J=7,4 Hz), to 1.80-2.00 (2H, m), of 3.81 (3H, s), of 4.08 (2H, t, J=6,7 Hz) of 6.63 (2H, s), to 6.42 (2H, d, J=8,8 Hz), 6,90-7,00 (3H, m), 7,10 (1H, DD, J=4.4 and from 9.0 Hz), 7,22 (1H, br.), a 7.58 (2H, d, J=8,8 Hz), of 7.83 (2H, d, J=8,8 Hz) of 7.88 (1H, s).

Example 238

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-(di-tert-butoxypropan)benzoate

5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-hidroxi�soat (2.2 g, 4.6 mmol) was suspended in acetone (50 ml). Tetrazol (420 mg) and di-tert-butyl-N,N - diisopropylphosphoramidite (1,9 ml) was added to the suspension and the suspension was stirred at room temperature for 2 hours. The reaction mixture was cooled and aqueous 30% hydrogen peroxide solution (2.9 ml) was added to the mixture, followed by stirring at the same temperature for 2 hours. Aqueous sodium thiosulfate solution and an aqueous solution of sodium bicarbonate was added to the reaction mixture. The resulting mixture was stirred and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=100:1→2:1). The material after purification was concentrated to dryness under reduced pressure to give a white solid substance in the amorphous state 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-(di-tert-butoxypropan)benzoate (2,51 g, yield: 81%).

¹H-NMR (CDCl₃) δ MD to 1.06 (3H, t, J=7,4 Hz) of 1.50 (18H, s) to 1.80-2.00 (2H, m), 3,84 (3H, s), of 4.08 (2H, t, J=6,7 Hz) of 6.63 (2H, s), 6,90-7,00 (3H, m), 7,10 (1H, DD, J=4.4 and from 9.0 Hz), 7,26 (2H, d, J=8,5 Hz), a 7.62 (2H, d, J=8,7 Hz), of 7.83 (1H, s), compared to 7.97 (2H, d, J=8,5 Hz).

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-phosphonocrotonate

Trifluoroacetic acid (2 ml) was added to a solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-(di-tert-butoxypropan)benzoate (500 mg) in dichloromethane (10 ml) under cooling with ice and the mixture is then stirred at the same temperature for 1 hour. The resulting mixture was concentrated under reduced pressure at the temperature of the bath is not higher than 30°C. the Residue is recrystallized from a mixture of ethyl acetate-n-hexaneobtaining a pale yellow powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-phosphonocrotonate (406,7 mg, yield: 98%).

¹H-NMR (DMSO-d₆) δ M. D.: of 0.93 (3H, t, J=7,4 Hz), 1,60 is 1.85 (2H, m), with 3.79 (3H, s) 4,06 (2H, t, J=6,5 Hz), at 6.64 (2H, s), 6,98 (2H, d, J=8,8 Hz), to 7.09 (1H, DD, J=9,1 that 11.5 Hz), 7,27 (2H, d, J=8,7 Hz), value of 7, 37 (1H, DD, J=4.4 and to 9.1 Hz), a 7.62 (2H, d, J=8,8 Hz), 7,92 (2H, d, J=8,7 Hz), to 8.38 (1H, s).

Example 240

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-phosphonocrotonate disodium salt

5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-phosphonocrotonate (397 mg) was suspended in isopropyl alcohol (10 ml) under cooling with ice. 1N Aqueous sodium hydroxide solution (1.5 ml) was added to the suspension and the suspension was stirred at the same �temperature for 1 hour. The precipitated insoluble substance was collected by filtration and recrystallized from a mixture of acetone-water to give a white powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-phosphonocrotonate sodium salt (338,6 mg).

Melting point: 205-207°C

¹H-NMR (D₂O) δ MD: 0,81 (3H, t, J=7,4 Hz), 1,50-2,00 (2H, m), 3,60 (3H, s), 3.89 points (2H, t, J=6,7 Hz), between 6.30 (2H, s), 6,68 (2H, d, J=8,7 Hz), at 6.92 (1H, DD, J=9,1, a 12.1 Hz), 7,05-7,20 (5H, m), the 7.75 (2H, d, J=8.9 Hz), 7,79 (1H, s).

Example 241

Getting 1-benzoyloxymethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 229 using the appropriate starting material.

¹H-NMR (CDCl₃) δ MD to 1.06 (3H, t, J=7.5 Hz), 1,75-2,00 (2H, m), 3,84 (3H, s), of 4.00 (2H, t, J=6.6 Hz), of 4.44 (2H, s), a 5.92 (2H, s), 6,90-7,40 (9H, m), members, 7.59 (2H, d, J=8,8 Hz), 7,76 (1H, s).

Example 242

Getting 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxyethylacrylate-2-yl)-1H-quinolin-4-it

1-Bromo-2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl (17.0 g, up 41.3 mmol), benzyltri-nbutylammonium (1.3 g, of 4.16 mmol), potassium carbonate (14,37 g, 104 mmol) and water (0.45 ml) were successively added in this order to a solution of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it (6.75 g, 20.6 mmol) in chloroform (90 ml). Chloroform (2 ml) was added to the obtained reaction mixture and the mixture is then stirred at room temperature for 39 hours. 2N Hydrochloric acid (80 ml) was added to the thus obtained mixture under cooling with ice, followed by extraction with dichloromethane. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:ethyl acetate=30:1→4:1). The product after purification was concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and an aqueous solution (8,16 ml) of potassium hydroxide (5.44 g) was added to the solution, followed by stirring at room temperature for 3 hours. Formed the reaction mixture was concentrated under reduced pressure. 2N Hydrochloric acid (20.4 ml) was added to the residue and extraction was performed with ethyl acetate. The thus obtained organic layer was washed with an aqueous saturated solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloro methane:methanol=50:1→20:1→ethyl acetate:methanol=30:1). The product after purification was concentrated under reduced pressure and then the residue was recrystallized from ethyl acetate to give a white powder of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxyethylacrylate-2-yl)-1H-quinolin-4-he� (0,38 g).

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 (3H, t, J=7.3 Hz), 1,79-of 1.88 (2H, m), 3,24-to 3.41 (3H, m), 3,54-of 3.70 (3H, m) to 3.76 (3H, s), 3,96-4,11 (2H, m), or 4.69 (1H, t, J=5,5 Hz), 5,14-5,16 (2H, m), is 5.33 (1H, d, J=5.4 Hz), is 6.51 (1H, d, J=8.9 Hz), 6.94 per-7,05 (3H, m), 7,29 (1H, DD, J=4.5 Hz, 9.1 Hz), 7,54 (2H, d, J=8,8 Hz), is 7.99 (1H, s).

Example 243

Getting 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-hydroxyethylacrylate-2-yl)-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 242, using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: of 1.03 (3H, t, J=7.3 Hz), 1,81-of 1.89 (2H, m), 3.30 x is 3.40 (1H, m), 3,57-3,58 (3H, m), 3,71 of 3.75 (2H, m), with a score of 3.77 (3H, s), 3,96 at 4.12 (2H, m), 4,67-to 4.76 (2H, m), of 4.91 (1H, d, J=5.7 Hz), of 5.17 (1H, d, J=5.4 Hz), gold 6.43 (1H, d, J=8,8 Hz), 6,96-7,05 (3H, m), 7,28 (1H, DD, J=4.5 Hz, 9.1 Hz), 7,52 (2H, d, J=8,8 Hz), with 8.05 (1H, s).

Example 244

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (di-tert-butoxypropan)acetate

The above compound was obtained in the same manner as described in example 23, using the appropriate starting materials.

¹H-NMR (CDCl₃) δ M. D.: of 1.09 (3H, t, J=7,4 Hz) of 1.44 (18H, s) to 1.80-2.00 (2H, m), 3,84 (3H, s) 4,06 (2H, t, J=6,7 Hz), a 4.53 (2H, d, J=8.9 Hz), is 6.51 (2H, s), 6,90-7,00 (3H, m), to 7.08 (1H, DD, J=4,5, 9,0 Hz), members, 7.59 (2H, d, J=8.9 Hz), 7,73 (1H, s).

Example 245

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-rhinolin-1-Almetyevneft

The above compound was obtained in the same manner as described in example 239 using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, d, J=7,4 Hz), 1,65-of 1.90 (2H, m), with 3.79 (3H, s) 4,07 (2H, t, J=6.6 Hz), of 4.45 (2H, d, J=9,0 Hz) of 6.49 (2H, s), 6,98 (2H, d, J=8.9 Hz), to 7.09 (1H, DD, J=9,1 that 11.5 Hz), of 7.36 (1H, DD, J=4.4 and to 9.1 Hz), members, 7.59 (2H, d, J=8.9 Hz), 8,16 (1H, s).

Example 246

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-Almetyevneft disodium salt

The above compound was obtained in the same manner as described in example 25, using the appropriate starting material.

Melting point: 160-162°C

¹H-NMR (D₂O) δ M. D.: from 0.84 (3H, d, J=7,4 Hz), 1,55-1,70 (2H, m), 3,61 (3H, s), 3,86 (2H, t, J=6.6 Hz), 4,25 (2H, d, J=6,9 Hz), a 6.26 (2H, s), 6,73 (2H, d, J=8,7 Hz), to 6.88 (1H, DD, J=9,2, a 12.1 Hz), to 7.08 (1H, DD, J=4,5, and 9.2 Hz), 7,18 (2H, d, J=8,7 Hz), 7,78 (1H, s).

Example 247

Getting 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl (S)-2,6-bis-tert-butoxycarbonylamino

The above compound was obtained in the same manner as described in example 229 using the appropriate starting material.

¹H-NMR (CDCl₃) δ M. D.: of 1.10 (3H, t, J=7,4 Hz), 1,20-1,75 (24H, m), to 1.80-2.00 (2H, m), 2,85 is 3.10 (2H, m), 3,84 (3H, s) 4,07 (2H, t, J=6.6 Hz), 4,15 is 4.30 (1H, m), 4,45-a 4.65 (1H, m), 5,00-5,25 (1H, m), 6,48 (2H, s), 6,90-7,05 (3H, m), 7,10 (1H, DD, J=4,5, 9,0 Hz), members, 7.59 (2H,d, J=8,8 Hz), 7,74 (1H, s).

Example 248

Obtaining 1-(1-ethylsulfanyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 229 using the appropriate starting materials.

¹H-NMR (CDCl₃) δ M. D.: of 1.08 (3H, t, J=7.3 Hz), of 1.12 (3H, t, J=7.3 Hz), to 1.79 (3H, d, J=6,7 Hz), 1,90-2,00 (2H, m), which is 2.30 (1H, sq, J=7,3 Hz) or 2.33 (1H, sq, J=7.3 Hz), 3,85 (3H, s) 4,00 (1H, TD, J=6,7, 8,9 Hz), 4,12 (1H, TD, J=6,7, 8,9 Hz), 6.80 per-7,10 (5H, m), with 7.66 (2H, d, J=8,8 Hz), to 8.29 (1H, s).

Example 249

Getting 5-fluoro-7-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 1 using the appropriate starting material.

¹H-NMR (DMSO-d₆) δ MD: to 3.76 (3H, s), 3,83 (3H, s), is 6.65 (1H, d, J=13,6 Hz) 6,76 (1H, s), at 6.92 (2H, d, J=8,8 Hz), 7,54 (2H, d, J=8,8 Hz), 7,90 (1H, d, J=5.8 Hz), of 11.75 (1H, br.C).

Example 250

Obtain 1-ethyl-5-fluoro-7-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-it

The above compound was obtained in the same manner as described in example 3 using the appropriate starting materials.

¹H-NMR (DMSO-d₆) δ M. D.: of 1.33 (3H, t, J=6.9 Hz), of 3.75 (3H, s), 3.89 points (3H, s) to 4.27 (2H, sq, J=7,0 Hz), 6,74 (1H, d, J=13.7 Hz), about 6,82 (1H, s), at 6.92 (2H, d, J=8,7 Hz), to 7.55 (2H, d, J=8,7 Hz), and 8.04 (1H, s).

Example 251

Obtain ethyl 4-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-1,4-dihydroquinoline-2-yl]butyrate

The above compound was obtained in the same manner as described in example 2, using appropriate starting materials.

White powder (ethyl acetate)

Melting point: 177 to 179°C

¹H-NMR (DMSO-d₆) δ M. D.: a 1.00 (3H, t, J=7,4 Hz) of 1.06 (3H, t, J=7,1 Hz), 1,67-of 1.88 (4H, m) of 2.16 (2H, t, J=7,4 Hz) to 2.58 (2H, t, J=7,0 Hz) to 3.76 (3H, s), 3,90 (2H, sq, J=7,1 Hz), 4,14 (2H, t, J=6.6 Hz), 6,81-6,94 (3H, m), 7,06 (2H, d, J=8.6 Hz), 7,15 (1H, DD, J=4.0 Hz and 8.8 Hz), 10,40 (1H, br.C).

Example 252

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]dipotassium monophosphate salt

[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate (800 mg, of 1.83 mmol) was suspended in isopropyl alcohol (30 ml). 1N Aqueous solution of potassium hydroxide (3,66 ml of 3.66 mmol) was added to the suspension at 0°C. the Resulting mixture was stirred at 0°C for 1.5 hours. The resulting insoluble substance was collected by filtration, recrystallized from a mixture of acetone-water and then dried to give a white powder from [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate dipotassium salt (445 mg, yield: 47%).

Melting point: 184-186°C

¹H-NMR (D₂O) δ MD: or = 0.97 (3H, t, J=7,4 Hz), 1,79-of 1.88 (2H, m) to 3.76 (3H, s) 4,01 (2H, t, J=6,7 Hz), to 6.05 (2H, d, J=9.1 Hz), 6,93-7,01 (3H, m), of 7.19 (1H, DD, J=4,6, or 9.1 Hz), the 7.43 (2H, d, J=8,8 Hz), 8,16 (1H, s).

Example 253

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H - quinolin-1-ylmethyl]monophosphate calcium salt

[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt (800 mg, of 1.66 mmol) was dissolved in water (4 ml). An aqueous solution (1 ml) of calcium chloride (202 mg, 1.82 mmol) was added at room temperature. The precipitated solid was collected by filtration, washed with water and acetone and then dried to give a white powder from [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate calcium salt (690 mg, yield: 87%).

Melting point: 255-258°C (with decomposition)

¹H-NMR (DMSO-d₆80°C) δ MD: 0,79-of 0.89 (3H, m), 1,68-of 1.76 (2H, m), is 3.62 (3H, s), of 3.91-4,01 (2H, m), 6,09-USD 6.16 (2H, m), 6,74-6,90 (3H, m), to 7.09-7,15 (1H, m), 7,40-of 7.70 (2H, m), 8,32 (1H, s).

Example 254

Obtain [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate magnesium salt

[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate disodium salt (1.0 g, 2.07 mmol) was suspended in methanol (10 ml). A solution of magnesium chloride (198 mg, 2,08 mmol) in methanol (4.3 ml) was added at room temperature. The resulting mixture was stirred at room temperature for 20 minutes. Firmly� substance, the precipitated after condensation, collected by filtration, washed with water and acetone and then dried to give a white powder from [5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl]monophosphate magnesium salt (845 mg, yield: 88%).

Melting point: 265-269°C (with decomposition)

¹H-NMR (DMSO-d₆80°C) δ M. D.: of 0.99 (3H, t, J=7,4 Hz), and 1.76-to 1.86 (2H, m) to 3.64 (3H, s) to 4.05 (2H, t, J=6,5 Hz) 6,09 (2H, d, J=10.4 Hz), 6.80 per-6,98 (3H, m), of 7.24 (1H, DD, J=4,6, or 8.6 Hz), a 7.58 (2H, d, J=8,7 Hz), 8,00 (1H, C).

Pharmacological test example 1

Assessment improve mitochondrial dysfunction as a result of studies on cell lines of human neuroblastoma SH-SY5Y treated with 1-methyl-4-phenylpyridinium (MPP⁺)

In the lines of human neuroblastoma cells SH-SY5Y, in which mitochondrial activity was violated in the processing of MRD⁺(Bollimuntha S. et al., J Biol Chem, 280, 2132-2140 (2005) and T. Shang et al., J Biol Chem, 280, 34644-34653 (2005)), the improvement of mitochondrial dysfunction was evaluated on the basis of the results of measuring the redox activity of mitochondria, using a fluorescent dye Alamar Blue after adding the connection (M. Nakai et al, Exp Neurol, 179, 103-110 (2003)).

Cell line human neuroblastoma SH-SY5Y cultured in modified according to the method of Dulbecco the medium eagle containing 10% fetal bovine serum (DMEM containing 50 units/ml penicillin and 50 µg/m� streptomycin as antibiotics) at 37°C in the presence of 5% carbon dioxide. Cells were placed in poly-D-lysine coated 96-well black tablet at a concentration of 3-6×10⁴cells/cm²(the number of protection: 100 μl/well) and were cultured in the above medium for two days. Next, the medium was replaced by DMEM containing 1% N₂additive (N₂-DMEM), or medium (100 μl/well), which was dissolved 1.5 mm MPP⁺. Cells were cultured for a time from 39 to 48 hours and then measured the redox activity of mitochondria. The sample connection, which is pre-dissolved in dimethylsulfoxide (DMSO), diluted with N2-DMEM and added in a volume of 10 μl/well 24 hours before measuring the activity (the final concentration of compounds: 0.01 to 1 μg/ml).

After removal of the medium by suction balanced salt solution containing 10% of the dye Alamar Blue (154 mm NaCl, 5.6 mm KCl, 2.3 mm calcium chloride, 1.0 mm magnesium chloride, 3.6 mm sodium bicarbonate, 5 mm glucose, 5 mm HEPES, pH of 7.2) was added in a volume of 100 μl/well, and the reaction was carried out in a thermostat at 37°C for 1 hour. Fluorescence intensity was measured using a fluorescence detector (instrument company Hamamatsu Photonics K. K., an excitation wavelength of 530 nm, the measurement at a wavelength of 580 nm) to evaluate the redox activity of mitochondria.

Intensity: high�of fluorescence of the cells in the wells, cultured in medium containing MPP⁺and in the presence of any of the samples of the compounds were evaluated on the basis of 100% of the fluorescence intensity of cells per well, cultured in a medium containing only DMSO (the final concentration is 0.1%). In cases where MPP⁺-induced cell group showed higher fluorescence intensity than the cell group, cultured only in DMSO, the test compound was considered as improving the activity of mitochondria with impaired function.

Pharmacological test 2

Assessment of dopamine�ergicheskoi neuronal protective activity in a mouse line C57BL/6, treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP)

To assess dopaminergic neuroprotective activity used the mouse with MRTR-induced dopaminergic neurons (Chan P. et al., J Neurochem, 57,348-351 (1991)), based on the content of dopamine and protein levels of tyrosine hydroxylase (TH) and dopamine Transporter (DAT) (i.e. dopaminergic neuronal marker proteins) in the striatum of the brain after the administration of compounds (A. Mori et al., Neurosci Res, 51, 265-274(2005)). The male mouse line C57BL/6 (provided by Charles River Japan Inc., from 10 to 12 weeks) was used as the test animal. MRTR was dissolved in physiological solution so that the concentration was 4 mg/ml, and then mice were injected subcutaneously in a volume of 10 ml/kg of the Test compound suspended in 5% Arabian gum/physiological solution (wt./about.) so that the concentration of the compound reached 1 mg/ml. Any of the tested compounds or solvents were introduced oral mouse after 30 minutes, 24 hours and 48 hours after administration MRTR. The mouse was decapitated after 72 hours after administration MRTR, the brain was removed and each part of the striatum was dissected.

The left striatum was used as a sample to determine levels of protein analysis Western blotting. Each tissue sample is homogenized in HEPES-buffer solution with sa�Arosa (of 0.32 M sucrose, 4 μg/ml of pepstatin, 5 μg/ml Aprotinin, 20 μg/ml trypsin inhibitor, 4 μg/ml leupeptin, 0.2 mm of phenylmethylsulfonyl, 2 mm ethylenediaminetetraacetic acid (EDTA), 2 mm ethylene glycol-bis(β-aminoacylase ether) vs acid, 20 mm HEPES, pH 7,2) and investigated the protein, using the set with bicinchoninic acid for protein analysis (set provided by Pierce Corporation). Each homogenized sample containing equal amount of protein was dissolved in buffer solution Lemli for sample, was subjected to electrophoresis in polyacrylamide gels with sodium dodecyl sulphate. Protein separated by electrophoresis, was moved in the electric field on PVDF membrane. The membrane was subjected to interaction with specific primary antibodies to T, DAT and auxiliary proteins, i.e. α1 subunit of Na⁺/K⁺-ATPase and actin (Na⁺/K⁺Atrata, the product UpState Biotechnology Inc.; other products are Chemi-Con Corporation). Next, labeled with horseradish peroxidase secondary antibody (product of Amersham K. K.) to each primary antibody was fixed and chemiluminescence associated with the enzymatic activity of peroxidase was determined using the x-ray film. The density of protein bands on the film were analyzed using a densitometer (a product of Bio-rad Laboratories Inc.), to obtain the greates�HN TN relative to Na ⁺/K⁺-ATPase and the value of the DAT relative to actin.

Right striatum, a mass of tissue which was measured immediately after excision, was used as a test sample for the determination of dopamine. Each tissue sample is homogenized in a 0.1 N solution perchloro acid containing isoproterenol as an internal standard substance measurements using ultrasonic homogenizer under cooling with ice. The supernatant obtained from the homogenate, which was centrifuged at 4°C for 15 minutes at 20000 g, was subjected to high performance liquid chromatography in a column of reversed phase (product Eicom Corporation). Mobile phase 15% methanol in 0.1 M citric acid/0.1 M sodium acetate buffer solution (containing 190 mg/l 1-octanesulfonate sodium, 5 mg/l EDTA, pH 3.5) was moving at a speed of 0.5 ml/min, and the peak of dopamine each sample was determined using an electrochemical detector (applied voltage of +750 mV vs. Ag/AgCl, the company's product Eicom Corporation). On the basis of the identified peak of dopamine, the dopamine content in the tissue mass was calculated in each sample using the analysis software (product Gilson company Inc.). In both tests the value of the sample obtained from MPTP-induced mice, in which only a test compound or a solvent was introduced, expressed relative consideration�but the magnitude of the sample, obtained from mice without treatment MRTR (100%). The values were statistically analyzed using non-clinical approach to statistical analysis. The magnitude of the statistical probability <0,05 were identified as reliable. I MRTR-induced mice, when the group received the test drug, observed an increase in protein levels compared with the group treated with the solvent, and a significant difference was observed between these groups in the t-analysis, the test drug was considered as having neuroprotective activity towards dopamine neurons.

Pharmacological test example 3

Evaluation of the neuroprotective actions in the model occlusion-reperfusion injury of the median artery of the brain of the rat

Neuroprotective effects of experimental compounds were evaluated in a model of occlusion-reperfusion injury of the median artery of the brain (MCA) rats at impact [J. Koizumi et al., Jpn J Stroke, 8, 1-8 (1986)] using the volume of cerebral infarction as the index [H. Kitagawa et al., Neurol Res, 24, 317-323 (2002)].

Male Wistar rats (12-16 weeks old, Japan SLC, Inc.) used as experimental animals. Each rat was kept at 37°C under anesthesia with isoflurane and were fixed in the supine position during natural breathing. Each rat was doing the middle section of the cervical spine and rights�Yu common carotid artery (CCA), right external carotid artery (ECA) and the right internal carotid artery (ICA) were exposed without damaging the vagus nerve. Further, the right CCA and the right ECA was ligated, right ICA controlled stitching at its beginning, and a small incision was made in the right CCA. Occlusion of the right MCA at its beginning was made by the introduction ICA covered with silicone nylon filament No. 4-0 with 0.30-0.35 mm in diameter and approximately 17 mm in length. Right ICA tied together with thread, the skin was sutured and the rats were returned to their cages. After 1.5 hours of occlusion of the cervical wound was opened again under anesthesia with isoflurane and the thread is slightly pulled out to allow reperfusion. The cervical wound was closed and the rats were returned to their cages. Experimental compounds were dissolved in Tris-buffer solution or physiological saline to achieve a concentration of from 1.5 to 15 mg/ml and prepared solutions or media intravenously administered in an amount of 2 ml/kg immediately after vessel occlusion and reperfusion.

Twenty-four hours after reperfusion whole brains of rats were removed and prepared coronal forebrain slices with 2 mm thickness of the boundary layer of the cerebrum and the cerebellum. The slices were incubated in 1% solution of chloride 2,3,5-triphenyltetrazolium (TTC) at 37°C for 30 minutes and fixed by immersion in 10% neutralization�iny formalin. Image slices were scanned and the area naikrasiveyshaya TTC area on the surface was measured using image analysis (Win Ver ROOF. 5.6, MitaniCorporation). The measured area was multiplied by the thickness of 2 mm to determine the volume of each slice, and the sum thus obtained volume was defined as the total volume of cerebral infarction.

A statistical difference in the volume of cerebral infarction between the group with the input media (control group) and the group with the input connection were analyzed by t-test (two-sided) using a non-clinical approach to statistical analysis. Probability less than 0.05 was defined as statistically significant difference. When a statistically significant reduction in the volume of cerebral infarction was observed in the group with the input connection compared with the control group, the determination was made that the experimental compound exhibits a neuroprotective effect.

1. Quinoline compound represented by the formula (1):

or its pharmaceutically acceptable salt,
where R₁is:
(1) hydrogen,
(2) C1-C6 alkyl,
(35), carbamoyl-C1-C6 alkyl, optionally containing morpholinyl-C1-C6 alkyl, or
(36) phosphonooxy-C1-C6 alkyl, optionally containing one or two C1-C6 alkyl group phosphono�XI group;
R₂is:
(1) hydrogen or
(2) C1-C6 alkyl;
R₃represents phenyl, thienyl or furyl, where the phenyl ring represented by R₃may be substituted with one C1-C6 alkoxygroup;
R₄and R₅associated with the formation of the group represented by any of the following formulas:


or the group represented by the following formula:

group, optionally containing one or more substituents selected from the group consisting of C1-C6 alkyl groups and oxoprop;
R₆represents hydrogen; and
R₇represents a C1-C6 alkoxygroup.

2. Quinoline compound of the General formula (1)

or its pharmaceutically acceptable salt, where
R₁is:
(1) hydrogen,
(2) C1-C6 alkyl, or
(36) phosphonooxy-C1-C6 alkyl, optionally containing one or two C1-C6 alkyl group,
R₂represents hydrogen;
R₃represents phenyl or thienyl where:
aromatic or heterocyclic ring represented by R₃may be substituted with one C1-C6 alkoxygroup;
R represents a C1-C6 alkyl or C1-C6 alkoxygroup; and
R₅represents hydrogen;
R₆and R₇associated with the formation of the group represented by any of the following formulas:
or.

3. Quinoline compound of the General formula (1)

or its pharmaceutically acceptable salt, where
R₁is:
(36) phosphonooxy-C1-C6 alkyl, optionally containing one or two C1-C6 alkyl group in phosphonopropyl,
R₂represents hydrogen;
R₃represents phenyl, pyrazolyl or pyrimidinyl where:
aromatic or heterocyclic ring represented by R₃may be substituted by one or two substituents selected from the group consisting of the following substituents (1), (2) and (4):
(1) C1-C6 alkyl,
(2) C1-C6 of alkoxygroup,
(4) halogen;
R₄is a halogen;
R₅represents hydrogen or halogen;
R₆represents hydrogen; and
R₇is any one of the following groups (2), (7) and (8):
(2) C1-C6 alkoxygroup,
(7) an amino group optionally containing one or two substituent selected from the group consisting of C1-C6 alkyl and cyclo C₃-C₈alkyl, and
(8) cyclo C₃-C₈Ala�oxygraph.

4. Quinoline compound of the General formula (1)

or its pharmaceutically acceptable salt, where
R₁represents hydrogen;
R₂is:
(7) carbamoyl, optionally containing morpholinyl-C1-C6 alkyl;
R₃represents phenyl, where phenyl, represented by R₃substituted with one C1-C6 alkoxygroup;
R₄is a halogen;
R₅represents hydrogen;
R₆represents hydrogen; and
R₇represents a C1-C6 alkoxygroup.

5. Quinoline compound of the General formula (1)

or its pharmaceutically acceptable salt according to claim 1, where
R₁represents hydrogen;
R₂represents hydrogen;
R₃represents phenyl, where:
phenyl, represented by R₃substituted with one substituent representing morpholinylcarbonyl;
R₄is a halogen;
R₅represents hydrogen;
R₆represents hydrogen; and
R₇represents a C1-C6 alkoxygroup.

6. Quinoline compound of the General formula (1)

or its pharmaceutically acceptable salt, where
R₁represents hydrogen;
R₂represents hydrogen;
R₃presents with�fight phenyl, where:
phenyl, represented by R₃may be substituted with one C1-C6 alkoxygroup,
R₄is a halogen;
R₅represents hydrogen;
R₆represents hydrogen; and
R₇is any one of the following groups (6), (9) and (10):
(6) carbamoyl-C1-C6 alkoxygroup, optionally containing one substituent selected from the group consisting of C1-C6 alkyl and morpholinyl-C1-C6 alkyl,
(9) hydroxy-C1-C6 alkoxygroup, and
(10) C1-C6 alkoxycarbonyl-C1-C6 alkoxygroup.

7. Quinoline compound according to claim 1, which is a combination of the following formula:






































or

8. Quinoline compound according to claim 2, which is a compound of the following formula:








or

9. Quinoline compound according to claim 3, which is a combination of the following formula:





































or

10. Pharmaceutical composition intended for the treatment of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by abnormal function of the mitochondria, containing a quinoline compound of the General formula (1) according to any one of claims. 1-9 or its pharmaceutically acceptable salt as an active ingredient; and a pharmaceutically acceptable carrier.

11. Preventive and/or therapeutic agent for the treatment of neurodegenerative diseases, for�of olivani, caused by neurological dysfunction, or diseases caused by abnormal function of the mitochondria, where the tool comprises as active ingredient a quinoline compound of the General formula (1) according to any one of claims. 1-9 or its pharmaceutically acceptable salt.

12. Preventive and/or therapeutic agent according to claim 11, where the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, strongley degeneration, progressive supranuclear palsy, Alzheimer's disease, pick's disease, prion disease, corticobasal degeneration, dementia with Lewy bodies, Huntington's chorea, essential tremor syndrome Gilles de La Tourette, rett syndrome, athetosis, cerebral palsy, Wilson's disease, the disease of Hallervorden-Spitze, neuroaxonal dystrophy, spinocerebellar degeneration, olivopontocerebellar atrophy, disease Joseph, dentatorubral-pallidoluysian atrophy, 's disease Gerstmann-Straussler-Sheinker, hereditary ataxias Friedreich's syndrome Mae white, teleangiectatic ataxia, amyotrophic lateral sclerosis, spinobulbar muscular atrophy, disease werdnig-Hoffmann, hereditary spastic paraparesis, syringomyelia, syndrome, Arnold-Chiari malformation, spina bifida, �of indrema Sjogren-Larsson, age-related macular degeneration and stroke selected from the group consisting of ischemic stroke and intracerebral hemorrhage and/or concomitant dysfunction or neurological disorders.

13. Preventive and/or therapeutic agent according to claim 11, where the disease is caused by neurological dysfunction is selected from the group consisting of spinal cord injury, neuropathy due to chemotherapy, diabetic neuropathy, radiation damage and demyelinizing disease selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing leukoencephalitis, chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome.

14. Preventive and/or therapeutic agent according to claim 11, where the disease caused by mitochondrial dysfunction, which are selected from the group consisting of Pearson syndrome, diabetes, deafness, malignant migraine syndrome Leber's syndrome MELAS, MERRF syndrome, overlap syndrome MERRF/MELAS, NARP, true myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, nedostatocno�and complex III, congenital variants of cytochrome b, diffuse lipoma of the neck, ataxia, myoclonia, retinopathy, MNGIE, disease ANTl, flicker in the eyes, POLG disease, paralytic myoglobinuria, SANDO, ARCO, deficiency of complex I, deficiency of complex II, optic nerve atrophy, failure, fatal infantile complex IV deficiency, mitochondrial DNA deficiency syndrome, mitochondrial DNA, encephalomyelopathy Lee, syndrome, chronic progressive external ophthalmoplegia (CREO), syndrome Kearns-they, encephalopathy, lactic-acidosis, myoglobinuria, drug induced mitochondrial diseases, schizophrenia, major depression, bipolar disorder type I, bipolar disorder type II, atypical depression, seasonal affective disorder, postpartum depression, minor depression, recurrent brief depressive disorder resistant depression/chronic depression, double depression and acute renal failure.

15. Preventive and/or therapeutic agent containing as an active ingredient the compound according to any one of claims. 1-9 or its pharmaceutically acceptable salt, where the specified prophylactic and/or therapeutic agent is intended for the treatment or prevention of ischemic heart disease and/�whether concomitant dysfunction, heart failure, myocardosis, dissections of the aorta, immune deficiency, autoimmune diseases, pancreatic insufficiency, diabetes, polycystic kidney disease, renal failure, hepatic encephalopathy, hepatic failure, chronic obstructive pulmonary disease, silicosis, pneumoconiosis miners, toxic epidermal necrolysis and muscular dystrophy.

16. The use of quinoline compounds of the General formula (1) according to any one of claims. 1-9 or its pharmaceutically acceptable salts as a drug for the treatment of neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases caused by abnormal function of the mitochondria.

17. A method of producing quinoline compounds represented by formula (1b):

where R₂, R₃, R₄, R₅, R₆and R₇are as defined in paragraphs. 1, 2, 3, 4, 5 or 6, and R₁'is a group represented by R₁as defined in paragraphs. 1, 2, 3, 4, 5 or 6, but is different from hydrogen, or its pharmaceutically acceptable salts; including the interaction of compounds represented by the formula:
R₁'-X₂
where X₂represents a group which undergoes the same substitution reactions, as a reaction for�of edenia halogen or halogen atom, with a compound represented by the formula:

where R₂, R₃, R₄, R₅, R₆and R₇are as defined in paragraphs. 1, 2, 3, 4, 5 or 6.

18. Quinoline compound or its pharmaceutically acceptable salt represented by the formula:






or
.