N, n-substituted 3-aminopyrrolidine compounds effective as monoamine reabsorption inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

 

The present invention relates to a derivative of pyrrolidine.

Three types of monoamines, known as serotonin, norepinephrine and dopamine, act in the body as neurotransmitters. Therefore, pharmaceutical drugs having inhibitory action reuptake of monoamines, was widely used as a therapeutic pharmaceuticals for diseases of the Central and peripheral nervous system.

Many of the pharmaceutical drugs used to date for treatment of depression, selectively inhibit the re-uptake of norepinephrine or serotonin. Examples of such pharmaceutical preparations include imipramine (an antidepressant of the first generation), maprotiline (second generation antidepressant), selective inhibitors of the uptake of serotonin, such as fluoxetine (an SSRI, antidepressants third generation), inhibitors of reuptake of serotonin and/or norepinephrine, such as venlafaxine (SNRI, antidepressants fourth generation), and the like (see Sadanori Miura, Rinshoseishinyakuri (Japanese Journal of Clinical Psychopharmacology), 2000, 3: 311-318).

But it takes at least three weeks for the manifestation of these pharmaceutical drugs to their therapeutic action, and, moreover, these pharmaceutical drugs do not exhibit a sufficient extent and effect in approximately 30% of patients suffering from depression (see Phil Skolnick, European Journal of Pharmacology, 2001, 375: 31-40).

The purpose of this invention to provide a pharmaceutical preparation with a wide range of therapeutic effects than the known antidepressants, and thus is able to show sufficient therapeutic effect after a short introduction.

The authors of the present invention conducted intensive studies to achieve the above objectives and found that the derived pyrrolidine represented by the following formula (1)may be used to obtain such a desired pharmaceutical preparation. The present invention was created on the basis of this discovery.

The present invention relates to the connection of pyrrolidine, compositions containing the specified connection, the agent containing a specified connection, use the specified connection, the method of treatment of disorders and the way to obtain this connection, as described below in paragraphs 1-14.

Paragraph 1. Derived pyrrolidine General formula (1)

or its salt,

where R101and R102, each independently, represent one of the following groups(1)-(86):

(1) phenyl group,

(2) pyridyloxy group,

(3) benzothiazoline group,

(4) indolenine group,

(5) 2,3-dihydro-1H-indenolol gr the PPU,

(6) naftalina group,

(7) benzofuranyl group,

(8) pinolillo group,

(9) thiazolidine group,

(10) pyrimidinyl group,

(11) personilnya group,

(12) benzothiazolyl group,

(13) thieno[3,2-b]pyridyloxy group,

(14) thienyl group,

(15) cycloalkyl group,

(16) tetrahydropyranyloxy group,

(17) pyrrolidinyl group,

(18) 2,4-dihydro-1,3-benzodioxolyl group,

(19) 2,3-dihydrobenzofuranyl group,

(20) 9H-fluorenyl group,

(21) pyrazolidine group,

(22) pyridazinyl group,

(23) indolinyl group,

(24) thieno[2,3-b]pyridyloxy group,

(25) thieno[3,2-d]pyrimidinyl group,

(26) thieno[3,2-e]pyrimidinyl group,

(27) 1H-pyrazolo[3,4-b]pyridyloxy group,

(28) izohinolinove group,

(29) 2,3-dihydro-1,4-benzoxazine group,

(30) khinoksalinona group,

(31) chinazolinei group,

(32) 1,2,3,4-tetrahydroquinoline group,

(33) cycloalkyl lower alkyl group,

(34) lower alkylthio lower alkyl group,

(35) amino-substituted lower alkyl group, optionally substituted by one or two lower alkyl groups on the amino group,

(36) phenoxy lower alkyl group,

(37) pyridyloxy lower alkyl group,

(38) the lower alkylamino group,

(39) a phenyl lower alkenylphenol group,

<> (40) 1,3-benzodioxolyl group,

(41) 2,3-dihydro-1,4-benzodioxolyl group,

(42) of 3,4-dihydro-1,5-benzodioxepine group,

(43) dihydropyridine group,

(44) 1,2-dihydropyridine group,

(45) 1,2,3,4-tetrahydroisoquinoline group,

(46) benzoxazolyl group,

(47) benzothiazolyl group,

(48) indazolinone group,

(49) benzoimidazolyl group,

(50) imidazolidinyl group,

(51) 1,2,3,4-tetrahydronaphthyl lower alkyl group,

(52) imidazo[1,2-a]pyridyl lower alkyl group,

(53) thiazolyl lower alkyl group,

(54) tetrahydropyranyl lower alkyl group,

(55) piperidyl lower alkyl group,

(56)a diphenyl lower alkoxy-substituted lower alkyl group,

(57) the lowest alkoxycarbonyl-substituted lower alkyl group,

(58) a phenyl lower alkoxycarbonyl-substituted lower alkyl group,

(59) hydroxy-substituted lower alkyl group,

(60) a lower alkoxy lower alkyl group,

(61) carboxy lower alkyl group,

(62) carbarnoyl-substituted lower alkyl group, optionally substituted by one or two lower alkyl groups on carbamoyl group,

(63) lower alkenylphenol group,

(64) morpholinylcarbonyl lower alkyl group,

(65) benzoyl lower alkyl group,

(66) phenylthio lower al the ilen group,

(67) naphthylthio lower alkyl group,

(68) cycloalkyl lower alkyl group,

(69) pyridylthio lower alkyl group,

(70) pyrimidinyl lower alkyl group,

(71) purity lower alkyl group,

(72) tianity lower alkyl group,

(73) 1,3,4-thiadiazolyl lower alkyl group,

(74) benzimidazolylthio lower alkyl group,

(75) benzothiazolylthio lower alkyl group,

(76) tetrazolyl lower alkyl group,

(77) benzoxazolyl lower alkyl group,

(78) Tesorillo lower alkyl group,

(79) imidazolidin lower alkyl group,

(80) amino-substituted lower alkylthio lower alkyl group, optionally substituted by one or two lower alkyl groups on the amino group,

(81) phenyl-substituted lower alkylthio lower alkyl group,

(82) furyl-substituted lower alkylthio lower alkyl group,

(83) pyridyl-substituted lower alkylthio lower alkyl group,

(84) hydroxy-substituted lower alkylthio lower alkyl group,

(85) phenoxy-substituted lower alkylthio lower alkyl group, and

(86) the lowest alkoxycarbonyl-substituted lower alkylthio lower alkyl group,

and each group(1)-(32), (37), (39)-(56), (64)-(79), (81)-(83) and (85) can have one or more substituents selected from the following groups (1-1)to(1-37) in cycloalkenes, aromatic or heterocyclic ring, such as

(1-1) halogen atoms,

(1-2) low allylthiourea, optionally substituted by one or more halogen atoms,

(1-3) lower alkyl groups optionally substituted by one or more halogen atoms,

(1-4) lower alkoxygroup, optionally substituted by one or more halogen atoms,

(1-5) the nitro-group,

(1-6) lower alkoxycarbonyl group,

(1-7) amino group, optionally substituted by one or two lower alkyl groups,

(1-8) lower alkylsulfonyl group,

(1-9) cyano,

(1-10) carboxypropyl,

(1-11) the hydroxy-group,

(1-12) thienyl groups,

(1-13) oxazolidine group,

(1-14) raftiline group,

(1-15) benzoline group,

(1-16) fenoxaprop, optionally substituted by one to three atoms of halogen in the phenyl ring,

(1-17) phenyl lower alkoxygroup,

(1-18) the lower alcoholnye group,

(1-19) phenyl group, optionally substituted in the phenyl ring by one to five substituents selected from the group consisting of halogen atoms, lower alkoxygroup, cyano, lower alcoholnye group and lower alkyl groups,

(1-20) phenyl lower alkyl groups,

(1-21) cyano lower alkyl group,

(1-22) sulfonylurea group, substituted 5-7-membered saturated GE is eroticlinks group, this heterocyclic group contains a heterocyclic ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,

(1-23) thiazolidine group, optionally substituted by one or two lower alkyl groups in the thiazole ring,

(1-24) imidazolidine group,

(1-25) amino lower alkyl group, optionally substituted by one or two lower alkyl groups on the amino group,

(1-26) pyrrolidinyl low alkoxygroup,

(1-27) isoxazolidine group,

(1-28) cycloalkylcarbonyl group,

(1-29) naphthyloxy,

(1-30) peredelnye group,

(1-31) foreline group,

(1-32) phenylthiourea,

(1-33) oxoprop,

(1-34) carnemolla group,

(1-35) 5-7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, while the heterocyclic group is optionally substituted with one to three substituents selected from the group containing oxoprop; lower alkyl groups; lower alcoholnye groups; phenyl lower alkyl groups; phenyl groups optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and lower alkoxygroup; and peredelnye group,

(1-36) aksigorta and

(1-37) low alkoxygroup,

provided that R101and R102are not both unsubstituted phenyl.

Paragraph 2. Derived pyrrolidine General formula (1) or its salt in accordance with paragraph 1, where

R101represents a

(1) phenyl group,

(3) benzothiazoline group,

(4) indolenine group,

(5) 2,3-dihydro-1H-indenolol group,

(6) naftalina group,

(7) benzofuranyl group,

(8) pinolillo group,

(12) benzothiazolyl group,

(18) 2,4-dihydro-1,3-benzodioxolyl group,

(19) 2,3-dihydrobenzofuranyl group,

(20) 9H-fluorenyl group,

(23) indolinyl group,

(28) izohinolinove group,

(29) 2,3-dihydro-1,4-benzoxazine group,

(30) khinoksalinona group,

(31) chinazolinei group,

(32) 1,2,3,4-tetrahydroquinoline group,

(40) 1,3-benzodioxolyl group,

(41) 2,3-dihydro-1,4-benzodioxolyl group,

(42) of 3,4-dihydro-1,5-benzodioxepine group,

(44) 1,2-dihydropyridine group,

(45) 1,2,3,4-tetrahydroisoquinoline group,

(46) benzoxazolyl group,

(47) benzothiazolyl group,

(48) indazolinone group or

(49) benzoimidazolyl group,

and each of which may be aromatic or heterocyclic ring one to three substituent selected from the group of (1-1)to(1-37), as indicated in paragraph 1.

Item . Derived pyrrolidine General formula (1) or its salt in accordance with paragraph 2, where

R101represents a

(1) phenyl group, or

(3) benzothiazoline group,

and each of which may be aromatic or heterocyclic ring one to three substituent selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms.

Item 4. Derived pyrrolidine General formula (1) or its salt in accordance with paragraph 3, where

R102represents a

(1) phenyl group,

(2) pyridyloxy group,

(9) thiazolidine group,

(10) pyrimidinyl group,

(11) personilnya group,

(14) thienyl group,

(48) indazolinone group,

(59) hydroxy-substituted lower alkyl group, or

(60) a lower alkoxy lower alkyl group,

and each group(1), (2), (9), (10), (11), (14) and (48) may be an aromatic or heterocyclic ring one to three substituent selected from the group of (1-1)to(1-37), as indicated in paragraph 1.

Paragraph 5. Derived pyrrolidine General formula (1) or its salt in accordance with paragraph 4, where

R101represents a

monovalently group, dihalogenoalkane group or a phenyl group substituted with one halogen atom and one lower alkyl group,

R 102represents a

(1) phenyl group,

(2) pyridyloxy group,

(9) thiazolidine group,

(10) pyrimidinyl group,

(11) personilnya group,

(14) thienyl group,

(48) indazolinone group,

(59) hydroxy-substituted lower alkyl group, or

(60) a lower alkoxy lower alkyl group,

and each group(1), (2), (9), (10), (11), (14) and (48) may be an aromatic or heterocyclic ring one or two substituent selected from the group consisting of (1-1) halogen atoms, (1-3) lower alkyl groups optionally substituted by one or more halogen atoms, and (1-9) cyano.

Item 6. Derived pyrrolidine General formula (1) or its salt in accordance with paragraph 5, selected from the group consisting of:

(4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,

(4-forfinal)phenyl-(S)-pyrrolidin-3-ylamine,

(3,4-differenl)phenyl-(S)-pyrrolidin-3-ylamine,

bis-(4-forfinal)-(S)-pyrrolidin-3-ylamine,

(3,4-differenl)-(4-forfinal)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(S)-pyrrolidin-3-yl-p-tolylamino,

4-[(S)-(4-fluoro-3-were)pyrrolidin-3-ylamino]benzonitrile,

bis-(3-forfinal)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(S)-pyrrolidin-3-iltiazem-2-ylamine,

(4-forfinal)-(S)-pyrrolidin-3-iltiazem-2-ylamine,

(3,4-dichlorophenyl)-(S)-pyrrolidin-3-iltiazem-2-ylamine,

(3,4-dichlorophe who yl)pyrimidine-5-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)pyridine-2-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)pyridine-3-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(6-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,

(3,4-dichlorophenyl)pyridine-3-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(S)-pyrrolidin-3-althofen-3-ylamine,

(3-chloro-4-forfinal)-(5-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,

(4-fluoro-3-were)-(5-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,

2-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]ethanol

1-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]-2-methylpropan-2-ol,

(3-chloro-4-forfinal)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine ylamine,

3-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]propane-1-ol,

(3-chloro-4-forfinal)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,

benzo[b]thiophene-6-yl-(S)-pyrrolidin-3-althofen-3-ylamine and

benzo[b]thiophene-5-yl-(S)-pyrrolidin-3-althofen-3-ylamine.

Item 7. The pharmaceutical composition containing the derivative pyrrolidine General formula (1) or its salt in accordance with paragraph 1 as an active ingredient and a pharmaceutically acceptable carrier.

Item 8. Preventive and/or therapeutic agent for disorders caused by the s decreased neurotransmission of serotonin, norepinephrine or dopamine containing as an active ingredient derived pyrrolidine General formula (1) or its salt in accordance with paragraph 1.

Item 9. Preventive and/or therapeutic agent in accordance with paragraph 8, where the violation is selected from the group including hypertension; depression; anxiety; fear; post-traumatic stress disorder; acute stress; avoidant personality disorder; dysmorphism body; premature ejaculation; nutritional disorders, obesity, addiction to chemical substances, alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines; cluster headache; migraine; pain disorders; Alzheimer's disease; obsessive convulsive disorder; panic disorder; memory disorders; Parkinson's disease; endocrine disorders; vascular spasm, cerebral ataxia; disorders of the gastrointestinal tract; the negative syndrome of schizophrenia; premenstrual syndrome; fibromyalgia syndrome; lack of restraint in stressful situations; Tourette syndrome; trichotillomania; kleptomania; male impotence; impaired attention hyperactivity disorder (ADHD), chronic paroxizmalnoe hemicrania; chronic fatigue; cataplexy; syndrome sleep apnea and headaches.

Paragraph 10. Preventive and/or therapeutic agent with the availa able scientific C, paragraph 8, where the violation is selected from the group consisting of:

depression is selected from the group including a deep depression; bipolar disorder 1; bipolar disorder 2; mixed episode; estimatesa disorders; "fast cycle"; atypical depression; seasonal affective disorder; postpartum depression; weak depression; repeated brief depressive disorder; non-permanent depression/chronic depression, double depression; alcohol-induced mood disorders; mixed anxiety and depressive disorders; depression, caused by various physical disorders selected from the group consisting of Cushing disease; hypothyroidism, syndrome hyperparathyroidism, Addison disease, syndrome, absence of menstruation and lactation, Parkinson's disease Alzheimer's disease, brain hemorrhage, diabetes, chronic fatigue syndrome and cancer; depression middle aged; geriatric depression; child and adolescent depression; depression caused by taking interferon; depression caused by adaptation; and anxiety, selected from the group consisting of anxiety, caused by adaptation, and anxiety caused by neuropathy, selected from the group consisting of a head injury, brain infection and disease of the inner ear.

Paragraph 11. The use of pyrolidine of the program the General formula (1) or its salt according to any of items 1-6 as a medicine.

Item 12. The application of the derived pyrrolidine General formula (1) or its salt according to any of items 1-6 as inhibitor of the reuptake of serotonin and/or an inhibitor of reuptake of norepinephrine and/or inhibitor of the reuptake of dopamine.

Paragraph 13. A method of treating or preventing disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine, which includes the introduction of a derived pyrrolidine General formula (1) or its salt according to any one of paragraphs 1 to 6 human or animal.

Paragraph 14. The method of obtaining the derived pyrrolidine General formula (1):

or its salts, where R101and R102are as defined above in paragraph 1

namely, that

(1) the compound of General formula (2)

where R101and R102are as defined above in paragraph 1, and R112represents an amino-protective group, is subjected to the reactions of elimination to remove the amino-protective group.

Preferred embodiments of the derived pyrrolidine (1) include compounds represented by the General formula (1)

and their salts,

where R101represents a

(1) phenyl group,

(3) benzothiazoline group is,

(4) indolenine group,

(5) 2,3-dihydro-1H-indenolol group,

(6) naftalina group,

(7) benzofuranyl group,

(8) pinolillo group,

(12) benzothiazolyl group,

(18) 2,4-dihydro-1,3-benzodioxolyl group,

(19) 2,3-dihydrobenzofuranyl group,

(20) 9H-fluorenyl group,

(23) indolinyl group,

(28) izohinolinove group,

(29) 2,3-dihydro-1,4-benzoxazine group,

(30) khinoksalinona group,

(31) chinazolinei group,

(32) 1,2,3,4-tetrahydroquinoline group,

(40) 1,3-benzodioxolyl group,

(41) 2,3-dihydro-1,4-benzodioxolyl group,

(42) of 3,4-dihydro-1,5-benzodioxepine group,

(44) 1,2-dihydropyridine group,

(45) 1,2,3,4-tetrahydroisoquinoline group,

(46) benzoxazolyl group,

(47) benzothiazolyl group,

(48) indazolinone group or

(49) benzoimidazolyl group,

and each of which may be aromatic or heterocyclic ring one to five (preferably one to three) substituents selected from the following (1-1)to(1-37):

(1-1) halogen atoms,

(1-2) low allylthiourea, optionally substituted by one or more (preferably one to three) halogen atoms,

(1-3) lower alkyl groups optionally substituted by one or more (preferably one to three) atoms halog is on,

(1-4) lower alkoxygroup, optionally substituted by one or more (preferably one to four) of the atoms of halogen,

(1-5) the nitro-group,

(1-6) lower alkoxycarbonyl group,

(1-7) amino group, optionally substituted by one or two lower alkyl groups,

(1-8) lower alkylsulfonyl group,

(1-9) cyano,

(1-10) carboxypropyl,

(1-11) the hydroxy-group,

(1-12) thienyl groups,

(1-13) oxazolidine group,

(1-14) raftiline group,

(1-15) benzoline group,

(1-16) fenoxaprop, optionally substituted by one to three atoms of halogen in the phenyl ring,

(1-17) phenyl lower alkoxygroup,

(1-18) the lower alcoholnye group,

(1-19) phenyl group, optionally substituted in the phenyl ring by one to five (preferably one to three) substituents selected from the group consisting of halogen atoms, lower alkoxygroup, cyano, lower alcoholnye group and lower alkyl groups,

(1-20) phenyl lower alkyl groups,

(1-21) cyano lower alkyl group,

(1-22) sulfonylurea group, substituted 5-7-membered saturated heterocyclic group, this heterocyclic group contains a heterocyclic ring one or two nitrogen atom (preferably piperidinophenyl),

(1-23) thiazolidine group, optional samisen the e one or two lower alkyl groups in the thiazole ring,

(1-24) imidazolidine group,

(1-25) amino lower alkyl group, optionally substituted by one or two lower alkyl groups on the amino group,

(1-26) pyrrolidinyl low alkoxygroup,

(1-27) isoxazolidine group,

(1-28) cycloalkylcarbonyl group,

(1-29) naphthyloxy,

(1-30) peredelnye group,

(1-31) foreline group,

(1-32) phenylthiourea,

(1-33) oxoprop,

(1-34) carnemolla group,

(1-35) 5-7-membered saturated heterocyclic group containing one or two nitrogen atom (preferably pyrrolidinyl, piperazinil or piperidyl), heterocyclic group optionally substituted by one to three substituents selected from the group containing oxoprop; lower alkyl groups; lower alcoholnye groups; phenyl lower alkyl groups; phenyl groups optionally substituted with one to three substituents selected from the group consisting of halogen atoms and lower alkoxygroup; and peredelnye group,

(1-36) aksigorta and

(1-37) low alkoxygroup,

provided that R101and R102are not both unsubstituted phenyl.

Preferred embodiments of the derived pyrrolidine (1) include compounds represented by the General formula (1)

and their salts,

where R101represents a

(1) phenyl group, or

(3) benzothiazoline group,

and each of which may be aromatic or heterocyclic ring one or two substituent selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with one to three halogen atoms, and

R102represents a

(1) phenyl group,

(2) pyridyloxy group,

(3) benzothiazoline group,

(4) indolenine group,

(5) 2,3-dihydro-1H-indenolol group,

(6) naftalina group,

(7) benzofuranyl group,

(8) pinolillo group,

(9) thiazolidine group,

(10) pyrimidinyl group,

(11) personilnya group,

(12) benzothiazolyl group,

(13) thieno[3,2-b]pyridyloxy group,

(14) thienyl group,

(15) cycloalkyl group,

(16) tetrahydropyranyloxy group,

(17) pyrrolidinyl group,

(18) 2,4-dihydro-1,3-benzodioxolyl group,

(19) 2,3-dihydrobenzofuranyl group,

(20) 9H-fluorenyl group,

(21) pyrazolidine group,

(22) pyridazinyl group,

(23) indolinyl group,

(24) thieno[2,3-b]pyridyloxy group,

(25) thieno[3,2-d]pyrimidinyl group,

(26) thieno[3,2-e]pyrimidinyl group,

(27) 1H-pyrazolo[3,4-b]pyridyloxy group,

(28) izohinolinove group,

(29) 2,3-dihydro-1,4-benzoxazine group,

(30) henok etinilnoy group,

(31) chinazolinei group,

(32) 1,2,3,4-tetrahydroquinoline group,

(40) 1,3-benzodioxolyl group,

(41) 2,3-dihydro-1,4-benzodioxolyl group,

(42) of 3,4-dihydro-1,5-benzodioxepine group,

(43) dihydropyridine group,

(44) 1,2-dihydropyridine group,

(45) 1,2,3,4-tetrahydroisoquinoline group,

(46) benzoxazolyl group,

(47) benzothiazolyl group,

(48) indazolinone group,

(49) benzoimidazolyl group,

(50) imidazolidinyl group,

(59) hydroxy-substituted lower alkyl group, or

(60) a lower alkoxy lower alkyl group,

and each of the groups (1)-(50) can be an aromatic or heterocyclic ring one to five (preferably one to three) substituents selected from the following groups (1-37), such as

(1-1) halogen atoms,

(1-2) low allylthiourea, optionally substituted by one or more (preferably one to three) halogen atoms,

(1-3) lower alkyl groups optionally substituted by one or more (preferably one to three) halogen atoms,

(1-4) lower alkoxygroup, optionally substituted by one or more (preferably one to four) of the atoms of halogen,

(1-5) the nitro-group,

(1-6) lower alkoxycarbonyl group,

(1-7) amino group, optionally substituted one or TLD shall I lower alkyl groups,

(1-8) lower alkylsulfonyl group,

(1-9) cyano,

(1-10) carboxypropyl,

(1-11) the hydroxy-group,

(1-12) thienyl groups,

(1-13) oxazolidine group,

(1-14) raftiline group,

(1-15) benzoline group,

(1-16) fenoxaprop, optionally substituted by one to three atoms of halogen in the phenyl ring,

(1-17) phenyl lower alkoxygroup,

(1-18) the lower alcoholnye group,

(1-19) phenyl group, optionally substituted in the phenyl ring by one to five (preferably one to three) substituents selected from the group consisting of halogen atoms, lower alkoxygroup, cyano, lower alcoholnye group and lower alkyl groups,

(1-20) phenyl lower alkyl groups,

(1-21) cyano lower alkyl group,

(1-22) sulfonylurea group, substituted 5-7-membered saturated heterocyclic group, this heterocyclic group contains a heterocyclic ring one or two nitrogen atom (preferably piperidinophenyl),

(1-23) thiazolidine group, optionally substituted by one or two lower alkyl groups in the thiazole ring,

(1-24) imidazolidine group,

(1-25) amino lower alkyl group, optionally substituted by one or two lower alkyl groups on the amino group,

(1-26) pyrrolidinyl low alkoxygroup,

(1-27) isoxazol the ilen group,

(1-28) cycloalkylcarbonyl group,

(1-29) naphthyloxy,

(1-30) peredelnye group,

(1-31) foreline group,

(1-32) phenylthiourea,

(1-33) oxoprop,

(1-34) carnemolla group,

(1-35) 5-7-membered saturated heterocyclic group containing one or two nitrogen atom (preferably pyrrolidinyl, piperazinil or piperidyl), heterocyclic group optionally substituted by one to three substituents selected from the group containing oxoprop; lower alkyl groups; lower alcoholnye groups; phenyl lower alkyl groups; phenyl groups optionally substituted with one to three substituents selected from the group consisting of halogen atoms and lower alkoxygroup; and peredelnye group,

(1-36) aksigorta and

(1-37) low alkoxygroup,

provided that R101and R102are not both unsubstituted phenyl.

In particular, preferred embodiments of the derived pyrrolidine (1) include compounds represented by the General formula (1)

and their salts,

where R101represents a

(1) a phenyl group substituted in the phenyl ring by one or two substituents selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted by one to three and the ohms of halogen, and

R102represents a

(1) phenyl group,

(2) pyridyloxy group,

(9) thiazolidine group,

(10) pyrimidinyl group,

(11) personilnya group,

(14) thienyl group,

(48) indazolinone group,

(59) hydroxy-substituted lower alkyl group, or

(60) a lower alkoxy lower alkyl group,

and each group(1), (2), (9), (10), (11), (14) and (48) may be an aromatic or heterocyclic ring one or two substituent selected from the group consisting of

(1-1) halogen atoms,

(1-3) lower alkyl groups optionally substituted with one to three halogen atoms and

(1-9) cyano.

Examples of specific preferred pyrrolidinone compounds of the present invention are the following:

(4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,

(4-forfinal)phenyl-(S)-pyrrolidin-3-ylamine,

(3,4-differenl)phenyl-(S)-pyrrolidin-3-ylamine,

bis-(4-forfinal)-(S)-pyrrolidin-3-ylamine,

(3,4-differenl)-(4-forfinal)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(S)-pyrrolidin-3-yl-p-tolylamino,

4-[(S)-(4-fluoro-3-were)pyrrolidin-3-ylamino]benzonitrile,

bis-(3-forfinal)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(S)-pyrrolidin-3-iltiazem-2-ylamine,

(4-forfinal)-(S)-pyrrolidin-3-iltiazem-2-ylamine,

(3,4-dichlorophenyl)-(S)-pyrrolidin-3-iltiazem-2-ylamine,

(3,4-dichloro enyl)pyrimidine-5-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)pyridine-2-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)pyridine-3-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(6-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,

(3,4-dichlorophenyl)pyridine-3-yl-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(S)-pyrrolidin-3-althofen-3-ylamine,

(3-chloro-4-forfinal)-(5-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,

(4-fluoro-3-were)-(5-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,

2-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]ethanol

1-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]-2-methyl-propane-2-ol,

(3-chloro-4-forfinal)-(2-methoxyethyl)-(S)-pyrrolidin-3-ylamine,

3-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]propane-1-ol,

(3-chloro-4-forfinal)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,

(3-chloro-4-forfinal)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,

benzo[b]thiophene-6-yl-(S)-pyrrolidin-3-althofen-3-ylamine and

benzo[b]thiophene-5-yl-(S)-pyrrolidin-3-althofen-3-ylamine.

Specific examples of the groups in General formula (1) are as follows.

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

Examples of the lower alkylthio, optionally substituted by one or more halogen atoms include straight or branched C1-6allylthiourea, n is necessarily substituted by one to three halogen atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, tert-butylthio, sec-butylthio, n-pentylthio, isopentyl, neopentyl, n-hexylthio, isohexyl, 3 methylphenylthio, triptoreline, trichloromethylthio, chlorotri, brometalia, formailty, idetity, deformality, Diplomatico, 2-chloroethylthio, 2,2,2-triptoreline, 2,2,2-trichloromethylthio, 3 chlorpropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutylene, 4-formality, 5-chlorinity, 3-chloro-2-methylpropyl, 5-Bromhexine, 5,6-dibromohexane etc.

Examples of lower alkyl groups optionally substituted by one or more halogen atoms include straight or branched C1-6alkyl group, optionally substituted by one to four halogen atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, trifluoromethyl, trichloromethyl, chloromethyl, methyl bromide, vermeil, iodomethyl, deformity, dibromomethyl, 2-chloroethyl, 2,2,2-triptorelin, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichloroethyl, 4-terbutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexane, 1,1,2,2-tetraborate etc.

Examples of the lower alkoxygroup, optionally substituted by one or more halogen atoms include straight or times twinnie C 1-6alkoxygroup, optionally substituted by one to four halogen atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentylamine, neopentane, n-hexyloxy, isohexane, 3 methylpentane, triptoreline, trichlormethane, chloromethoxy, bromoethoxy, formatosi, admetox, deformedarse, dibromoethane, 2-chloroethoxy, 2,2,2-triptoreline, 2,2,2-trichloroethane, 3 chloropropoxy, 2,3-dichloropropene, 4,4,4-trichlorobutane, 4-forbooks, 5-chloropentane, 3-chloro-2-methylpropoxy, 5-Bromhexine, 5,6-dibromohexane, 1,1,2,2-tetrafluoroethoxy etc.

Examples of the lower alkoxycarbonyl groups include alkoxycarbonyl group, where the alkoxy portion is a straight or branched C1-6alkoxygroup, such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, tert-butoxycarbonyl, second-butoxycarbonyl, n-pentyloxybenzoyl, neopentylglycol, n-hexyloxymethyl, isohexadecane, 3-methylbenzyloxycarbonyl etc.

Examples of lower alkyl groups include straight or branched C1-6alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl,3-methylpentyl etc.

Examples of the lower alkanoyl groups include straight or branched C1-6alkanine groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbamoyl, hexanoyl etc.

Examples of the lower alkylsulfonyl groups include straight or branched C1-6alkylsulfonyl groups, such as methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, isobutylamine, tert-butylsulfonyl, second-butylsulfonyl, n-peterculter, isopentylamine, neopentylene, n-hexylsilane, isohexanol, 3-methylphenylsulfonyl etc.

Examples of fenoxaprop, optionally substituted by one to three atoms of halogen in the phenyl ring include phenoxy, 2-fervency, 3 fervency, 4-fervency, 2-chlorophenoxy, 3 chlorophenoxy, 4-chlorophenoxy, 2-bromophenoxy, 3 bromophenoxy, 4-bromophenoxy, 2-iodinate, 3 iodinate, 4-iodinate, 2,3-divergence, 3,4-divergence, 3,5-divergence, 2,4-divergence, 2,6-divergence, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3,5-dichlorophenoxy, 2,4-dichlorphenoxy, 2,6-dichlorophenoxy, 3,4,5-tryptophanate, 3,4,5-trichlorophenoxy, 2,4,6-tryptophanate, 2,4,6-trichlorophenoxy, 2-fluoro-4-bromophenoxy, 4-chloro-3-fervency, 2,3,4-trichlorophenoxy etc.

Examples of phenyl lower alkoxygroup include fenilalanina, where the alkoxy part ol dstanley a straight or branched C 1-6alkoxygroup, such as benzyloxy, 2-phenylethane, 1 venlafaxi, 3 phenylpropoxy, 4-phenylbutane, 5-phenylpentane, 6-phenylhexanoic, 1,1-dimethyl-2-phenylethane, 2-methyl-3-phenylpropoxy etc.

Examples of phenyl lower alkyl groups include phenylaniline group, where the alkyl portion is a straight or branched C1-6alkyl group such as benzyl, 1-phenethyl, 2-phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, 5-fenilpentil, 4-fenilpentil, 6-phenylhexa, 2-methyl-3-phenylpropyl, 1,1-dimethyl-2-phenylethyl, etc.

Examples of cyano lower alkyl groups include cyanoaniline group, where the alkyl portion is a straight or branched C1-6alkyl group, such as cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanomethyl, 1,1-dimethyl-2-cyanoethyl, 5-cyanophenyl, 6-cyanogenesis, 1-linosopril, 2-methyl-3-cyanopropyl etc.

Examples thiazolidine groups, optionally substituted by one or two lower alkyl groups in the thiazole ring include thiazolidine group, optionally substituted by one or two straight or branched C1-6alkyl groups in the thiazole ring, such as (2-, 4 - or 5-)thiazolyl, 2-methyl-(4 - or 5-)thiazolyl, 4-methyl-(2 - or 5-)thiazolyl, 2-ethyl-(4 - or 5-)thiazolyl, 4-n-propyl-(2 - or 5-)thiazolyl, 5-n-butyl-(2 - or 4-)thiazolyl, 2-n-pentyl-(4 - and the and 5)thiazolyl, 4-n-hexyl-(2 - or 5-)thiazolyl, 2,4-dimethyl-5-thiazolyl etc.

Examples of the amino lower alkyl group, optionally substituted by one or two lower alkyl groups on the amino group include aminoalkyl group, where the alkyl portion is a straight or branched C1-6alkyl group and which is optionally substituted on the amino group by one or two straight or branched C1-6alkyl groups, such as aminomethyl, 2-amino-ethyl, 1-amino-ethyl, 3-aminopropyl,

4-aminobutyl, 5-aminopentyl, 6-aminohexyl,

1,1-dimethyl-2-amino-ethyl, 2-methyl-3-aminopropyl,

methylaminomethyl, 2-ethylaminomethyl, 3-propylaminoethyl,

3-isopropylaminomethyl, 4-butylaminoethyl,

5-intellingencer, 6-hexylamine,

2-dimethylaminoethyl, 2-diisopropylaminoethyl,

3-dimethylaminopropyl, diisopropylaminomethyl,

3-diisopropylaminoethyl, (N-ethyl-N-propylamino)methyl,

2-(N-methyl-N-hexylamino)methyl etc.

Examples pyrrolidinyl lower alkoxygroup include pyrrolidinyloxy, where the alkoxy portion is a straight or branched C1-6alkoxygroup, such as

(1-, 2 - or 3-)pyrrolidinyloxy,

2-[(1-, 2 - or 3-)pyrrolidinyl]ethoxy,

1-[(1-, 2 - or 3-)pyrrolidinyl]ethoxy,

3-[(1-, 2 - or 3-)pyrrolidinyl]propoxy,

4-[(1-, 2 - or 3-)pyrrolidinyl]butoxy,

5-[(-, 2 - or 3-)pyrrolidinyl]pentyloxy,

6-[(1-, 2 - or 3-)pyrrolidinyl]hexyloxy,

1,1-dimethyl-2-[(1-, 2 - or 3-)pyrrolidinyl]ethoxy,

2-methyl-3-[(1-, 2 - or 3-)pyrrolidinyl]propoxy etc.

Examples cycloalkyl groups include C3-8cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.

Examples cycloalkylcarbonyl groups include cycloalkylcarbonyl group, where cycloalkyl part represents a C3-8cycloalkyl group, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl etc.

Examples of the lower alkoxygroup include straight or branched C1-6alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentylamine, neopentane, n-hexyloxy, isohexane, 3 methylpentane etc.

Examples of the lower alkylthio include straight or branched C1-6allylthiourea, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, tert-butylthio, sec-butylthio, n-pentylthio, isopentyl, neopentyl, n-hexylthio, isohexyl, 3 methylphenylthio etc.

Examples of phenyl groups, optionally substituted in the phenyl ring od is them three substituents, selected from the group consisting of halogen atoms and lower alkoxygroup include phenyl group, optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and straight or branched C1-6alkoxygroup, such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxide, 4-hexyloxyphenyl, 3,4-acid, 3,4-dioxyphenyl, 2,4-acid, 2,5-acid, 2,6-acid, 3,4,5-trimethoxyphenyl, 2-methoxy-4-forfinal, 4-forfinal, 2.5-differenl, 2,4-differenl, 3,4-differenl, 3,5-differenl, 2,6-differenl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3-forfinal, 2-forfinal, 3-bromophenyl, 4-iopener, 2-bromophenyl, 4-bromophenyl, 3,5-dichlorophenyl, 2,4,6-tryptophanyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-iopener, 3-iopener, 2,3-dibromophenyl, 2,4-goodfeel, 2,4,6-trichlorophenyl etc.

Examples 5-7-membered saturated heterocyclic groups containing heterocyclic ring one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, include pyrrolidinyl, piperazinil, piperidinyl, morpholino, thiomorpholine, homopiperazine, homopiperazine, imidazolidinyl, thiazole is dinil, isothiazolinones, oxazolidinyl, isoxazolidine, isothiazolinones and pyrazolidine.

Examples of the above heterocyclic groups substituted by one to three substituents selected from the group containing oxoprop; lower alkyl groups; lower alcoholnye groups; phenyl lower alkyl groups; phenyl groups optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and lower alkoxygroup; and peredelnye groups:

include the above heterocyclic group, substituted by one to three substituents selected from the group consisting of the carbonyl group; straight or branched (C1-6alkyl groups; straight or branched (C1-6alcoholnye group; phenylaniline group, where the alkyl portion is a straight or branched C1-6alkyl group; phenyl group, optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and straight or branched C1-6alkoxygroup; and peredelnye group;

such as 2-oxo-(1-, 3-, 4 - or 5-)pyrrolidinyl,

2-oxo-(1-, 3-, 4-, 5 -, or 6-)piperazinil,

4-methyl-(1-, 2 - or 3-)piperazinil,

4-acetyl-(1-, 2 - or 3-)piperazinil,

4-ethyl-(1-, 2 - or 3-)piperazinil,

2-methyl-(1-, 2-, 3-, 4 - or 5-)pyrrolidinyl,

2-methyl-(1-,2-, 3-, 4-, 5 -, or 6-)piperidinyl,

2,4-dimethyl-(1-, 2-, 3-, 5 -, or 6-)piperidinyl,

3-methyl-(1-, 2-, 3-, 4 - or 5-)pyrrolidinyl,

2,3,4-trimethyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil,

4-acetyl-3-methyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil,

3-methyl-(2-, 3-, 4-, 5 -, or 6-)morpholino,

2-acetyl-(2-, 3-, 4-, 5 -, or 6-)morpholino,

4-(2-phenylethyl)-(1-, 2 - or 3-)piperazinil,

4-(3,4-dichlorophenyl)-(1-, 2-, 3 - or 4-)piperazinil,

4-(4-methoxyphenyl)-(1-, 2 - or 3-)piperazinil,

4-(2-chlorophenyl)-(1-, 2 - or 3-)piperazinil,

4-[(2-, 3 - or 4-)pyridyl]-(1-, 2 - or 3-)piperazinil,

4-phenyl-(1-, 2 - or 3-)piperazinil,

4-benzyl-(1-, 2 - or 3-)piperidinyl,

4-(3,4-dichlorophenyl)-(1-, 2 - or 3-)morpholino,

2-(4-methoxyphenyl)-(1-, 2-, 3-, 4 - or 5-)pyrrolidinyl,

4-(2-chlorophenyl)-(1-, 2 - or 3-)piperidinyl,

4-[(2-, 3 - or 4-)pyridyl]-(1-, 2 - or 3-)piperidinyl,

4-phenyl-(1-, 2 - or 3-)piperidinyl,

4-phenyl-3-methyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil,

4-[(2-, 3 - or 4-)pyridyl]-2-acetyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil etc.

Examples cycloalkyl lower alkyl groups include cycloalkyl alkyl groups, where cycloalkyl part represents a C3-8cycloalkyl group, and the alkyl portion is a straight or branched C1-6alkyl group, such as cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylmethyl, cyclopentylmethyl, 3-cyclopentylpropionyl, 4-cyclohexylmethyl, 5-cycloheptylmethyl, 6-kloosterhuis, 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylmethyl etc.

Examples of lower alkylthio lower alkyl groups include alkylthiomethyl group, where alkylthio part is a straight or branched C1-6allylthiourea and the alkyl portion is a straight or branched C1-6alkyl group, such as methylthiomethyl, 2-methylthioethyl, 1-ethylthioethyl, 2-ethylthioethyl, 3-n-butylthiophene, 4-n-propylthiouracil, 1,1-dimethyl-2-n-intertiatic, 5-n-hexylthiophene, 6-methylthioethyl, 1-ethylthioethyl, 2-methyl-3-metaltipped etc.

Examples of phenoxy lower alkyl groups include finacially group, where the alkyl portion is a straight or branched C1-6alkyl group, such as phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropionyl, 2-phenoxypropan, 4-phenoxybutyl, 5-phenoxyphenyl, 4-phenoxyphenyl, 6-phenoxyethyl, 2-methyl-3-phenoxypropan, 1,1-dimethyl-2-phenoxyethyl etc.

Examples of pyridyloxy lower alkyl groups include pyridyloxyacetic group, where the alkyl portion is a straight or branched C1-6alkyl group, such as

[2-, 3 - or 4-]pyridyloxy]methyl,

1-[2-, 3 - or 4-]pyridyloxy]ethyl,

2-[2-, 3 - or 4-]pyridyloxy]ethyl,

3-[2-, 3 - or 4-]pyridyloxy]propyl,

2-[2-, 3 - or 4-]pyridyloxy]propyl,

4-[2-, 3 - or 4-]pyridi the oxy]butyl,

5-[2-, 3 - or 4-]pyridyloxy]pentyl,

4-[2-, 3 - or 4-]pyridyloxy]pentyl,

6-[2-, 3 - or 4-]pyridyloxy]hexyl,

2-methyl-3-[2-, 3 - or 4-] pyridyloxy]propyl,

1,1-dimethyl-2-[2-, 3 - or 4-]pyridyloxy]ethyl etc.

Examples of the lower etkinlik groups include straight or branched C2-6alkyline groups, such as ethinyl, (1 - or 2-PROPYNYL, 1-methyl-(1 - or 2-PROPYNYL, 1-ethyl-(1 - or 2-PROPYNYL, (1-, 2 - or 3-)butenyl, (1-, 2-, 3 - or 4-)pentenyl, (1-, 2-, 3-, 4 - or 5-)hexenyl etc.

Examples of phenyl lower alkenyl groups include phenylalkylamine group containing one to three double bonds, where Alchemilla part is a straight or branched C2-6alkenylphenol group, such as styryl, 3-phenyl-2-propenyl (trivial name: cinnamyl), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 4-phenyl-1,3-butadienyl, 6-phenyl-1,3,5-hexatriene etc.

Examples cycloalkyl lower alkyl groups include cycloalkenyl group, where cycloalkyl part represents a C3-8cycloalkyl group, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of lower alkylthio lower alkyl groups include alkylthiomethyl group, where alkylthio part ol dstanley a straight or branched C 1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of amino-substituted lower alkyl groups, optionally substituted by one or two lower alkyl groups on the amino group include amino-substituted alkyl groups, optionally substituted by one or two straight or branched C1-6alkyl groups on the amino group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of phenoxy lower alkyl groups include finacially group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of pyridyloxy lower alkyl groups include pyridyloxyacetic group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of the 1,2,3,4-tetrahydronaphthyl lower alkyl groups include 1,2,3,4-tetrahydronaphthalene group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of imidazo[1,2-a]pyridyl lower alkyl groups include imidazo[1,2-a]pyridylamine group, where the alkyl part is a direct the second or branched C 1-6alkyl group as described above.

Examples thiazolyl lower alkyl groups include tutorialnya group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples tetrahydropyranyl lower alkyl groups include tetrahydropyranyl group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples piperidyl lower alkyl groups include piperidylidene group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of the diphenyl lower alkoxy-substituted lower alkyl groups include diphenylalkanes-substituted alkyl groups where the alkoxy part is a straight or branched C1-6alkoxygroup, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of the lower alkoxycarbonyl-substituted lower alkyl groups include alkoxycarbonyl-substituted alkyl groups where the alkoxy part is a straight or branched C1-6alkoxygroup, as described above, and the alkyl portion is a straight or branched C1-6alkyl group, as indicated the above.

Examples of phenyl lower alkoxycarbonyl-substituted lower alkyl groups include generalconditions-substituted alkyl groups where the alkoxy part is a straight or branched C1-6alkoxygroup, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of hydroxy-substituted lower alkyl groups include hydroxy-substituted alkyl groups where the alkyl portion is a straight or branched C1-6alkyl group, as defined above, with 1-3 hydroxy-group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 5-hydroxyphenyl, 4-hydroxyphenyl, 6-hydroxyhexyl, 2,2-dimethyl-3-hydroxypropyl, 1,1-dimethyl-2-hydroxyethyl, 2,3,4-trihydroxybutane etc.

Examples of the lower alkoxy lower alkyl groups include alkoxyalkyl group, where the alkoxy portion is a straight or branched C1-6alkoxygroup, as described above, and the alkyl portion is a straight or branched C1-6alkyl group, as defined above, such as methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxypropan, 3-methoxypropyl, 3-ethoxypropan, 3-propoxyphenyl, 4-methoxybutyl, 3-way shall libutil, 5-methoxyphenyl, 4-ethoxyphenyl, 6-methoxyphenyl, 2,2-dimethyl-3-methoxypropyl, 1,1-dimethyl-2-methoxyethyl etc.

Examples of carboxy lower alkyl groups include carboxialkilnuyu group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples carbarnoyl-substituted lower alkyl groups, optionally substituted by one or two lower alkyl groups on carbamoyl group include carbarnoyl-substituted alkyl groups, optionally substituted by one or two straight or branched C1-6alkyl groups on carbamoyl group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples morpholinylcarbonyl lower alkyl groups include morpholinylcarbonyl alkyl groups, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of the benzoyl lower alkyl groups include benzoylcholine group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of phenylthio lower alkyl groups include phenylthiourea group, where the alkyl portion is a straight or branched C1-6alkyl g is the SCP, as specified above.

Examples of naphthylthio lower alkyl groups include naphthylthiourea group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of cycloalkyl lower alkyl groups include cycloalkylcarbonyl group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of pyridylthio lower alkyl groups include pyridylmethylene group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of pyrimidinyl lower alkyl groups include pyrimidinediamine group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of purity lower alkyl groups include paritially group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of tianity lower alkyl groups include toinitialize group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples 1,3,4-thiadiazolyl lower alkyl groups include 1,3,4-thiadiazolidine group, where alkyl is Naya part is a straight or branched C 1-6alkyl group as described above.

Examples of benzimidazolylthio lower alkyl groups include benzimidazolylthio group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of benzothiazolylthio lower alkyl groups include benzothiazolylthio group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of tetrazolyl lower alkyl groups include tetraallylsilane group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of benzoxazolyl lower alkyl groups include benzoxazolyl group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of Tesorillo lower alkyl groups include thiazolidinedione group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of imidazoline lower alkyl groups include imidazolylalkyl group, where the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of amino-substituted lower and is kiltie lower alkyl groups, optionally substituted by one or two lower alkyl groups on one or two amino groups include amino-substituted alkylthiomethyl group, optionally substituted by one or two straight or branched C1-6alkyl groups on the amino group, where alkylthio part is a straight or branched C1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of phenyl-substituted lower alkylthio lower alkyl groups include phenyl-substituted alkylthiomethyl group, where alkylthio part is a straight or branched C1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples furyl-substituted lower alkylthio lower alkyl groups include furyl-substituted alkylthiomethyl group, where alkylthio part is a straight or branched C1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of pyridyl-substituted lower alkylthio lower alkyl groups include pyridyl-substituted alkylthiomethyl group, where alkylthio h is a R is a straight or branched C 1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of hydroxy-substituted lower alkylthio lower alkyl groups include hydroxy-substituted alkylthiomethyl group, where alkylthio part is a straight or branched C1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of phenoxy-substituted lower alkylthio lower alkyl groups include phenoxy-substituted alkylthiomethyl group, where alkylthio part is a straight or branched C1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

Examples of the lower alkoxycarbonyl-substituted lower alkylthio lower alkyl groups include alkoxycarbonyl-substituted alkylthiomethyl group, where the alkoxy portion is a straight or branched C1-6alkoxygroup, as stated above, alkylthio part is a straight or branched C1-6allylthiourea, as described above, and the alkyl portion is a straight or branched C1-6alkyl group as described above.

the reamers lower alkenyl groups include straight or branched C 2-6alkeneamine groups such as vinyl,

1-propenyl, allyl, 1-methylallyl, (1-, 2 - or 3-)butenyl,

(1-, 2-, 3 - or 4-)pentenyl and (1-, 2-, 3-, 4 - or 5-)hexenyl.

Examples dihydropyridine groups include 1,2-dihydropyridin, 3,4-dihydropyridin and the like.

Examples sulfanilic groups, substituted 5-7-membered saturated heterocyclic group, which heterocyclic group contains one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur include

pyrrolidinylcarbonyl, piperazinylcarbonyl,

piperidinylcarbonyl, morpholinomethyl, Tomorrowland,

homopiperazines, homopiperazine,

imidazolidinethione, diazolidinylurea,

isothiazolinones, oxazolidinediones,

isoxazolidinone, isothiazolinones,

pyrazolidinone etc.

Examples of the lower alkoxygroup include straight or branched C1-6alkoxygroup, such as methoxide, ethoxide etc.

Derivatives pyrrolidine represented by the General formula (1)can be obtained in various ways and, for example, a method in accordance with the following reaction scheme 1.

[Reaction scheme 1]

where R101and R102are such as defined above, and R112not only is em an amino-protective group.

Derived pyrrolidine (1) can be obtained by subjecting the compound (2) reaction of elimination to remove the amino-protective group.

Examples of amino protective groups, which can be used in this case include lower alkoxycarbonyl group, lower alcoholnye group, aryloxyalkyl group, aryl-substituted lower alkyl group, etc.

Examples of the lower alkoxycarbonyl groups include straight or branched C1-6alkoxycarbonyl groups, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, hexyloxybenzoyl etc.

Examples of the lower alkanoyl groups include straight or branched C1-6alcoholnye groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbamoyl, hexanoyl etc.

Examples aryloxyalkyl groups include phenoxy carbonyl group, optionally substituted with one to three substituents; naphthyloxy carbonyl group, optionally substituted with one to three substituents; and so Examples of the substituents for aryl groups include methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxic is l, 5,5,4-trihydroxyphenyl, 5-hydroxyphenyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, methyl bromide, vermeil, iodomethyl, deformity, dibromomethyl, 2-chloroethyl, 2,2,2-triptorelin, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichloroethyl, 4-terbutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-diclohexal, 3-hydroxy-2-chloropropyl, or similar direct or branched C1-6alkyl group, optionally substituted with one to three substituents selected from the group consisting of halogen atoms and hydroxyl group; methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxyethoxy, 2-hydroxyethoxy, 1 hydroxyethoxy, 3 hydroxypropoxy, 2,3-dihydroxypropane, 4-hydroxybutane, 1,1-dimethyl-2-hydroxyethoxy, 5,5,4-trihydroxyanthracene, 5-hydroxyethyloxy, 6-hydroxyhexyloxy, 1 hydroxyisopropyl, 2-methyl-3-hydroxypropoxy triptoreline, trichlormethane, chloromethoxy, bromoethoxy, formatosi, admetox, deformedarse, dibromoethane, 2-chloroethoxy, 2,2,2-triptoreline, 2,2,2-trichloroethane, 3 chloropropoxy, 2,3-dichloropropene, 4,4,4-trichlorobutane, 4-forbooks, 5-chloropentane, 3-chloro-2-methylpropoxy, 5-Bromhexine, 5,6-dichlorohexane, 3-hydroxy-2-chloropropoxy, or similar straight or branched Csub> 1-6alkoxygroup, optionally substituted with one to three substituents selected from the group consisting of halogen atoms and hydroxyl group; halogen atoms such as fluorine, bromine, chlorine, and iodine; and so When there are two or more substituents, the substituents may be the same or different.

Examples of aryl-substituted lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-fenilpentil, 6-phenylhexa, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, 2-(α-naphthyl)ethyl, 1-(β-naphthyl)ethyl, 3-(α-naphthyl)propyl, 4-(β-naphthyl)butyl, 5-(α-naphthyl)pentyl, 6-(β-naphthyl)hexyl, 1,1-dimethyl-2-(α-naphthyl)ethyl, 2-methyl-3-(β-naphthyl)propyl, similar to the phenyl-substituted straight or branched C1-6alkyl group, optionally substituted with one to three substituents; or similar naphthyl-substituted straight or branched C1-6alkyl group, optionally substituted with one to three substituents. Examples of substituents for aryl groups include methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxyphenyl, 5-hydroxyphenyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trial rmeil, chloromethyl, methyl bromide, vermeil, iodomethyl, deformity, dibromomethyl, 2-chloroethyl, 2,2,2-triptorelin, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichloroethyl, 4-terbutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-diclohexal, 3-hydroxy-2-chloropropyl, or similar straight or branched C1-6alkyl group, optionally substituted with one to three substituents selected from the group consisting of halogen atoms and hydroxyl group; methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxyethoxy, 2-hydroxyethoxy, 1 hydroxyethoxy, 3 hydroxypropoxy, 2,3-dihydroxypropane, 4-hydroxybutane, 1,1-dimethyl-2-hydroxyethoxy, 5,5,4-trihydroxyanthracene, 5-hydroxyethyloxy, 6-hydroxyhexyloxy, 1 hydroxyisopropyl, 2-methyl-3-hydroxypropoxy triptoreline, trichlormethane, chloromethoxy, bromoethoxy, formatosi, admetox, deformedarse, dibromoethane, 2-chloroethoxy, 2,2,2-triptoreline, 2,2,2-trichloroethane, 3 chloropropoxy, 2,3-dichloropropene, 4,4,4-trichlorobutane, 4-forbooks, 5-chloropentane, 3-chloro-2-methylpropoxy, 5-Bromhexine, 5,6-dichlorohexane, 3-hydroxy-2-chloropropoxy, or similar straight or branched C1-6alkoxygroup, optionally substituted with one to three substituents selected from the group consisting of halogen atoms and guide auxillou group; the atoms of halogen, such as fluorine, bromine, chlorine and iodine; etc. When there are two or more substituents, the substituents may be the same or different.

The reaction of obtaining compound (1) from compound (2) is carried out in a suitable solvent or without solvent in the presence of acid or basic compound. This reaction later in this description referred to as “reaction A”.

Examples of solvents include water; lower alcohols such as methanol, ethanol, isopropanol and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers, such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-organic; dimethylsulfoxide; triamide hexamethylphosphoric acid; and mixtures of such solvents.

Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid and Hydrobromic acid; and organic acids such as formic acid, acetic acid, triperoxonane acid and p-toluensulfonate acid.

Note the factors used bases include carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide.

Acidic or basic compound is usually used in amounts of at least about 1 mol, preferably about 1 to about 10 mol, per mol of compound (2). However, the acid can also be used in a large excess relative to the compound (2).

Usually the reaction is conveniently carried out at a temperature of from about 0 to about 200°C, preferably about 0 to about 150°C, and the reaction is usually completed within from about 10 minutes to about 30 hours.

When R112in the compound (2) is an aryl-substituted lower alkyl group, you can also get a connection (1) the restoration of such compounds (2).

The reduction can be realized, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst.

Examples of solvents include water; acetic acid; alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as n-hexane and cyclohexane; ethers such as dioxane, tetrahydrofuran, diethyl ether and dimethyl ether of ethylene glycol; esters such as ethyl acetate and methyl acetate; protoni the polar solvents, such as dimethylformamide; and mixtures of such solvents.

Examples of catalysts include palladium, palladium black, palladium on carbon, platinum, platinum oxide, copper chromite, Raney Nickel, and mixtures thereof. The catalyst is preferably used in amounts of from about 0.02 to about 1 parts by weight of the compound (2).

The reaction temperatures when carrying out the reaction, recovery is usually about -20 to about 100°C, preferably about 0 to about 80°C and the hydrogen pressure is usually from 1 to 10 ATM. Normally, the reaction is complete within about 0.5 to about 20 hours.

When R112in the compound (2) is an aryl-substituted lower alkyl group, compound (2) can be converted to the compound (1) stages (i) treatment of the compound (2) dealkylase agent in a suitable solvent; and (ii) by heating the compounds in a suitable solvent.

The solvent used in the reaction in stage (i)may be such as any solvent used in the reaction (A).

The examples used dealkylase agents include esters of formic acid, such as 1-chloroethylphosphonic, ethylchloride and tert-butylchloroformate. Dealkylase agent is usually used in amounts of at least about 1 mol of compound 2), preferably from about 1 mol to about 10 mol, per mol of compound (2).

Usually the reaction is conveniently carried out at a temperature of from about 0 to about 150°C, preferably at a temperature from room temperature to about 100°C, and usually the reaction is completed within about 1 to about 25 hours.

Examples of the solvent used in stage (ii)include alcohols such as methanol, ethanol and isopropanol. Heating is usually carried out at a temperature from about 0 to about 150°C, preferably at a temperature from room temperature to about 100°C, for about 1 to about 10 hours.

The compound of General formula (2)used as starting substances, can be easily obtained, for example, by the method shown in reaction scheme 2:

[Reaction scheme 2]

where R101, R102and R112are as described above.

The reaction of the compound (3) with compound (4) is conducted, for example, without solvent or in a suitable solvent in the presence of a reducing agent.

When carrying out the reaction of the compound (4) is usually used in amounts of at least about 1 mol per mol of compound (3) and preferably equivalent to a large excess relative to the compound (3).

Examples of solvents include water, lower alcohols, such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; acetonitrile; aliphatic acids such as formic acid and acetic acid; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and carbon tetrachloride; and mixtures of such solvents.

Examples of reducing agents include aliphatic acids such as formic acid; alkali metal salts of aliphatic acids, such as formate, sodium hydride reducing agents such as sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium, sociallyengaged or a mixture of such hydride reducing agents; reducing agents for catalytic hydrogenation, such as palladium black, palladium on carbon, platinum oxide, platinum black and Raney Nickel.

When the reducing agent used aliphatic acid or the alkali metal salt of aliphatic acid, a suitable temperature is usually from room temperature to about 200°C, preferably from about 50 to about 150°C. Usually the reaction is completed within about 10 minutes to about 10 hours. Aliphatic acid or the ol alkali metal aliphatic acid is preferably used in large excess relative to the compound (3).

When the reducing agent used hydride reducing agent, a suitable reaction temperature is usually about -80 to about 100°C, preferably from about -80 to about 70°C. Usually the reaction is completed within about 30 minutes to about 60 hours. Hydride reducing agent is usually used in an amount of about 1 to about 20 mol per mol of compound (3), preferably from about 1 to about 6 mol per mol of compound (3). When a hydride reducing agent used sociallyengaged, especially preferred is the use of ethers, such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme, aromatic hydrocarbons such as benzene, toluene and xylene, or mixtures of such solvents as solvents. In the reaction system may be added amine(s), such as trimethylamine, triethylamine and N-ethyldiethanolamine, or molecular sieves such as molecular sieves type 3Å (MS-3Å) and molecular sieves type 4Å MS-4Å).

When the reducing agent used reducing agent for the catalytic hydrogenation, the reaction is usually carried out at a temperature of from about -30 to about 100°C, preferably about 0 to about 60°C, in an atmosphere of hydrogen p and a pressure of from about atmospheric pressure to about 20 ATM, preferably from about atmospheric pressure to about 10 ATM, or in the presence of a hydrogen donor such as formic acid, ammonium formate, cyclohexene and hydrazinehydrate. Normally, the reaction is complete within about 1 to about 12 hours. Reducing agent for the catalytic hydrogenation is usually used in amounts of from about 0.1 to about 40 wt.%, preferably from about 1 to about 20 wt.%, relative to compound (3).

[Reaction scheme 3]

where R101, R102and R112are as above; R113represents a lower alkylsulfonates, phenylsulfonylacetate, optionally substituted in the phenyl ring by one or more lower alkyl groups or halogen atom.

Lowest alkylsulfonates is a group consisting of C1-6alkyl groups and sulfonyloxy, examples of which include methanesulfonate, econsultancy, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate.

Examples of phenylsulfonylacetate, optionally substituted in the phenyl ring by one or more lower alkyl groups, are benzolsulfonate, which may be substituted by one to three straight or RA is extensive C 1-6alkyl groups, such as benzosulfimide, on-toluensulfonate, m-toluensulfonate, p-toluensulfonate, 2-ethylbenzonitrile, 3 ethylbenzaldehyde, 4-ethylbenzaldehyde, 2-propylbenzenesulfonyl, 3 propylbenzenesulfonyl, 4-propylbenzenesulfonyl, 2,3-dimethylbenzenesulfonic, 2,4-dimethylbenzenesulfonic and 2,4,6-trimethylbenzenesulfonyl.

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

The reaction of the compound (4) with compound (5) is carried out in a suitable solvent in the presence of a basic compound.

Examples of inert solvents include water; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme and diglyme; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; aliphatic acids such as acetic acid; esters such as ethyl acetate and methyl acetate; ketones such as acetone and methyl ethyl ketone; acetonitrile, pyridine, N-organic, dimethylsulfoxide, N,N-dimethylformamide and hexamethylphosphoramide; and mixtures of such solvents.

Examples of the main connection is in include carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and cesium carbonate; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and calcium hydroxide; phosphates such as potassium phosphate and sodium phosphate; hydrides of alkali metals, such as sodium hydride and potassium hydride; alkali metals such as sodium and potassium; sodium amide; metal alcoholate such as sodium methylate, sodium ethylate, n-piperonyl sodium tert-piperonyl sodium tert-piperonyl potassium; organic bases, such as pyridine, imidazole,

N-ethyldiethanolamine, dimethylaminopyridine, triethylamine,

trimethylamine, dimethylaniline, N-methylmorpholine,

1,5-diazabicyclo[4.3.0]nonan-5 (DBN),

1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and

1,4-diazabicyclo[2.2.2]octane (DABCO); and mixtures of such bases.

The compound (5) are usually used in amounts of at least about 0.1 mol per mol of compound (4), preferably from about 0.1 to about 10 mol per mol of compound (4).

The primary connection (ground) are usually used in amounts of at least about 1 mol per mol of compound (4), preferably about 1 to about 10 mol per mol of compound (4).

If the reaction instead of adding a basic compound may be used in a large excess of the compound (4).

When carrying out the reaction, the reaction system may be added to compounds of halides of alkali metals, such as sodium iodide and potassium iodide.

The reaction is usually carried out at a temperature of from about 0 to about 200°C, preferably about 0 to about 150°C, and the reaction usually completed within from about 5 minutes to about 80 hours.

[Reaction scheme 4]

where R101, R102and R112are such as defined above, and X represents a halogen atom.

The reaction between the compounds (6) and (7) and the reaction between the compounds (8) and (9) is carried out in the same conditions as described for the reaction between compounds (5) and (4)shown in reaction scheme 3.

When R101or R102in the compound (6) are any of the groups represented(1)-(14), (17)-(32) and (40)-(50), the reaction between the compound (6) and compound (7) is carried out in a suitable solvent in the presence of a basic compound and catalyst. Similarly, when R101or R102in the compound (8) represents any of groups represented(1)-(14), (17)-(32) and (40)-(50), the reaction between the compound (8) and compound (9) is carried out in a suitable solvent in the presence of a basic compound and a catalyst.

The solvent and the base used in the reaction, each may be the same as that used when conducting the reaction between the compounds (5) and (4)shown in reaction scheme 3.

<> Examples of catalysts include palladium compounds such as palladium acetate,

bis(tributylamine)/bis(dibenzylideneacetone)palladium

iodide of copper/2,2'-bipyridyl, bis(dibenzylideneacetone)palladium

Tris(dibenzylideneacetone)dipalladium,

[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and

tetrakis(triphenylphosphine)palladium; binaphthalene compounds such as R-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (R-BINAP), S-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (S-BINAP) and RAC-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (RAC-BINAP); xanthene compounds such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; borates, such as tri-tert-butyltetrahydrofuran; 2,2-bis(diphenylimidazole); and mixtures thereof.

The base is usually used in amounts of at least about 0.5 mol per mol of compound (6) or (8), preferably from about 0.5 to about 40 mol per mol of compound (6) or (8).

The catalyst may be used in conventional catalytic amount of for compound (6) or (8).

Compounds (7) and (9) are usually used in amounts of at least about 0.5 mol per mol of compound (6) and (8) respectively, preferably from about 0.5 to about 3 mol per mol of compound (6) and (8).

These reactions usually conveniently carried out at a temperature of from room temperature to about 200°C, preferably from room temperature to PR is approximately 150°C, and usually the reaction is complete within about 0.5 to about 20 hours.

When R101or R102in the compound (6) are any of the groups represented(1)-(14), (17)-(32) and (40)-(50), the reaction between the compound (6) and compound (7) is carried out in a suitable solvent in the presence of a basic compound, copper iodide and ethylene glycol. Similarly, when R101or R102in the compound (8) represents any of groups represented(1)-(14), (17)-(32) and (40)-(50), the reaction between the compound (8) and compound (9) is carried out in a suitable solvent in the presence of a basic compound, copper iodide and ethylene glycol.

The solvent and the base used in the reaction, each may be the same as that used when conducting the reaction between the compounds (5) and (4)shown in reaction scheme 3.

The copper iodide and ethylene glycol, each may be usually in an amount of about from 0.1 to 3 mol, preferably from about 0.05 to about 1 mol, per mol of compound (6) or (7).

Compounds (7) and (9) are usually used in amounts of at least about 1 mole per mole of the compounds (6) and (8) respectively, preferably from about 1 to about 2 mol per mole of the compounds (6) and (8).

These reactions usually conveniently carried out at a temperature of from room temperature to about 200°C, preferably from room temperature the temperature to about 150°C, and usually the reaction is complete within about 0.5 to about 50 hours.

When R101or R102in the compound (6) are any of the groups represented(1)-(14), (17)-(32) and (40)-(50), the reaction between the compound (6) and compound (7) is carried out in a suitable solvent in the presence of silane compounds, such as bis(trimethylsilyl)amide and sodium. Similarly, when R101or R102in the compound (8) are any of the groups represented(1)-(14), (17)-(32) and (40)-(50), the reaction between the compound (8) and compound (9) is carried out in a suitable solvent in the presence of silane compounds, such as bis(trimethylsilyl)amide and sodium.

The solvent used in the reaction may be the same as that used when conducting the reaction between the compounds (5) and (4)shown in reaction scheme 3.

The silane compound is usually used in amounts of from about 0.1 to about 3 mol, preferably from about 0.1 to about 2 mol, per mole of the compounds (6) or (7).

Compounds (7) and (9) are usually used in amounts of at least about 1 mole per mole of the compounds (6) and (8) respectively, preferably from about 1 to about 2 mol per mole of the compounds (6) and (8).

These reactions usually conveniently carried out at a temperature of from about 0 to about 200°C, preferably about 0 to approx the RNO 150°C, and usually the reaction is complete within about 0.5 to about 20 hours.

Depending on the type of compounds (7) the interaction of compounds (6) and compound (7) gives, instead of the compound (8), the compound (10)shown below:

where R101and R112are as described above.

[Reaction scheme 5]

where R101and X are such as defined above, R108represents any of the groups (1-1)to(1-37), as indicated in the General formula (1), R110and R111associated with education together with the nitrogen atom to which they are attached, a 5-7 membered ring containing one nitrogen atom, a saturated heterocyclic group which may have one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, while the heterocyclic group is optionally substituted with one to three substituents selected from the group containing oxoprop; lower alkyl groups; lower alcoholnye groups; phenyl lower alkyl groups; phenyl groups optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and lower alkoxygroup; and peredelnye group,

and b' is an integer from 0 to 3.

Examples 5-7-membered containing one atom AZ is the saturated heterocyclic group which may have one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, include pyrrolidinyl, piperazinil, piperidinyl, morpholino, thiomorpholine, homopiperazine, homopiperazine, imidazolidinyl, diazolidinyl, isothiazolinones, oxazolidinyl, isoxazolidine, isothiazolinones and pyrazolidine.

Examples of the above heterocyclic groups substituted by one to three substituents selected from the group containing oxoprop; lower alkyl groups; lower alcoholnye groups; phenyl lower alkyl groups; phenyl groups optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and lower alkoxygroup; and peredelnye groups:

include the above heterocyclic group, substituted by one to three substituents selected from the group consisting of the carbonyl group; straight or branched (C1-6alkyl groups; straight or branched (C1-6alcoholnye group; phenylaniline group, where the alkyl portion is a straight or branched C1-6alkyl group; phenyl group, optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and straight or branched C1-6alkoxy is a group; and peredelnye group;

such as 2-oxo-(1-, 3-, 4 - or 5-)pyrrolidinyl,

2-oxo-(1-, 3-, 4-, 5 -, or 6-)piperazinil,

4-methyl-(1-, 2 - or 3-)piperazinil,

4-acetyl-(1-, 2 - or 3-)piperazinil,

4-ethyl-(1-, 2 - or 3-)piperazinil,

2-methyl-(1-, 2-, 3-, 4 - or 5-)pyrrolidinyl,

2-methyl-(1-, 2-, 3-, 4-, 5 -, or 6-)piperidinyl,

2,4-dimethyl-(1-, 2-, 3-, 5 -, or 6-)piperidinyl,

3-methyl-(1-, 2-, 3-, 4 - or 5-)pyrrolidinyl,

2,3,4-trimethyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil,

4-acetyl-3-methyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil,

3-methyl-(2-, 3-, 4-, 5 -, or 6-)morpholino,

2-acetyl-(2-, 3-, 4-, 5 -, or 6-)morpholino,

4-(2-phenylethyl)-(1-, 2 - or 3-)piperazinil,

4-(3,4-dichlorophenyl)-(1-, 2-, 3 - or 4-)piperazinil,

4-(4-methoxyphenyl)-(1-, 2 - or 3-)piperazinil,

4-(2-chlorophenyl)-(1-, 2 - or 3-)piperazinil,

4-[(2-, 3 - or 4-)pyridyl]-(1-, 2 - or 3-)piperazinil,

4-phenyl-(1-, 2 - or 3-)piperazinil,

4-benzyl-(1-, 2 - or 3-)piperidinyl,

4-(3,4-dichlorophenyl)-(1-, 2 - or 3-)morpholino,

2-(4-methoxyphenyl)-(1-, 2-, 3-, 4 - or 5-)pyrrolidinyl,

4-(2-chlorophenyl)-(1-, 2 - or 3-)piperidinyl,

4-[(2-, 3 - or 4-)pyridyl]-(1-, 2 - or 3-)piperidinyl,

4-phenyl-(1-, 2 - or 3-)piperidinyl,

4-phenyl-3-methyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil,

4-[(2-, 3 - or 4-)pyridyl]-2-acetyl-(1-, 2-, 3-, 5 -, or 6-)piperazinil etc.

The reaction between the compound (11) and compound (12) is carried out in the same conditions as described for the reaction between compounds (6) and (7)that are listed on the reactivity of the scheme 4.

[Reaction scheme 6]

where R101, R108, b' and X are as described above.

The compound (14) is produced by interaction of the compound (11) with a compound of the metal cyanide in a suitable solvent in the presence of a catalyst.

Examples of compounds cyanide metal include sodium cyanide, potassium cyanide, hydrogen cyanide zinc, copper cyanide, etc.

The solvent and catalyst used in the reaction, each may be the same as that used when conducting the reaction between the compounds (6) and (7)shown in reaction scheme 4. For compound (11) the catalyst may be used in conventional catalytic amount.

The connection of the metal cyanide is usually used in amounts of at least about 1 mol per mol of compound (11), preferably from about 1 to about 3 mol per mol of compound (11).

The reaction is conveniently carry out usually at a temperature of from room temperature to about 200°C, preferably at room temperature to about 150°C, and the reaction usually completed within from about 0.5 to about 20 hours.

[Reaction scheme 7]

where R101, R108, b' and X are such as defined above, and R114represents any of groups represented (1-3), (1-12), (1-14), (1-19), (1-23), (1-30) and (1-31) in the General formula (1).

The reaction between the compound (11) and compound (15) is carried out in the same conditions as described for the reaction between compounds (6) and (7)shown in reaction scheme 4.

[Reaction scheme 8]

where R101and R112are as above; R115represents a phenyl group, a phenyl lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, a lower alkylthio lower alkyl group, amino-substituted lower alkyl group, optionally substituted on the amino group by one or two lower alkyl groups, phenoxy lower alkyl group or a pyridyl lower alkyl group; and R116represents a hydrogen atom or a lower alkyl group. Alternative, R115and R116can be linked together with the formation of cycloalkyl group provided that the total number of carbon atoms in the fragment CH(R116)(R115) in the side chain -(R101)CH(R116)(R115the connection (18) does not exceed 6.

The reaction between the compound (8) and compound (17) is carried out in the same conditions as described for the reaction between compounds (3) and (4)shown in reaction scheme 2, except that the compound (17) is used usually in an amount of at least 1 mol per mol of compound (8), preferably 1-5 mol per mol soy is inane (8).

[Reaction scheme 9]

where R101and R112are as described above; a' is an integer from 0 to 4; R103represents any of the groups (1-1)to(1-37), as indicated in the General formula (1), R117represents the lowest alkoxycarbonyl group; and R118is carboxypropyl.

The compound (20) obtained by hydrolysis of compound (19).

Hydrolysis of the compound (19) is carried out in a suitable solvent or without solvent in the presence of acid or basic compound.

Examples of solvents include water; lower alcohols such as methanol, ethanol, isopropanol and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers, such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aliphatic acids such as acetic acid and formic acid; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; dimethylsulfoxide, N,N-dimethylformamide and hexamethylphosphorotriamide; and mixtures of such solvents.

Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid and Hydrobromic acid; and organic acids such as mu is Avina acid, acetic acid and sulfonic acids such as triperoxonane acid and p-toluensulfonate acid. Such acids can be used separately or in combination.

Examples of bases include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide; and other similar basic connectivity. These basic compounds may be used separately or in combination.

The hydrolysis reaction is usually conveniently carried out at a temperature of from about 0 to about 200°C, preferably about 0 to about 150°C, and usually the reaction is completed within about 10 minutes to about 30 hours.

The compound (19) is produced by interaction of the compound (20) with the compound represented by the General formula (21):

R119OH(21)

where R119represents a lower alkyl group.

The conditions chosen usually for esterification reactions are such that acceptable for the interactions between the compounds (20) and (21). For example, the reaction between the compounds (20) and (21) which can be carried out in the presence of a mineral acid, such as hydrochloric acid and sulfuric acid; or a halogenation agent such as thionyl chloride, oxychloride fosefor, pentachloride fosefor and trichloride Fosfor. The compound (21) is used in large excess relative to the compound (20). The reaction is usually conveniently carried out at a temperature of from about 0 to about 150°C, preferably from about 50 to about 100°C, and usually the reaction is completed within about 1 to about 10 hours.

[Reaction scheme 10]

where R101, R103, a' and R112are as above; R120represents a lower alkylthiols; and R121represents the lowest alkylsulfonyl group.

The reaction of obtaining compound (23) from compound (22) is carried out in a suitable solvent in the presence of an oxidizing agent.

Examples of solvents include water; aliphatic acids such as formic acid, acetic acid and triperoxonane acid; alcohols such as methanol and ethanol; halogenated hydrocarbons such as chloroform and dichloromethane; and mixtures of such solvents.

Examples of oxidizing agents include percolate, such as paranavitana acid, peracetic acid, perceptionally acid, phenoxybenzoic acid, m-chloroperoxybenzoic key is lots and on-carboxyphenoxypropane acid; hydrogen peroxide; metaperiodate sodium; dichromate, such as darmowa acid, sodium dichromate and potassium dichromate; permanganates such as permanganate acid, sodium permanganate and potassium permanganate; lead salts, such as leads to compounds, which lead.

The oxidizing agent is usually used in amounts of at least about 2 mol per mol of compound (22), preferably from about 2 to 4 mol per mol of compound (22).

The reaction is usually carried out at a temperature of from about -10 to about 150°C, preferably from about -10 to about 100°C, and usually the reaction is completed within about 1 to about 10 hours.

[Reaction scheme 11]

where R101and R112are as above; R122represents a lower alkyl group containing one or more atoms of halogen; R123is an amino-substituted lower alkyl group, optionally substituted on the amino group by one or two lower alkyl groups; and R123arepresents an amino group, optionally substituted on the amino group by one or two lower alkyl groups.

The reaction between the compound (24) and compound (25) is carried out in the same conditions as described for the reaction between compounds (5) and (4)shown in reaction scheme 3.

Compound (7) is (9), used as starting substances can be easily obtained, for example, by the method shown in the reaction scheme below:

[Reaction scheme 12]

where X is as above, and R124represents a lower alkyl group containing one or more halogen atoms.

The reaction between the compound (27) and compound (28) is carried out in the same conditions as described for the reaction between compounds (5) and (4)shown in reaction scheme 3.

Compound (8)used as starting substances can be obtained, for example, by the method shown in reaction scheme 13 below:

[Reaction scheme 13]

where R103, a', X and R112are as described above.

The reaction of obtaining the compound (31) of the connection (30) is conducted, for example, without solvent or in a suitable solvent in the presence of a reducing agent.

Examples of solvents include water; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; acetonitrile; aliphatic acids such as formic acid and acetic acid; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; aromatic hydrocarbons such as benzene, toluene and the COP is lol; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; and mixtures of such solvents.

Examples of the reducing agent include reducing agents for catalytic hydrogenation, such as palladium black, palladium on carbon, platinum oxide, platinum black and Raney-Nickel and the like.

Reducing agent for the catalytic hydrogenation is usually used in an amount of about from 0.1 to 40 wt.%, preferably from about 0.1 to about 20 wt.% regarding the connection (30).

The reaction is conveniently conducted by adding to the reaction system when carrying out the reaction of the compound(s)such as sodium hydroxide.

The reaction is usually carried out at a temperature of from about -30 to about 100°C, preferably about 0 to about 60°C, in an atmosphere of hydrogen at a pressure of from atmospheric to about 20 ATM, preferably from atmospheric pressure to about 10 ATM. The reaction is usually complete within about 1 to about 12 hours.

Compounds (3), (5) and (6)used as starting substances can be easily obtained, for example, in accordance with the reaction scheme below:

[Reaction scheme 14]

where R112and X are such as defined above, and R125p is ecstasy oxoprop, the group represented by R113or amino group, where R113has the values listed above.

The reaction between the compounds (32) and (33) is carried out in the same conditions as described for the reaction between compounds (5) and (4)shown in reaction scheme 3 above.

The compound (4)used as starting substances, easy to get, for example, by the method shown in the reaction scheme below:

[Reaction scheme 15]

where R101, R102and X are as described above.

The reaction of the compound (35) with compound (9) is carried out in the same conditions as described for the reaction of compound (6) with compound (7)shown in reaction scheme 4.

Connection(2), (8), (13), (14), (16), (18), (19), (20), (23) and (26), in each of which R112represents a hydrogen atom, can be obtained by replacing R112the hydrogen atom in compounds(3), (5), (6), (8), (11), (19), (20), (22) and (24), which are used as the source in each reaction shown in the reaction schemes 2-11 using the thus obtained compound as the starting material and subjecting a starting material interaction in the same conditions as described for the reactions shown in reaction schemes 2-11.

If the initial substance (connection(5), (6), (8), (11), (19), (20), (22) and (24)) in the reactions shown in reactionism 3-11, use of optically active substance, the optically active compounds(2), (8), (13), (14), (16), (18), (19), (20), (23) and (26) can be obtained by reaction of the compound under the same conditions as described for the reaction shown in the reaction schemes 3-11.

It is also possible to obtain compound (1) of the present invention using compounds(2), (8), (13), (14), (16), (18), (19), (20), (23) or (26)formed in the reactions according to the reaction schemes 2-11, using them as the starting material in the reaction according to reaction scheme 1, without highlighting.

Each of the target compounds obtained in accordance with the above reaction scheme, can be isolated from the reaction mixture and purified, for example, after cooling the reaction mixture, the selection is carried out by methods such as filtration, concentration, extraction, etc. for the extraction of the crude reaction product, and then subjecting the crude reaction product of conventional purification methods such as column chromatography, recrystallization, etc.

The compound of General formula (1) in accordance with the present invention includes stereoisomers and optical isomers.

Some of the initial compounds and the target pyrolidine compounds of the present invention having a basic group or groups, can form salts with known pharmaceutically acceptable acid is I. Examples of such acids include hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and other inorganic acids; methansulfonate acid, p-toluensulfonate acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid and other organic acids, etc.

Some of the initial compounds and the target pyrolidine compounds of the present invention having the acid group or groups may form salts with known pharmaceutically acceptable bases. Examples of such bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.

In addition to the original compounds and target compounds are presented in each of the reaction formulas connection added in the form of a solvate (e.g. hydrate, ethanolate, etc), and they are included for each of the General formulas.

Pharmaceutical preparations containing the compound of the present invention as an active ingredient, discussed below.

Such pharmaceutical preparations are prepared by incorporating the compounds of the present invention in a standard pharmaceutical preparations using commonly used is aslavital and/or excipients, such as fillers, extenders, binders, moisturizing agents, disintegrant, surfactants, lubricants, etc.

The form of such pharmaceutical preparations may be selected from various forms according to therapy goals. Specific examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc. and the like.

Upon receipt of the tablets can be used any of various known carriers, including, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, solutions of starch, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, powder of laminaran, sodium bicarbonate, calcium carbonate, esters of fatty acids and polyoxyethylenesorbitan, sodium lauryl sulfate, monoglycerides of stearic acid, starch, lactose and other disintegrant; white sugar, stearin, cacao butter, hydrogenated oils and other inhibitors of decomposition; Quaternary ammonium bases, sodium lauryl sulfate and other amplifiers absorption; CH is zerin, starch and other moisturizing agents; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; and so on

These tablets, if necessary, can be covered with the usual substances for coating to obtain, for example, tablets, coated sugar pellets coated with gelatin, tablets with a coating resistant to gastric juice, tablets, film-coated, tablets with bilateral or multilayer coating, etc.

Upon receipt of the pills can be used any of various known carriers, including, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; powdered gum Arabic, powdered tragakant, gelatin, ethanol and other binders; laminaran, agar-agar and other disintegrant; etc.

Upon receipt of the suppositories can be used any of various known carriers, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

When receiving the injection, solution, emulsion or suspension of their sterilized and preferably do is isotonic with respect to blood. To obtain a solution, emulsion or suspension Can be COI is used any of various well-known widely used diluents. Examples of such diluents include water, ethanol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, esters of fatty acids 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 soljubilizatory, buffers, analgesic agents, etc. and additionally, if necessary, coloring agents, preservatives, flavoring agents, sweetening agents, etc. and/or other medicines.

The quantitative content of the compounds of the present invention in the pharmaceutical preparation is not limited and may be appropriately selected from a wide area. Usually preferably, the pharmaceutical preparation contains the compound of the present invention in an amount of from 1 to 70 wt.%.

Route of administration of the pharmaceutical preparation of the present invention is not limited, and the drug is administered in a way that is appropriate for the form of the drug, age and sex of the patient, status of the disease and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are injected separately or mixed with conventional inj klonnie solutions such as glucose, amino acid solutions or the like, or injected separately intramuscularly, intracutaneously, subcutaneously or intraperitoneally, if necessary. Suppositories administered rectally.

The dosage of the pharmaceutical preparation select a suitable manner in accordance with the method of application, age and sex of the patient, severity of disease and other conditions, and it is usually from about 0.001 to about 100 mg/kg body weight/day, preferably 0.001 to 50 mg/kg body weight/day, in single or divided doses.

Since the dose varies depending on various conditions, it may be sufficient dosage is less than that specified above, or can be used higher doses than specified above.

Derived pyrrolidin the present invention has inhibitory effect of re-absorption of one, two or three kinds of monoamines (i.e. serotonin, norepinephrine, dopamine).

Derived pyrrolidine of the present invention exhibits a significantly stronger inhibitory activity absorption against a representative of the three monoamines in comparison with known compounds with inhibitory activity acquisitions in respect of monoamines in experiments in vitro or ex vivo. In microdialysis study derived pyrrolidine this is th invention also exhibits a significantly stronger effect in strengthening one of the three monoamines in the rat brain compared with the known compounds, possessing inhibitory activity acquisitions in respect of monoamines.

Derived pyrrolidin the present invention has a wider range for medical treatment than known antidepressants.

Derived pyrrolidine of the present invention exhibits a sufficient therapeutic effect even after a short introduction.

Derived pyrrolidin the present invention has excellent bioavailability, weak suppressive metabolism enzymes in the liver activity, small side effects and is very safe.

Derived pyrrolidine of the present invention exhibits strong activity in mice in the forced swimming test/hanging by the tail, which is used in the screening of antidepressant drugs. Derived pyrrolidin the present invention also exhibits strong activity in rats in the forced swimming test, which is used in the screening of antidepressant drugs. Derived pyrrolidin the present invention also exhibits a strong activity on the model of reserpine-induced hypothermia, which is used as a screening test for antidepressants.

Derived pyrrolidin the present invention also exhibits strong activity in mice in the test behavioral helplessness (marble-burying behavior test) and the MTM is ECCA, the due to fear, which are models of diseases associated with anxiety or stress.

Derived pyrrolidin the present invention has inhibitory effect of re-absorption of one, two or three kinds of monoamines (i.e. serotonin, norepinephrine, dopamine), and is therefore effective in the treatment of various disorders caused by reduced neurotransmission of serotonin, norepinephrine or dopamine.

Examples of such diseases include hypertension, depression (i.e. a deep depression, bipolar disorder 1 bipolar disorder 2, a mixed episode, estimatesa disorders, "fast cycle", atypical depression, seasonal affective disorder, postpartum depression, mild depression, recurrent brief depressive disorder, irregular depression/chronic depression, double depression, alcohol-induced mood disorders mixed anxiety and depressive disorder; depression caused by a variety of physical disorders, such as Cushing's disease, hypothyroidism, syndrome hyperparathyroidism, Addison disease, syndrome, absence of menstruation and lactation, Parkinson's disease, Alzheimer's disease, bleeding in the brain, diabetes, chronic fatigue syndrome and cancer; depression middle aged, senile depression, Detskoye teenage depression, depression caused by drugs, such as interferon, depression, caused by adaptation, anxiety, caused by adaptation, anxiety, caused by various physical disorders (i.e. neuropathy (head injury, brain infection, a disease of the inner ear), cardiovascular disease (cardiac arrest, abnormal heart rhythm), endocrine disorders (hyperthyroidism, adrenal, exophthalmic cachexia), breathing problems (asthma, chronic obstructive pulmonary disease), disorders caused by anxiety, fears (e.g. agoraphobia, social phobia and simple phobias), post-traumatic stress disorder syndrome of acute stress, avoidant personality disorder, disorder dysmorphism body, premature ejaculation, eating disorders (i.e. anorexia nervosa and bulimia nervosa), obesity, addiction to chemical substances (i.e. alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain disorders, Alzheimer's disease, obsessive convulsive disorder, panic disorder, memory disorders (e.g. dementia, amnesia and the ageing-related weakening of trainability (ARCD)), Parkinson's disease (i.e. dementia caused by Parkinson's disease, Parkinson's disease, caused by narola the political agent, late dyskinesia), endocrine disorders (i.e., hyperprolactinaemia), vascular spasm (in particular, in the circulatory system of the brain), cerebral ataxia, a disorder of the gastrointestinal tract (including the change in contraction and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia, incontinence in stressful situations, Tourette syndrome, trichotillomania, kleptomania, male impotence, impaired attention hyperactivity disorder (ADHD), chronic paroxizmalnoe hemicrania, chronic fatigue, cataplexy syndrome sleep apnea and headache (angiopathy).

Example of receipt, reference examples, examples and Pharmacological examples of the study are presented below.

Example obtain 1

The compound of the present invention (100 g), 40 g of Avicel (trade name, produced by firm Asahi Kasei Corporation), 30 g of corn starch and 2 g of magnesium stearate were mixed, triturated and then alloy preformed using a punching stamp with a diameter of 10.0 mm for covered sugar pills. On the thus obtained tablets were coated using the agent for the deposition of films containing 10 g TC-5 (trade name, Shin-Etsu Chemical Co., Ltd., the hypromellose), 3 g of polyethylene glycol 6000, 40 g of castor oil, and a suitable amount of ethanol, getting treatment is haunted film tablet, containing the above ingredients.

Reference example 1

Synthesis of tert-butyl ester 3-[(3,4-dichlorophenyl)-(4-forfinal)amino]pyrrolidin-1-carboxylic acid

Sodium hydride (0,19 g, 60%in oil) was added to 10 ml of dimethyl sulfoxide (DMSO) and stirred at 60°C for one hour. Next, to the mixture was added 1.0 g (3,4-dichlorophenyl)-(4-forfinal)amine and stirred at 60°C for one hour. Gradually to the mixture was added a DMSO solution containing 2.0 g of tert-butyl methyl ether 3-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylic acid, and stirred at 60°C for 15 hours. To the reaction solution were added ethyl acetate. The solution is then washed with water and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=20:1). The solvent used as an elution solvent, drove away under reduced pressure, thus obtaining 0,29 g of a brown oily product, tert-butyl ester 3-[(3,4-dichlorophenyl)-(4-forfinal)amino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,74-of 1.92 (1H, m), 2,04-2,22 (1H, m), 3,10-to 3.35 (3H, m), 3,61-of 3.85 (1H, m), or 4.31-4,48 (1H, m), 6.42 per (1H, DD, J=2,9 Hz, J=8,9 Hz), to 6.67 (1H, d, J=2,8 Hz), 6.90 to-7,22 (5H, m).

Reference example 2

Synthesis of tert-butyl methyl ether 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidin-1-Carbo the OIC acid

To 20 ml of dimethyl sulfoxide (DMSO) was added sodium hydride (0.36 g, 60%in oil) and stirred at 60°C for one hour. Next, to the mixture was added 2.0 g of 3,4-dichlorophenylamino and stirred at 60°C for one hour. Gradually to the mixture was added a DMSO solution containing 1.5 g of tert-butyl methyl ether 3(R)-methanesulfonanilide-1-carboxylic acid, and stirred at 60°C for 15 hours. To the reaction solution was added ethyl acetate, the reaction solution is then washed with water and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=20:1). The solvent used as an elution solvent, drove away under reduced pressure, thus obtaining of 0.13 g of a light brown amorphous solid product, tert-butyl ester 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine 1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.42 (9H, s), 1,73-of 1.93 (1H, m), 2.05 is-of 2.23 (1H, m), 3,10-to 3.36 (3H, m), 3,61-a 3.83 (1H, m), 4,33-4,50 (1H, m), 6.48 in (1H, DD, J=2,9 Hz, J=10.3 Hz), 6,74 (1H, d, J=2,8 Hz), of 6.96-7,07 (2H, m), 7,16-7,34 (2H,, m), 7,35-7,46 (2H, m).

Reference example 3

Synthesis of ((S)-1-benzylpyrrolidine-3-yl)-(3-forfinal)Amin

Toluene solution containing 2.2 g (S)-1-benzylpyrrolidine-3-ylamine (12.5 mmol), 2.2 g of 3-bromptonville (12.5 mmol), 0.31 g of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 0.51 mmol who), 0.14 g of bis(dibenzylideneacetone)palladium (Pd(dba)2, 0.22 mmol) and 1.3 g of tert-butoxide sodium (13,2 mmol) was heated at boiling under reflux in nitrogen atmosphere for 3 hours. The reaction solution was filtered to remove undissolved products and to the filtrate was added ethyl acetate and water to separate the solution into layers. The organic layer was washed with water, the solvent is kept under reduced pressure, and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=20:1→1:1). The solvent used as an elution solvent, drove away under reduced pressure, thus obtaining 3.0 g colorless oily product ((S)-1-benzylpyrrolidine-3-yl)-(3-forfinal)amine.

1H-NMR (CDCl3) δ ppm:: 1,59-of 1.78 (2H, m), 2.21 are of 2.38 (1H, m), 2,39-of 2.50 (1H, m)to 2.55 (1H, DD, J=3.3 Hz, J=9.7 Hz), 2.71 to to 2.85 (2H, m), 3,63 (2H, s), 3,90-4,10 (1H, m), 6,24 (1H, dt, J=2.3 Hz, J=11,6 Hz), 6,29-6,41 (2H, m), 7,02-7,11 (1H, m), 7,21-7,39 (5H, m).

Reference example 4

Synthesis of ((S)-1-benzylpyrrolidine-3-yl)phenylamine

((S)-1-Benzylpyrrolidine-3-yl)-phenylamine was synthesized by using (S)-1-benzylpyrrolidine-3-ylamine and Brabanthal, similarly to the method of reference example 3.

Oily brown substance

1H-NMR (CDCl3) δ ppm:: 1,56-of 1.78 (2H, m), 2,22-2,39 (1H, m), 2,41-of 2.58 (1H, m), 2,70-2,84 (2H, m), 3,63 (2H, s)to 4.01 (1H, s), to 6.57 (2H, d, J=8.5 Hz), 6,64-of 6.73 (1H, m), 7,11-7,19 (2H, m), 7,21 and 7.36 (5H, m).

Reference example 5

SinTe the ((S)-1-benzylpyrrolidine-3-yl)-(3-forfinal)-(4-triptoreline)Amin

Toluene solution containing 0.7 g ((S)-1-benzylpyrrolidine-3-yl)-(3-forfinal)amine (2.6 mmol), of 0.59 g of 4-bromobenzonitrile (2.6 mmol), 65 mg of BINAP (0.1 mmol), 23 mg of palladium acetate (0.1 mmol) and 0.28 g of tert-butoxide sodium (2.9 mmol) was heated at boiling under reflux in nitrogen atmosphere for 3 hours. The reaction solution was filtered to remove undissolved products and to the filtrate was added ethyl acetate and water to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=20:1→10:1). The solvent used as an elution solvent, drove away under reduced pressure, thus obtaining of 0.48 g of colorless oily product ((S)-1-benzylpyrrolidine-3-yl)-(3-forfinal)-(4-triptoreline)amine.

1H-NMR (CDCl3) δ ppm:: 1,82 is 2.01 (1H, m), 2,17-2,31 (1H, m), 2,61-2,78 (3H, m), of 3.45 (1H, d, J=12.9 Hz), to 3.64 (1H, d, J=12.9 Hz), 4,55 (1H, m), 6,78-6,86 (3H, m), 6,88-of 6.96 (2H, m), 7,19 and 7.36 (6H, m).

Reference example 6

Synthesis of tert-butyl methyl ether 3(S)-(3-chloro-4-forgenerating)pyrrolidin-1-carboxylic acid

To 50 ml of toluene solution containing 5.0 g of tert-butyl methyl ether 3(S)-aminopyrrolidine-1-carboxylic acid (27 mmol) and 5.7 g of 4-bromo-2-chloro-1-fervently (27 mmol), was added 1.7 g BINAP (2.7 mmol), 0,30 g and is of Etat palladium (1.3 mmol) and 3.5 g of tert-butoxide sodium (36 mmol). The mixture was heated at boiling under reflux in nitrogen atmosphere for 8 hours and then cooled to room temperature. To the reaction solution was added water and was extracted with ethyl acetate. After drying over sodium sulfate and concentration under reduced pressure the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=4:1). The solvent is kept under reduced pressure and the residue was recrystallized from diethyl ether, thus obtaining the value of 4.76 g of a white powdery product, tert-butyl ester 3(S)-(3-chloro-4-forgenerating)pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.47 (9H, s), 1,78 is 1.96 (1H, m), 2,10-of 2.28 (1H, m), 2,10-of 2.28 (1H, m), 3,11-3,30 (1H, m), 3,30 of 3.56 (2H, m), 3,57-with 3.79 (2H, m), 3,85-a 4.03 (1H, m), 6,38-6,47 (1H, m), 6,60 (1H, DD, J=6.0 Hz, J=2,9 Hz), 6,90-7,00 (1H, m).

Reference example 7

Synthesis of tert-butyl methyl ether 3(S)-(3-chloro-4-forgenerating)pyrrolidin-1-carboxylic acid

To 50 ml of isopropyl alcohol containing 15.0 g of tert-butyl methyl ether 3(S)-aminopyrrolidine-1-carboxylic acid (80,5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-yogashala (96.7 mmol)was added 1.54 g of copper iodide (I) (8.1 mmol), and 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol) and was heated at the boil under reflux in nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and Phi is travali, using celite. The remaining product on the filter was washed with ethyl acetate, the filtrate was concentrated under reduced pressure together with the washings and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=4:1). The solvent is kept under reduced pressure and the residue was recrystallized from diethyl ether, thus obtaining 15.9 g of a white powdery product, tert-butyl ester 3(S)-(3-chloro-4-forgenerating)pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.47 (9H, s), 1,78 is 1.96 (1H, m), 2,10-of 2.28 (1H, m), 2,10-of 2.28 (1H, m), 3,11-3,30 (1H, m), 3,30 of 3.56 (2H, m), 3,57-with 3.79 (2H, m), 3,85-a 4.03 (1H, m), 6,38-6,47 (1H, m), 6,60 (1H, DD, J=6.0 Hz, J=2,9 Hz), 6,90-7,00 (1H, m).

Reference example 8

Synthesis of tert-butyl methyl ether 3(S)-(3-cyanovinylene)pyrrolidin-1-carboxylic acid

To a toluene solution (7 ml)containing 2,82 g tert-butyl ester 3(S)-aminopyrrolidine-1-carboxylic acid (15 mmol) and 1,82 g 3-bromobenzonitrile (10 mmol)was added and 68.5 mg of BINAP (0.11 mmol), the 22.5 mg of palladium acetate (0.1 mmol) and 3,91 g of cesium carbonate (12 mmol). The mixture was heated at boiling under reflux in nitrogen atmosphere for 8 hours. After cooling to room temperature, to the reaction solution was added water and was extracted with dichloromethane. After drying over sodium sulfate and concentration under reduced pressure the residue was then purified chromium is cografya on a column of silica gel (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 1.56 g of light-yellow powdery product, tert-butyl ester 3(S)-(3-cyanovinylene)pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.46 (9H, s), 1,8-2,0 (1H, m), 2,1-2,3 (1H, m), 3,1-3,6 (3H, m), 3,6-3,8 (1H, m), 3,9-4,1 (2H, m), 6,7-6,9 (2H, m), of 6.99 (1H, d, J=7,6 Hz), 7.23 percent (1H, DD, J=7,6 Hz, J=8,4 Hz).

Reference example 9

Synthesis of tert-butyl methyl ether 3(S)-(3-chloro-4-methoxybenzylamine)pyrrolidin-1-carboxylic acid

To 5 ml of toluene solution containing 0.20 g of tert-butyl methyl ether 3(S)-aminopyrrolidine-1-carboxylic acid (1.1 mmol) and 0,238 g of 2-chloro-3-bromoanisole (1.1 mmol)was added 67,0 mg BINAP (0.11 mmol), 24 mg of Tris(dibenzylideneacetone)diplegia (or 0.027 mmol) and 144 mg of tert-butoxide sodium (1.5 mmol). The mixture was heated at boiling under reflux in a nitrogen atmosphere at 100°C for one hour. After cooling to room temperature the reaction solution was filtered using celite. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=10:1→3:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 0.28 g of a light yellow amorphous solid product, tert-butyl ester 3(S)-(3-chloro-4-methoxybenzylamine)pyrrolidin-1-carboxylic acid./p>

1H-NMR (CDCl3) δ ppm:: of 1.47 (9H, s), 1,80-1,90 (1H, m), 2,10-of 2.20 (1H, m), 3,10-of 3.25 (1H, m), 3,38 of 3.75 (3H, m), 3,83 (3H, s), 3,92-of 3.96 (1H, m), 6,47 (1H, DD, J=2,8 Hz, J=8,8 Hz), to 6.67 (1H, d, J=2,8 Hz), for 6.81 (1H, d, J=8,8 Hz).

Reference example 10

Synthesis of tert-butyl methyl ether 3(S)-(4-methoxybenzylamine)pyrrolidin-1-carboxylic acid

To 10 ml of an ethanol solution containing 0.28 g of tert-butyl methyl ether 3(S)-(3-chloro-4-methoxybenzylamine)pyrrolidin-1-carboxylic acid, was added to 0.2 ml of 5N. solution of sodium hydroxide and 0.1 g of 10% palladium on carbon. Catalytic reduction was carried out at room temperature and atmospheric pressure (normal pressure). The reaction solution was filtered using celite, and concentrated under reduced pressure. To the residue was added water and was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated to dryness under reduced pressure, thus obtaining 0.25 g of yellow amorphous solid product, tert-butyl ester 3(S)-(4-methoxybenzylamine)pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.46 (9H, s), 1,79-of 1.88 (1H, m), 2,10-2,22 (1H, m), 3,12-of 3.25 (1H, m), 3,30-to 3.52 (3H, m), 3,60 of 3.75 (4H, m), 3,88-4,00 (1H, m), 6,50 return of 6.58 (2H, m), 6,72-to 6.80 (2H, m).

Reference example 11

Synthesis of tert-butyl methyl ether 3(S)-[bis-(3-forfinal)amino]pyrrolidin-1-carboxylic acid

To 10 ml of toluene solution containing 1.0 g of tert-butyl methyl ether 3(S)-Amin is pyrrolidin-1-carboxylic acid (5.3 mmol) and 2.3 g of 3-bromo-1-fervently (13 mmol), added 32 mg of tetrafluoroborate three-tert-butylphosphine (0.11 mmol), 24 mg of palladium acetate (0.11 mmol) and 1.5 g of tert-butoxide sodium (16 mmol). The mixture was heated at boiling under reflux in nitrogen atmosphere for 8 hours. After cooling to room temperature, to the reaction solution was added water and was extracted with ethyl acetate. After drying over sodium sulfate and concentration under reduced pressure the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 1.56 g of a yellow oily product, tert-butyl ester 3(S)-[bis-(3-forfinal)amino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,78-of 1.95 (1H, m), 2,02-of 2.26 (1H, m), 3,12-3,39 (3H, m), 3,65-a 3.83 (1H, m), 4,35-4,51 (1H, m), is 6.61 (2H, dt, J=2.1 Hz, J=11,0 Hz), 6,61 of 6.68 (2H, m), 6,77 (2H, t, J=8.0 Hz), 7.18 in-7,31 (2H,, m).

Reference example 12

Synthesis of tert-butyl methyl ether 3(S)-[(3,4-dichlorophenyl)thiazole-2-ylamino] pyrrolidin-1-carboxylic acid

To 150 ml of toluene solution containing 20,0 g tert-butyl ester 3(S)-(3,4-dichlorophenylamino)pyrrolidin-1-carboxylic acid (60,4 mmol) and 15.0 g of 2-bromothiazole (from 91.5 mmol)was added 1.86 g of tetrafluoroborate three-tert-butylphosphine (6.4 mmol), 2,88 g of Tris(dibenzylideneacetone)diplegia (3,15 mmol) and 11.6 g of tert-butoxide sodium (120 is the mole). The mixture was heated at boiling under reflux in nitrogen atmosphere for 9 hours. The reaction solution was cooled to room temperature and filtered using celite. To the filtrate was added water and was extracted with ethyl acetate. After drying over sodium sulfate and concentration under reduced pressure the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 7,94 g of a yellow powdery product, tert-butyl ester 3(S)-[(3,4-dichlorophenyl)thiazole-2-ylamino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,83-2,03 (1H, m), 2,11 to 2.35 (1H, m), 3,18-of 3.42 (3H, m), of 3.73-a 3.87 (1H, m), equal to 4.97-5,09 (1H, m), 6,53 (1H, d, J=3.5 Hz), 7,14 (1H, DD, J=2.5 Hz, J=8.5 Hz), 7,22 (1H, users), 7,39 (1H, d, J=2,5 Hz), 7,56 (1H, userd, J=8,5 Hz).

Reference example 13

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)pyridine-3-ylamino]pyrrolidin-1-carboxylic acid

To 10 ml of toluene solution containing 1.0 g of tert-butyl methyl ether 3(S)-(3-chloro-4-forgenerating)pyrrolidin-1-carboxylic acid (3.2 mmol) and 0.75 g of 3-bromopyridine and 4.75 mmol), was added 50 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 0.09 mmol), 21,4 mg of palladium acetate (0.10 mmol) and 11.6 g of tert-butoxide sodium (120 mmol). The mixture was heated at boiling under reflux in ATM is the field of nitrogen for 9 hours. After cooling to room temperature the reaction solution was filtered using celite. To the filtrate was added water and was extracted with ethyl acetate. After drying over sodium sulfate and concentration under reduced pressure the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, thus obtaining 1,14 g of light yellow oily product, tert-butyl ester 3(S)-[(3-chloro-4-forfinal)pyridine-3-ylamino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,79-to 1.98 (1H, m), 2,08-to 2.29 (1H, m), 3,12-to 3.41 (3H, m), 3,65-of 3.85 (1H, m), of 4.38-4,51 (1H, m), 6,83-6,91 (1H, m), 7,00-of 7.23 (4H, m [? 7.04 baby mortality including ppm: (DD, J=2.7 Hz, J=6,4 Hz)]), 8,14 (1H, s), by 8.22 (1H, d, J=4.4 Hz).

Reference example 14

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)cyclohexylamino]pyrrolidin-1-carboxylic acid

3 ml of acetic acid containing 0,60 g tert-butyl ester 3(S)-[(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid (1.9 mmol) and 0.56 g of cyclohexanone (5.7 mmol), stirred at room temperature overnight. To the mixture was added to 1.21 g triacetoxyborohydride sodium (5.7 mmol), then stirred at room temperature for 8 hours. To the reaction solution was added dichloromethane, the reaction solution was washed with water and saturated water is astorm of sodium bicarbonate and then dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=10:1). The solvent drove from purified product under reduced pressure, thus obtaining 0.24 g of colorless oily product, tert-butyl ester 3-[(S)-(3-chloro-4-forfinal)cyclohexylamino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: 0,81-of 1.32 (6H, m)of 1.44 (9H, s), 1,60-2,00 (6H, m), 2,79-of 2.93 (1H, m), 2,98-3,10 (1H, m), 3,16-of 3.31 (1H, m), 3,35-3,70 (2H, m), 3,35-3,70 (2H, m), 3,85-4,07 (1H, m), 6,85-7,13 (3H, m).

Reference example 15

Synthesis of tert-butyl methyl ether 3(S)-[(4-carboxyphenyl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid

To the ethanol solution containing 1.7 g of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(4-ethoxycarbonylphenyl)amino]pyrrolidin-1-carboxylic acid (3.7 mmol), was added 6 ml of 5N. the sodium hydroxide solution, and then stirred at room temperature for 15 hours. To the reaction solution was added dichloromethane and acetic acid for acidification of the reaction solution. After washing with water three times and with saturated aqueous solution of sodium bicarbonate once the solvent had slipped away under reduced pressure, thus obtaining 1.50 g of a white powdery product, tert-butyl ester 3(S)-[(4-carboxyphenyl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carbon is acid.

1H-NMR (DMSO-d6) δ ppm:: of 1.33 (9H, s), 1,72-of 1.88 (1H, m), 2.06 to and 2.26 (1H, m), 2,99 is 3.23 (3H, m), 3,61 (1H, DD, J=6,4 Hz, J=11.3 Hz), 4.53-in-4,69 (1H, m), 6,57-of 6.65 (2H, m), 7,19-7,28 (1H, m), 7,46-7,58 (2H, m), 7.68 per for 7.78 (2H, m), to 12.3 (1H, users).

Reference example 16

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(4-methanesulfonyl)amino]pyrrolidin-1-carboxylic acid

To a dichloromethane solution containing 0.45 g of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(4-methanesulfonyl)amino]pyrrolidin-1-carboxylic acid (1.0 mmol)was added 0.54 g of metallocarboxypeptidase acid (3.1 mmol) at 0°C, then stirred at 0°C for 2 hours. The reaction solution was washed with water, dried over magnesium sulfate and the solvent is kept at reduced pressure. Next, the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=5:1→1:1). Of the purified product under reduced pressure drove the solvent, thus obtaining 0,42 g of light yellow oily product, tert-butyl ester 3(S)-[(3-chloro-4-forfinal)-(4-methanesulfonyl)amino]pyrrolidine 1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,80 is 1.91 (1H, m), 2,11-to 2.29 (1H, m), 3,01 (3H, s), 3,16 is 3.40 (3H, m), 3,70-3,86 (1H, m), 4,49-br4.61 (1H, m), 6,62 (2H, d, J=9.0 Hz), 7,03 (1H, DDD, J=2.6 Hz, J=4,1 Hz, J=8.6 Hz), 7,01-7,06 (1H, m), 7,19-of 7.23 (1H, m), 7.24 to 7,31 (1H, m), 7,66-7,74 (2H, m).

Reference example 17

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-fluoro who enyl)-(6-cyano-2-yl)amino]pyrrolidin-1-carboxylic acid

tert-Butyl ether 3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid (500 mg, 1.06 mmol), cyanide zinc (250 mg, a 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0,106 mmol) suspended in 8 ml of dimethylformamide (DMF), and then stirred in nitrogen atmosphere at 110°C for 9 hours. After cooling to room temperature, to the reaction solution were added ethyl acetate and water to separate the solution into layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=6:1→3:1). Of the purified product under reduced pressure drove the solvent, thus obtaining 398 mg of colorless oily product, tert-butyl ester 3(S)-[(3-chloro-4-forfinal)-(6-cyano-2-yl)amino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: the 1.44 (9H, s), 1,74-of 1.84 (1H, m), 2,03-of 2.24 (1H, m), is 3.08-of 3.32 (3H, m), 3,76-3,86 (1H, m), 5,28 is 5.38 (1H, m), 6,21 (1H, d, J=8.7 Hz),? 7.04 baby mortality-7,11 (2H, m), 7.23 percent-7,42 (3H, m).

Reference example 18

Synthesis of tert-butyl methyl ether 3(S)-{(3-chloro-4-forfinal)-[5-(4-forfinal)pyridine-2-yl]amino}pyrrolidine-1-carboxylic acid

tert-Butyl ether 3(S)-[(5-bromopyridin-2-yl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid (300 mg, 0.64 mmol), 4-ftorhinolony acid (98 mg, 0.7 mmol who), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and 2M aqueous sodium carbonate (0,83 ml) was added to toluene (3 ml), then stirred under nitrogen atmosphere at 100°C for 10 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the solution into layers. The organic layer was washed with saturated salt solution, then dried over sodium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=5:1). Of the purified product under reduced pressure drove the solvent, thus obtaining 255 mg of a white solid product, tert-butyl ester 3(S)-{(3-chloro-4-forfinal)-[5-(4-forfinal)pyridine-2-yl]amino}pyrrolidine-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: the 1.44 (9H, s), 1,78-1,89 (1H, m), 2.05 is-of 2.23 (1H, m), 3,07-of 3.31 (3H, m), 3,85 (1H, DD, J=7,1, to 10.8 Hz), 5,31-5,42 (1H, m), between 6.08 (1H, d, J=8,8 Hz), 7,06-7,14 (3H, m), 7,20-7,28 (2H, m), 7,41-to 7.50 (3H, m), of 8.37-to 8.41 (1H, m).

Reference example 19

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(4-thiophene-3-ylphenyl)amino]pyrrolidin-1-carboxylic acid

Using tert-butyl ether 3(S)-[(4-bromophenyl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid and 3-tiefenbronn acid, synthesized tert-butyl ether (S)-[(3-chloro-4-forfinal)-(4-thiophene-3-ylphenyl)amino]pyrrolidin-1-carboxylic acid what you similar to the method of reference example 93.

Colorless oily substance

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,83-of 1.88 (1H, m), 2.05 is-of 2.20 (1H, m), 3,18-of 3.31 (3H, m), 3,63-a-3.84 (1H, m), 4,40-4,51 (1H, m), of 6.71-to 6.80 (1H, m), 6,85-to 6.88 (2H, m)6,94 (1H, DD, J=2,8 Hz, J=6.4 Hz), 7,05-7,10 (1H, m), 7,30 was 7.45 (3H, m), 7,50-of 7.55 (2H, m).

Reference example 20

Synthesis of tert-butyl methyl ether (S)-{(3-chloro-4-forfinal)-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid

tert-Butyl ether 3(S)-[(6-bromopyridin-2-yl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid (200 mg, 0.43 mmol), 1-methylpiperazine (and 0.61 ml, 0.55 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 12 mg, 0.02 mmol), Tris(dibenzylideneacetone)diplegia (9 mg, 0.01 mmol) and tert-butoxide sodium (61 mg, mmol 0,63) were added to toluene (5 ml), then stirred under nitrogen atmosphere at 100°C for 8 hours. Undissolved products were removed by filtration and the resulting filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=4:1). Of the purified product under reduced pressure drove the solvent, thus obtaining 102 mg of a colorless oily product, tert-butyl methyl ether (S)-{(3-chloro-4-forfinal)-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: the 1.44 (9H, s), 1,74-1,89 (1H, m), 2,03-of 2.21 (1H, m), a 2.36 (3H, s), of 2.51 is 2.55 (4H, m), is 3.08-of 3.31 (3H, m), of 3.54 (4H, usher.is), 3,64-are 3.90 (1H, m), 5,10-5,23 (1H, m), 5,32 (1H, d, J=8.1 Hz), 6,01 (1H, d, J=8.1 Hz), 7.03 is-was 7.08 (1H, m), 7,19-of 7.25 (3H, m).

Reference example 21

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(4-piperidine-1-ylphenyl)amino]pyrrolidin-1-carboxylic acid

Using tert-butyl ether 3(S)-[(4-bromophenyl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid and piperidine, tert-butyl ester 3(S)-[(3-chloro-4-forfinal)-(4-piperidine-1-ylphenyl)amino]pyrrolidin-1-carboxylic acid was synthesized analogously to the method of reference example 11.

Colourless oily product substance

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,55-of 1.62 (2H, m), 1,68-of 1.73 (4H, m), 1,74-1,90 (1H, m), 2,02-to 2.18 (1H, m), 3,16-3,29 (7H, m), 3,61-3,81 (1H, m), 4,23-to 4.38 (1H, m), 6,40-6,46 (1H, m), 6,59-6,62 (1H, m), 6,86-6,92 (5H, m).

Reference example 22

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid

To an anhydrous toluene solution containing tert-butyl ether 3(S)-[(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid (0.50 g, 1.6 mmol) and 2-chloro-4-perbenzoate (0,30 g, 1.9 mmol)was added to 1.45 ml tertrahydrofuran ring solution containing bis(trimethylsilyl)amide, sodium (1,1M), using a syringe. The mixture was heated at boiling under reflux in nitrogen atmosphere for 8 hours and cooled to room temperature. To the reaction solution were added water and the extras who were garofali diethyl ether. After drying over sodium sulfate and concentration under reduced pressure the residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure, thus obtaining 0.56 g of a white amorphous solid product, tert-butyl ester 3(S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: USD 1.43 (9H, s), 1,76-of 1.93 (1H, m), 2,11-of 2.27 (1H, m), 3,15-3,39 (3H, m), 3,66-a 3.87 (1H, m), 4,39-4,55 (1H, m), 6.42 per (1H, DD, J=2.5 Hz, J=9.0 Hz), to 6.57 (1H, d, J=2.5 Hz), 6,98? 7.04 baby mortality (1H, m), 7,20 (1H, DD, J=2.5 Hz, J=6.5 Hz), 7.23 percent-to 7.32 (1H, m), 7,40 (1H, d, J=8,5 Hz).

Reference example 23

Synthesis of 2-(4-chloroethoxy)pyridine

To a solution in DMF (110 ml)containing 2-pyridinol (10 g, 105 mmol) and 1-bromo-4-chlorobutane (36 ml, 315 mmol), was added potassium carbonate (16 g, 116 mmol), then stirred at room temperature for 8 hours. To the reaction solution were added water (300 ml) and then extracted with ethyl acetate (300 ml). The organic layer was washed with water (300 ml) twice and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=5:1). The purified product was concentrated under reduced pressure, thus obtaining of 3.32 g of colorless oily product, 2-(4-chloroethoxy)pyridine.

Reference example 24

Synthesis of tert-butyl methyl ether 3(S)-[4-(pyridine-2-yloxy)butylamino]pyrrolidin-1-carboxylic acid

tert-Butyl ether 3(S)-aminopyrrolidine-1-carboxylic acid (0,93 g, 5.0 mmol), 2-(4-chloroethoxy)pyridine (0,93 g, 5.0 mmol), potassium carbonate (0,83 g, 6.0 mmol) and sodium iodide (0,83 g, 5.5 mmol) suspended in acetonitrile (20 ml) and was heated at the boil under reflux for 24 hours. After cooling to room temperature, to the reaction solution was added water (50 ml) and was extracted with ethyl acetate (50 ml). The organic layer was washed with water twice and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=3:1). The purified product was concentrated under reduced pressure, thus obtaining 372 mg of colorless oily product, tert-butyl ester 3(S)-[4-(pyridine-2-yloxy)butylamino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.46 (9H, s), of 1.5-1.9 (6H, m), 1,95-2,15 (1H, m), 2,68 (2H, t, J=7 Hz), 2.95 and is 3.15 (1H, m), 3.25 to the 3.65 (4H, m), 4,30 (2H, t, J=6.5 Hz), of 6.71 (1H, d, J=8.5 Hz), 6,85 (1H, DD, J=5.5 Hz, J=6,5 Hz), 7,5-the 7.65 (1H, m)to 8.14 (1H, DD, J=2 Hz, J=5 Hz).

Reference example 25

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(3-chloropropyl)amino]pyrrolidin-1-carboxylic acid

tert-Butyl ether 3(S)-[(3-chloro-4-forgenerating]pyrrolidin-1-carboxylic acid (3 g, 9.5 mmol), 1-bromo-3-chloropropane (4,7 ml, 48 mmol) and potassium carbonate (1.97 g, and 14.3 mmol) suspended in N-organic (NMP, 15 ml), then stirred at 100°C for 8 hours. After cooling to room temperature, to the reaction solution was added water and was extracted with ethyl acetate. After drying the organic layer over sodium sulfate the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=3:1) and the purified product was concentrated under reduced pressure, thus obtaining 1.0 g of colorless oily product, tert-butyl ester 3(S)-[(3-chloro-4-forfinal)-(3-chloropropyl)amino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.46 (9H, s), with a 1.7-2.1 (4H, m), 3.1 to the 3.35 (4H, m), 3,35 is 3.7 (4H, m), of 3.8-4.1 (1H, m), 6,7-6,9 (1H, m), 6,9-7,1 (2H, m).

Reference example 26

Synthesis of tert-butyl methyl ether 3(S)-[(3-chloro-4-forfinal)-(3-dimethylaminopropyl)amino]pyrrolidin-1-carboxylic acid

tert-Butyl ether 3(S)-[(3-chloro-4-forfinal)-(3-chloropropyl)amino]pyrrolidin-1-carboxylic acid (0.5 g, 1,24 mmol), 50%solution of dimethylamine (1 ml) and sodium iodide (0,37 g, 2.5 mmol) suspended in DMF (3 ml), then stirred at 60°C for 4 hours. After cooling to room temperature, to the reaction solution was added water and was extracted with ethyl acetate. The organic layer sushi is whether over sodium sulfate and then drove away the solvent under reduced pressure. The residue was purified primary column chromatography on silica gel (ethyl acetate) and the purified product was then concentrated under reduced pressure, thus obtaining, 0.36 g colorless oily product, tert-butyl ester 3(S)-[(3-chloro-4-forfinal)-(3-dimethylaminopropyl)amino]pyrrolidin-1-carboxylic acid.

1H-NMR (CDCl3) δ ppm:: of 1.46 (9H, s), 1,5-1,75 (4H, m), of 1.75 and 2.1 (2H, m), 2,19 (6H, s), 3,0-3,3 (4H, m), 3,3-of 3.75 (2H, m), 3,8-4,2 (1H, m), 6,6-6,8 (1H, m), 6,8-7,1 (2H, m).

The compounds below were obtained by methods similar to above reference examples.

Example 1

Synthesis dihydrochloride (3,4-dichlorophenyl)phenylpyrrolidine-3-ylamine

A solution of acetic acid (15 ml)containing tert-butyl ether containing 3-oxopyrrolidin-1-carboxylic acid (0,67 g) and (3,4-dichlorophenyl)phenylamine (0,94 g), was stirred at room temperature overnight. To the mixture was added 1.5 g of triacetoxyborohydride sodium, then stirred at room temperature for 8 hours. To the reaction solution was added dichloromethane and washed with water, then dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=20:1). Of the purified product had slipped away under reduced pressure, the solvent, the residue was dissolved in a mixture of 1H. aristolochiaceae acid-ethanol and heated at boiling under reflux for one hour. The reaction solution was concentrated to dryness, thus obtaining 50 mg brown amorphous solid, dihydrochloride (3,4-dichlorophenyl)phenylpyrrolidine-3-ylamine.

1H-NMR (DMSO-d6) δ ppm:: 1,50 by 1.68 (1H, m), 2,10-to 2.29 (1H, m), 2,74-2,90 (1H, m), 3,02-up 3.22 (2H, m), 3,51-3,66 (1H, m), br4.61-rate 4.79 (1H, m), to 6.58 (1H, DD, J=2,9 Hz, J=9.0 Hz), 6.87 in (1H, d, J=2,9 Hz), 7,13-7,19 (2H, m), 7,29-7,44 (2H, m), 7,45-rate of 7.54 (2H, m), 9,03 (2H, users).

Example 2

Synthesis dihydrochloride (S)-(3,4-dichlorophenyl)phenylpyrrolidine-3-ylamine

tert-Butyl ether 3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidin-1-carboxylic acid (0,13 g) was dissolved in a mixture of 1H. hydrochloric acid-ethanol and heated at boiling under reflux for one hour. The reaction solution was concentrated to dryness, thus obtaining 0.11 g of a brown amorphous solid, hydrochloride 3(S)-(3,4-dichlorophenyl)phenylpyrrolidine-3-ylamine.

1H-NMR (DMSO-d6) δ ppm:: 1,50 by 1.68 (1H, m), 2,10-to 2.29 (1H, m), 2,75-2,90 (1H, m), 3,02 is 3.23 (2H, m), 3,51-the 3.65 (1H, m), 4,60-4,80 (1H, m), to 6.58 (1H, DD, J=2,9 Hz, J=9.0 Hz), 6.87 in (1H, d, J=2,9 Hz), 7,12-7,19 (2H, m), 7,29-7,44 (2H, m), 7,45-rate of 7.54 (2H, m), 9,05 (2H, users).

Example 3

Synthesis of difumarat (3-forfinal)-(S)-pyrrolidin-3-yl(4-triptoreline)Amin

To 1,2-dichloromethane solution (1 ml)containing (S)-1-benzylpyrrolidine-3-yl)-(3-forfinal)-(4-triptoreline)Amin (of 0.48 g, 1.1 mmol), was added 1-chloroethylphosphonic (0,82 g, 5.8 mmol). Semipermissive at room temperature for 15 hours and was heated at the boil under reflux for 3 hours. The solvent is kept under reduced pressure, then the residue was added 5 ml of methanol and heated at the boil under reflux for 3 hours. After removal of the solvent under reduced pressure the residue was then dissolved in dichloromethane and washed with saturated aqueous solution of sodium bicarbonate. After drying over magnesium sulfate the solvent is kept at reduced pressure. The residue was dissolved in ethanol, then added fumaric acid (128 mg, 1.1 mmol)to give a homogeneous solution. The solvent is kept under reduced pressure and the crystals formed when added to the residue dichloromethane was separated by filtration and dried, obtaining 0.24 g of light brown powder product, difumarat (3-forfinal)-(S)-pyrrolidin-3-yl-(4-triptoreline)amine.

Melting point 144, 0mm-to 146.2°C.

Example 4

Synthesis of hydrochloride (3-chloro-4-forfinal)-(4-methanesulfonyl)-(S)-pyrrolidin-3-ylamine

tert-Butyl ether 3(S)-[(3-chloro-4-forfinal)-(4-methanesulfonyl)amino]pyrrolidin-1-carboxylic acid (0,42 g, 0.9 mmol) was added to a mixture of 4h. hydrochloric acid/ethyl acetate, then was stirred at room temperature for one hour. The reaction solution was concentrated to dryness under reduced pressure, and thus, 0.35 g of a white powdery product, GI is rochloride (3-chloro-4-forfinal)-(4-methanesulfonyl)-(S)-pyrrolidin-3-ylamine.

1H-NMR (DMSO-d6) δ ppm:: 1,56 by 1.68 (1H, m), 2,19-to 2.29 (1H, m), 2,82-to 2.94 (1H, m), is 3.08 (3H, s), of 3.10-3.20 (2H, m), 3,57-3,68 (1H, m), 4,70-is 4.85 (1H, m), 6,69 to 6.75 (2H, m), 7,32-7,37 (1H, m), 7,58-to 7.64 (1H, m), 7,65-of 7.69 (3H, m), 9,10-to 9.45 (2H, m).

Example 5

Synthesis of difumarat (3-chloro-4-forfinal)-[4-(pyridine-2-yloxy)butyl]-(S)-pyrrolidin-3-ylamine

To a toluene solution (4 ml)containing tert-butyl ether 3(S)-[4-(pyridine-2-yloxy)butylamino]pyrrolidin-1-carboxylic acid (0.2 g, 0.6 mmol) and 4-bromo-2-chloro-1-torbenson (0.8 ml, of 0.65 mmol), was added tetrafluoroboric three-tert-butylphosphine (14 mg, 0.05 mmol), Tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol) and tert-piperonyl sodium (110 mg, 1.2 and mmol) and heated at boiling under reflux in nitrogen atmosphere for 12 hours. After cooling to room temperature, to the reaction solution was added water and was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated under reduced pressure and the residue was then purified by chromatography on a column of silica gel (n-hexane:ethyl acetate=3:1). Of the purified product had slipped away under reduced pressure the solvent. The residue was dissolved in 0.4 ml of dichloromethane and added triperoxonane acid (0.06 ml, 0.8 mmol), then stirred at room temperature for 3 hours. After concentration under reduced pressure the residue was purified HPLC. After selection of the appropriate f the shares solvent drove away under reduced pressure, to the residue was added 10% aqueous potassium carbonate solution and then was extracted with dichloromethane. The extract was dried over magnesium sulfate, concentrated under reduced pressure and to the residue (ethanol solution) was added to the ethanol solution containing fumaric acid (8.1 mg), thus obtaining a homogeneous solution. After concentration under reduced pressure, to the residue was added water (3 ml), then dried by freezing, thus obtaining 19 mg of a white solid product, difumarat (3-chloro-4-forfinal)-[4-(pyridine-2-yloxy)butyl]-(S)-pyrrolidin-3-ylamine.

1H-NMR (DMSO-d6) δ ppm:: 1,45-1,55 (2H, m), 1,65-1,8 (2H, m), 1,8-of 1.95 (1H, m), 2.05 is-to 2.15 (1H, m), 2,6-4,05 (11H, m), 4,25 (2H, t, J=6.5 Hz), a 4.3 and 4.4 (1H, m), 6,55 (4H, s), 6,77 (1H, d, J=8.5 Hz), 6.8 or 6.9 (1H, m), 6,9-7,0 (1H, m), 7,03 (1H, DD, J=3 Hz, J=6.5 Hz), 7,22 (1H, DD, J=9 Hz, J=9 Hz), 7,65 is 7.7 (1H, m), 8,1-of 8.15 (1H, m).

Example 6

Synthesis of hydrochloride (3-chloro-4-forfinal)-(3-methylsulfinylpropyl)-(S)-pyrrolidin-3-ylamine

A solution of acetic acid (3 ml)containing tert-butyl ether 3(S)-[(3-chloro-4-forfinal)amino]pyrrolidin-1-carboxylic acid (of 0.60 g, 1.9 mmol) and 3-methylthiopropionate aldehyde (0.6 g, 5.7 mmol), stirred at room temperature overnight. To the mixture was added triacetoxyborohydride sodium (0,81 g, 3.8 mmol), then stirred at room temperature for 15 hours. To the reaction solution was added dichloromethane, and the reactions the config solution was washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent is kept under reduced pressure and the residue then was dissolved in a mixture of 1H. hydrochloric acid-ethanol (10 ml) and was heated at the boil under reflux for one hour. The reaction solution was concentrated to dryness, thus obtaining 0.16 g of yellow amorphous solid, hydrochloride (3-chloro-4-forfinal)-(3-methylsulfinylpropyl)-(S)-pyrrolidin-3-ylamine.

1H-NMR (DMSO-d6) δ ppm:: 1,52 is 1.70 (2H, m), 1,80-2,18 (including 5H, m [2,07 ppm: (C)]), 2,40 is 2.51 (2H, m), 2,84-to 3.49 (6H, m), 4,29-of 4.49 (1H, m), 6,85-to 6.95 (1H, m), 7,05-to 7.35 (2H, m), of 9.30-9,79 (2H, m).

Example 7

Synthesis dimethanesulfonate (3-chloro-4-forfinal)pyridine-3-yl-(S)-pyrrolidin-3-ylamine

To a dichloromethane solution (100 ml)containing tert-butyl ether 3(S)-[(3-chloro-4-forfinal)pyridine-3-ylamino]pyrrolidin-1-carboxylic acid (16.0 g, 41 mmol)was added triperoxonane acid (20 ml), then stirred at room temperature for 3 hours. The solvent is kept under reduced pressure, to the residue was added a saturated aqueous solution of sodium bicarbonate to balance alkalizing and then was extracted with dichloromethane. The extract was dried over magnesium sulfate, the solvent is kept under reduced pressure and the residue was purified primary column chromatography on silica gel (dichloromethane:methanol=10:1). Of the purified product had slipped away under reduced d is the pressure of the solvent. To the ethanol solution containing the residue, was added methanesulfonyl acid (9.2 grams) and the solvent then drove away under reduced pressure. The residue was recrystallized ethanol, thus obtaining of 16.9 g of a white powdery product, dimethanesulfonate (3-chloro-4-forfinal)pyridine-3-yl-(S)-pyrrolidin-3-ylamine.

Melting point 194,0-195,0°C.

Connection examples 8-1180 presented in the tables below, can be obtained by methods analogous specified in the above examples, using appropriate starting compound. In the following tables connection with specified physical and chemical characteristics such as crystal form, TPL (melting point), salt,1H-NMR and MS (mass spectrum)were actually received.

Pharmacological investigation 1

Evaluation of inhibitory activity of the compounds against the absorption of serotonin (5-HT) in synaptosome rat brain

Male Wistar rats were decapotable, the brain was removed and cut off the frontal part of the brain. Separated frontal part of the brain homogenized in 20 volumes of 0,32M sucrose solution using a homogenizer type homogenizer Potter. The homogenate was centrifuged at 1000gat 4°C for 10 minutes and the supernatant was then centrifuged at 20000gat 4°C in the tip is of 20 minutes. Sediment resuspendable in incubation buffer (20 mm HEPES buffer (pH of 7.4))containing 10 mm glucose, 145 mm NaCl, 4.5 mm KCl, 1.2 mm magnesium chloride and 1.5 mm calcium chloride)and used as the crude synaptosomal fractions.

The reaction mixture to absorb suspended in a final volume of 200 μl containing pargyline (final concentration 10 μm) and sodium ascorbate (final concentration 0.2 mg/ml) in each well of 96-well plate with a round bottom.

To each well was added the solvent, unlabeled 5-HT, and serially diluted tested compound was added in synaptosomal fractions in the amount of 1/10 of the volume from the final volume. After a 10 minute pre-incubation at 37°C, the uptake was initiated by adding a solution of 5-HT labeled with tritium (final concentration of 8 nm), at a temperature of 37°C. the Uptake was stopped after 10 minutes by vacuum filtration through a 96-well filter plate with glass fiber. After washing the filter with cold saline solution and drying was added Microscint-O (Perkin-Elmer) and measured residual radioactivity on the filter.

The total activity of absorption with only one solvent is taken as 100% and nonspecific activity absorption with unlabeled 5-HT (final concentration 10 μm) were taken at 0%. 50%inhibiting to the ncentratio was calculated based on the concentrations of the studied compounds and their inhibitory activity. The results are presented in table 160.

Table 160
The analyzed connection50% inhibitory concentration (nm)
The compound of example 51,6
The compound of example 73,0
The compound of example 190,7
The compound of example 400,8
The compound of example 730,6
The compound of example 901,2
The compound of example 1140,8
The compound of example 1310,6
The compound of example 1450,6
The compound of example 1491,2
The compound of example 1510,8
The compound of example 1540,8
Connect the tion of example 268 0,8
The compound of example 2782,2
The compound of example 3061,4
Connection example 8942,6
Connection example 8953,0
Connection example 8962,5
Connection example 8990,7
Connection example 9001,5
Connection example 9010,7
Connection example 9031,2
Connection example 9121,0
Connection example 9130,8
Connection example 9170,7
Connection example 9300,8
Connection example 9341,8
Connection example 9612,8
Connection example 9631,0
Connection example 9670,9
Connection example 9890,6

Pharmacological study 2

Evaluation of inhibitory activity of the compounds against uptake of norepinephrine (NE) in synaptosome rat brain

Male Wistar rats were decapotable, the brain was removed and cut hippocampus. Separated hippocampus homogenized in 20 volumes of 0,32M sucrose solution using a homogenizer type homogenizer Potter. The homogenate was centrifuged at 1000gat 4°C for 10 minutes and the supernatant was then centrifuged at 20000gat 4°C for 20 minutes. Sediment resuspendable in incubation buffer (20 mm HEPES buffer (pH of 7.4))containing 10 mm glucose, 145 mm NaCl, 4.5 mm KCl, 1.2 mm magnesium chloride and 1.5 mm calcium chloride)and used as the crude synaptosomal fractions.

The reaction mixture to absorb suspended in a final volume of 200 μl containing pargyline (final concentration 10 μm) and sodium ascorbate (final concentration 0.2 mg/ml) in each well of 96-well plate with a round bottom.

To each well was added the solvent, unlabeled NE, and serially-fu is given to the compounds and added synaptosomal fraction in the amount of 1/10 of the volume from the final volume. After a 10 minute pre-incubation at 37°C, the uptake was initiated by adding a solution of NE, labeled with tritium (final concentration of 12 nm), at a temperature of 37°C. the Uptake was stopped after 10 minutes by vacuum filtration through a 96-well filter plate with glass fiber. After washing the filter with cold saline solution and drying was added Microscint-O (Perkin-Elmer) and measured residual radioactivity on the filter.

The total activity of absorption with only one solvent is taken as 100%, and nonspecific activity absorption with unlabeled NE (final concentration 10 μm) were taken at 0%. 50%inhibiting concentration was calculated based on the concentrations of the studied compounds and their inhibitory activity. The results are presented in table 161.

Table 161
The analyzed connection50% inhibitory concentration (nm)
Connection example 10,6
The compound of example 70,4
The compound of example 200,8
With the unity of example 22 2,2
The compound of example 440,4
The compound of example 900,7
The compound of example 980,3
The compound of example 1140,4
The compound of example 1160,1
The compound of example 1310,2
The compound of example 1540,2
The compound of example 1880,1
The compound of example 2230,2
The compound of example 2420,2
The compound of example 2440,5
The compound of example 2560,1
The compound of example 2780,3
The compound of example 2890,1
The compound of example 3060,8
Connection example 8940,3
Connection example 8950,5
Connection example 8960,9
Connection example 9000,6
Connection example 9030,7
Connection example 9130,8
Connection example 9220,5
Connection example 9301,0
Connection example 9510,5
Connection example 9610,7
Connection example 9630,8
Connection example 9670,1
Connection example 9890,3
Connection example 9900,8
Connection example 10000,4
Connection example 10010,1
Connection example 10020,1

Pharmacological study of 3

Evaluation of inhibitory activity of the compounds against absorption of dopamine (DA) in synaptosome rat brain

Male Wistar rats were decapotable, the brain was removed and cut striped body. Separated striatum homogenized in 20 volumes of 0,32M sucrose solution using a homogenizer type homogenizer Potter. The homogenate was centrifuged at 1000gat 4°C for 10 minutes and the supernatant was then centrifuged at 20000gat 4°C for 20 minutes. Sediment resuspendable in incubation buffer (20 mm HEPES buffer (pH of 7.4))containing 10 mm glucose, 145 mm NaCl, 4.5 mm KCl, 1.2 mm magnesium chloride and 1.5 mm calcium chloride)and used as a crude synaptosomal fractions

The reaction mixture to absorb suspended in a final volume of 200 μl containing pargyline (final concentration 10 μm) and sodium ascorbate (final concentration 0.2 mg/ml) in each well of 96-well plate with a round bottom.

To each well was added the solvent, unlabeled DA, and serially diluted tested compound was added in synaptosomal fractions in the amount of 1/10 of the volume from the final volume. After 10 minutes has preliminarily the second incubation at 37°C, the uptake was initiated by adding a solution of DA, tritium-labeled (final concentration of 28 nm), at a temperature of 37°C.

The uptake was stopped after 10 minutes by vacuum filtration through a 96-well filter plate with glass fiber. After washing the filter with cold saline solution and drying was added Microscint-O (Perkin-Elmer) and measured residual radioactivity on the filter.

Activity absorption with only one solvent is taken as 100%, and nonspecific activity absorption with unlabeled DA (final concentration 10 μm) were taken at 0%. 50%inhibiting concentration was calculated based on the concentrations of the studied compounds and their inhibitory activity. The results are presented in table 162.

Table 162
The analyzed connection50% inhibitory concentration (nm)
The compound of example 745,0
The compound of example 448,7
The compound of example 469,3
The compound of example 739,0
The compound of example 90 4,8
The compound of example 11432,5
The compound of example 1168,9
The compound of example 1549,2
The compound of example 200the 3.8
The compound of example 2014,3
The compound of example 2686,5
The compound of example 2708,2
The compound of example 27230,0
The compound of example 27332,9
The compound of example 27834,7
The compound of example 28930,6
The compound of example 29424,0
The compound of example 29948,6
The compound of example 3009,6
Connection example 8949,4
Link the example 895 38,0
Connection example 91230,2
Connection example 9136,5
Connection example 9306,8
Connection example 95129,8
Connection example 9619,6
Connection example 96347,1
Connection example 96725,4
Connection example 9895,8
Connection example 99026,0
Connection example 100116,4
Connection example 100232,9

Pharmacological study 4

Test the forced swimming

Test the forced swimming was carried out on the basis of the method described by Porsolt, R.D., et al. (Porsolt, R.D., et al., Behavioural despair in mice: a primary screening test for antidepressants. Arch. Int. Pharmacodyn., 229, pp 327-336 (1977) with some modifications.

The analyzed connection suspend./about.) and then typed peroral the male ICR mice (from the firm Clea Japan Inc., 5-6 weeks). One hour after injection, the mice were thrown into a tank containing 9.5 cm of water, maintaining the temperature of 21-25°C. Then, the mice were forced to swim for 6 minutes. In the last four minutes of study defined period of time during which the mouse was not moving (i.e. the absence of mobility). The analysis and processing of data on time lack of mobility was performed using the system SCANET MV-20 AQ (product name company Melquest Co., Ltd.).

In this study, the animal treated with the investigational compound, showed a reduction of the time lack of mobility. Therefore it is clear that the test compound is effective as an antidepressant.img src="https://img.russianpatents.com/1073/10739749-s.jpg" height="239" width="164" />

1. Derived pyrrolidine General formula (1)

or its pharmaceutically acceptable salt,
where R101represents (1) phenyl group, and R102represents one of the following groups (1)-(86):
(1) phenyl group,
(2) pyridyloxy group,
(3) benzothiazoline group,
(4) indolenine group,
(5) 2,3-dihydro-1H-indenolol group,
(6) naftalina groups who,
(7) benzofuranyl group,
(8) pinolillo group,
(9) thiazolidine group,
(10) pyrimidinyl group,
(11) personilnya group,
(12) benzothiazolyl group,
(13) thieno[3,2-b]pyridyloxy group,
(14) thienyl group,
(15)3-8cycloalkyl group,
(16) tetrahydropyranyloxy group,
(17) pyrrolidinyl group,
(18) 2,4-dihydro-1,3-benzodioxolyl group,
(19) 2,3-dihydrobenzofuranyl group,
(20) N-fluorenyl group,
(21) pyrazolidine group,
(22) pyridazinyl group,
(23) indolinyl group,
(24) thieno[2,3-b]pyridyloxy group,
(25) thieno[3,2-d]pyrimidinyl group,
(26) thieno[3,2-e]pyrimidinyl group,
(27) 1H-pyrazolo[3,4-b]pyridyloxy group,
(28) izohinolinove group,
(29) 2,3-dihydro-1,4-benzoxazine group,
(30) khinoksalinona group,
(31) chinazolinei group,
(32) 1,2,3,4-tetrahydroquinoline group,
(33)3-8cycloalkyl C1-6alkyl group,
(34) C1-6alkylthio C1-6alkyl group,
(35) amino-substituted C1-6alkyl group, optionally substituted by one or two C1-6alkyl groups on the amino group,
(36) phenoxy C1-6alkyl group,
(37) pyridyloxy C1-6alkyl group,
(38)2-6alkylamino group,
(39) phenyl2-6alkenylphenol group,
(40) 1,3-benzodioxolyl group,
(41) 2,-dihydro-1,4-benzodioxolyl group,
(42) of 3,4-dihydro-1,5-benzodioxepine group,
(43) dihydropyridine group,
(44) 1,2-dihydropyridine group,
(45) 1,2,3,4-tetrahydroisoquinoline group,
(46) benzoxazolyl group,
(47) benzothiazolyl group,
(48) indazolinone group,
(49) benzoimidazolyl group,
(50) imidazolidinyl group,
(51) 1,2,3,4-tetrahydronaphthyl C1-6alkyl group,
(52) imidazo [1,2-a]pyridyl C1-6alkyl group,
(53) thiazolyl C1-6alkyl group,
(54) tetrahydropyranyl C1-6alkyl group,
(55) piperidyl C1-6alkyl group,
(56) diphenyl C1-6alkoxy, C1-6alkyl group,
(57) C1-6alkoxycarbonyl C1-6alkyl group,
(58) phenyl C1-6alkoxycarbonyl C1-6alkyl group,
(59) hydroxy, C1-6alkyl group,
(60) C1-6alkoxy, C1-6alkyl group,
(61) carboxy C1-6alkyl group,
(62) carbarnoyl C1-6alkyl group, optionally substituted by one or two C1-6alkyl groups on carbamoyl group,
(63)2-6alkenylphenol group,
(64) morpholinylcarbonyl C1-6alkyl group,
(65) benzoyl C1-6alkyl group,
(66) phenylthio C1-6alkyl group,
(67) naphthylthio C1-6alkyl group,
(68)3-8cycloalkylation C1-6alkyl group,
(69) pyridylthio C 1-6alkyl group,
(70) pyrimidinyl C1-6alkyl group,
(71) furylthio C1-6alkyl group,
(72) tianity C1-6alkyl group,
(73) 1,3,4-thiadiazolyl C1-6alkyl group,
(74) benzimidazolylthio C1-6alkyl group,
(75) benzothiazolylthio C1-6alkyl group,
(76) tetrazolate C1-6alkyl group,
(77) benzoxazolyl C1-6alkyl group,
(78) Tesorillo C1-6alkyl group,
(79) imidazolidin C1-6alkyl group,
(80) amino, C1-6alkylthio C1-6alkyl group, optionally substituted by one or two C1-6alkyl groups on the amino group,
(81) phenyl C1-6alkylthio C1-6alkyl group,
(82) furyl C1-6alkylthio C1-6alkyl group,
(83) pyridyl C1-6alkylthio C1-6alkyl group,
(84) hydroxy, C1-6alkylthio C1-6alkyl group,
(85) phenoxy C1-6alkylthio C1-6alkyl group and
(86) C1-6alkoxycarbonyl C1-6alkylthio C1-6alkyl group,
and each group(1)-(32), (37), (39)-(56), (64)-(79), (81)-(83) and (85) can have one or more substituents selected from the following groups (1-1)to(1-37), cycloalkenes, aromatic or heterocyclic ring, such as:
(1-1) halogen atoms,
(1-2) C1-6allylthiourea, optionally substituted ar is them or more atoms of halogen,
(1-3) C1-6alkyl group, optionally substituted by one or more atoms of halogen,
(1-4) C1-6alkoxygroup, optionally substituted by one or more atoms of halogen,
(1-5) the nitro-group,
(1-6) C1-6alkoxycarbonyl group,
(1-7) amino group, optionally substituted by one or two C1-6alkyl groups,
(1-8) C1-6alkylsulfonyl group,
(1-9) cyano,
(1-10) carboxypropyl,
(1-11) the hydroxy-group,
(1-12) thienyl groups,
(1-13) oxazolidine group,
(1-14) raftiline group,
(1-15) benzoline group,
(1-16) fenoxaprop, optionally substituted by one to three atoms of halogen in the phenyl ring,
(1-17) phenyl C1-6alkoxygroup,
(1-18) C1-6alcoholnye group,
(1-19) phenyl group, optionally substituted in the phenyl ring by one to five substituents selected from the group consisting of halogen atoms, C1-6alkoxygroup, cyano, C1-6alcoholnye group and C1-6alkyl group,
(1-20) phenyl C1-6alkyl group,
(1-21) cyano, C1-6alkyl group,
(1-22) sulfonylurea group, a substituted 5-membered saturated heterocyclic group with one nitrogen atom in the ring,
(1-23) thiazolidine group, optionally substituted by one or two C1-6alkyl groups in the thiazole ring,
(1-24) imide Yelnya group,
(1-25) amino, C1-6alkyl group, optionally substituted by one or two lower alkyl groups on the amino group,
(1-26) pyrrolidinyl C1-6alkoxygroup,
(1-27) isoxazolidine group,
(1-28)3-8cycloalkylcarbonyl group,
(1-29) naphthyloxy,
(1-30) peredelnye group,
(1-31) foreline group,
(1-32) phenylthiourea,
(1-33) oxoprop,
(1-34) carnemolla group,
(1-35) 5-membered saturated heterocyclic group containing one nitrogen atom, which may optionally contain a second heteroatom selected from nitrogen or oxygen, this heterocyclic group optionally substituted by one to three substituents selected from the group containing oxoprop; C1-6alkyl groups; C1-6alcoholnye group; phenyl C1-6alkyl groups; phenyl groups optionally substituted in the phenyl ring by one to three substituents selected from the group consisting of halogen atoms and C1-6alkoxygroup; and peredelnye group/or its pharmaceutically acceptable salt;
(1-36) aksigorta and
(1-37) C1-6alkoxygroup,
provided that R101and R102are not both unsubstituted phenyl.

2. Derived pyrrolidine (1) or its pharmaceutically acceptable salt according to claim 1, where
R102represents a
(1) phenyl group,
(2) p is rigelnuyu group,
(9) thiazolidine group,
(10) pyrimidinyl group,
(11) personilnya group
(14) thienyl group,
(48) indazolinone group,
(59) hydroxy, C1-6alkyl group, or
(60) C1-6alkoxy, C1-6alkyl group,
and each group(1), (2), (9), (10), (11), (14) and (48) may be an aromatic or heterocyclic ring one to three substituent selected from the group of (1-1)to(1-37), as specified in claim 1.

3. Derived pyrrolidine General formula (1) or its pharmaceutically acceptable salt according to claim 2, where
R101represents monovalently group, dihalogenoalkane group or a phenyl group substituted with one halogen atom and one C1-6alkyl group,
R102represents a
(1) phenyl group,
(2) pyridyloxy group,
(9) thiazolidine group,
(10) pyrimidinyl group,
(11) personilnya group,
(14) thienyl group,
(48) indazolinone group,
(59) hydroxy, C1-6alkyl group, or
(60) C1-6alkoxy, C1-6alkyl group,
and each group(1), (2), (9), (10), (11), (14) and (48) may be an aromatic or heterocyclic ring one or two substituent selected from the group consisting of (1-1) halogen atoms, (1-3) C1-6alkyl group, optionally substituted by one or more halogen atoms, and (1-9) cyano.

4. Derived pyrrolidin the General formula (1) or its pharmaceutically acceptable salt according to claim 3, selected from the group consisting of:
(4-chlorophenyl)phenyl-(S)-pyrrolidin-3-ylamine,
(4-forfinal)phenyl-(S)-pyrrolidin-3-ylamine,
(3,4-differenl)phenyl-(S)-pyrrolidin-3-ylamine,
bis-(4-forfinal)-(S)-pyrrolidin-3-ylamine,
(3,4-differenl)-(4-forfinal)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)-(S)-pyrrolidin-3-yl-p-tolylamino,
4-[(S)-(4-fluoro-3-were)pyrrolidin-3-ylamino]benzonitrile,
bis-(3-forfinal)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)-(S)-pyrrolidin-3-iltiazem-2-ylamine,
(4-forfinal)-(S)-pyrrolidin-3-iltiazem-2-ylamine,
(3,4-dichlorophenyl)-(S)-pyrrolidin-3-iltiazem-2-ylamine,
(3,4-dichlorophenyl)pyrimidine-5-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)pyrazin-2-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)-(5-chloropyridin-2-yl)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)pyridine-2-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)pyridine-3-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)-(6-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,
(3,4-dichlorophenyl)pyridine-3-yl-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)-(S)-pyrrolidin-3-althofen-3-ylamine,
(3-chloro-4-forfinal)-(5-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,
(4-fluoro-3-were)-(5-herperidin-3-yl)-(S)-pyrrolidin-3-ylamine,
2-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]ethanol,
1-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]-2-methyl-propane-2-ol,
(3-chloro-4-forfinal)-(2-methoxyethyl)-(S)-pyrrolidin-alamin,
3-[(S)-(3-chloro-4-forfinal)pyrrolidin-3-ylamino]propane-1-ol,
(3-chloro-4-forfinal)-(3-methoxypropyl)-(S)-pyrrolidin-3-ylamine,
(3-chloro-4-forfinal)-(1-methyl-1H-indazol-5-yl)-(S)-pyrrolidin-3-ylamine,
benzo[b]thiophene-6-yl-(S)-pyrrolidin-3-althofen-3-ylamine and
benzo[b]thiophene-5-yl-(S)-pyrrolidin-3-althofen-3-ylamine.

5. The pharmaceutical composition inhibiting the re-uptake of serotonin and/or norepinephrine and/or dopamine containing derived pyrrolidine General formula (1) or its pharmaceutically acceptable salt according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

6. The inhibitor of the reuptake of serotonin and/or norepinephrine and/or dopamine, containing as an active ingredient derived pyrrolidine General formula (1) or its pharmaceutically acceptable salt according to claim 1.

7. The inhibitor of the reuptake of serotonin and/or norepinephrine and/or dopamine according to claim 6 for the treatment of depression and anxiety disorders.

8. The application of the derived pyrrolidine General formula (1) or its pharmaceutically acceptable salt salt according to any one of claims 1 to 4 as an inhibitor of the reuptake of serotonin and/or an inhibitor of reuptake of norepinephrine and/or inhibitor of the reuptake of dopamine.

9. A method of treating depression and anxiety disorders due to ingebyra the project of re-absorption of serotonin and/or norepinephrine and/or dopamine, including the introduction of a derived pyrrolidine General formula (1) or its pharmaceutically acceptable salt according to any one of claims 1 to 4 human or animal.

10. The method of obtaining the derived pyrrolidine General formula (1):

or farmatsevticheskii acceptable salts, where R101and R102defined above in claim 1,
namely, that
(1) the compound of General formula (2)

where R101and R102are as indicated above in claim 1, and R112represents an amino-protective group,
subjected to the reactions of elimination to remove the amino-protective group.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula I and to their pharmaceutically acceptable salts. In formula I p is integer, equal to 0-1; L2 is selected from group including -XOX-, -XSX- and -XSXO-; where X is independently selected from group, including bond and C1-C4alkylene; R13 is selected from group, including halogen, C1-C6alkyl, C1-C6alkoxygroup, -C(O) C1-C6alkyl; R14 is selected from group, including -XOXC(O)OR17 and -C1-C4alkylene-C(O)OR17; where X represents bond or C1-C4alkylene; and R17 is selected from group, including hydrogen and C1-C6alkyl; R15 and R16 are independently selected from group, including -R18 and -YR18; where Y represents C2-C6alkenylene, and R18 is selected from group, including C6-C10aryl, benzo[1,3]dioxolyl, pyridinyl, pyrimidinyl, quinolyl, phenoxatiinyl, benzofuranyl, dibenzofuranyl, benzoxasolyl, 2,3-dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzooxasolyl, indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, where any C6-C10aryl, pyridinyl, benzoxasolyl, indolyl in R18 is optionally substituted by 1-2 radicals, independently selected from group, including halogen, nitrogroup, cyanogroup, C1-C6alkyl, C1-C6alkoxygroup, C1-C6alkylthiogroup, hydroxy-C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, XS(O)0-2R17, -XNR17R17, -XNR17S(O)2R17, -XNR17C(O)R17, -XC(O)NR17R17, -XC(O)NR17R19, -XC(O)R17, -XC(O)R19 and -XOXR19, where X represents bond; R17 is selected from group, including hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, and R19 is selected from group, including C3-C12cycloalkyl, phenyl, piperidinyl, morpholinyl.

EFFECT: ensuring application of invention compounds for production of medication, modulating activity of activated receptors of peroxisome proliferators δ (ARPPδ), to pharmaceutical composition, possessing properties of ARPPδ activity modulator, including therapeutically efficient quantity of invention compound and to application of pharmaceutical composition for medication manufacturing.

8 cl, 1 tbl, 301 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), where R1 denotes a 5- or 6-member ring of formulae

(II) or (III), respectively: R2 denotes H, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m,-Ra; R3 denotes aryl or heteroaryl, which can be substituted with CN, Cl, F, Br, CF3, CHF2, C3-C6-cycloalkyl or denotes heteroaryl which can be possibly substituted with C1-C7-alkyl; R4 denotes H, -OH, Cl, F, Br, CN, -CHF2, CF3, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m-Re; R5 denotes C1-C7-alkyl, -(CH2)n-O-Rf, or -(CH2)n-Re; Ra denotes -OH; Re denotes -OH; Rf denotes C1-C7-alkyl; m equals 1-4; n equals 2-6; and pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent containing said derivatives, use thereof in preparing medicinal agents suitable for treating diseases of the central nervous system.

EFFECT: novel compounds suitable for treating diseases of the central nervous system are obtained and described.

29 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel antibacterial compounds of formula (I). Compounds of formula (I) Q-NH-CO-R3, where Q stands for group of the following structure , R1 represents hydrogen, halogen, hydroxy, amino, mercapto, alkyl, heteroalkyl, alkeloxy, heteroalkyloxy, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, cycloalkyloxy, alkylcycloalkyloxy, heterocycloalkyloxy or heteroalkylcycloalkyloxy, X1, X2, X3, X4, X5 and X6 each independently on each other represent nitrogen atom or group of formula CR2, R2 represents hydrogen, halogen or hydroxy, amino, alkyl, alkenyl, alkinyl or heteroalkyl group, R3 is selected from the following groups R5 represents group of formula -B-Y, where B represents alkylene, alkenylene, alkinylene, -NH- or heteroalkylene, and Y represents aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or heteroalkylcycloalkyl, or their pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable composition, as well as to pharmaceutical composition, which possesses antibacterial activity, based on said compounds and to their application for preparation of medication, intended for treatment of bacterial infections.

EFFECT: obtained and described are compounds, which can be useful in medicine.

9 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives of formula I

or pharmaceutically acceptable salts thereof, where R1 denotes (1-6C)alkyl; R2, R3 independently denote halogen, (1-4C)alkoxy; R4 denotes phenyl or a 5-6-member heteroaryl, having one or two heteroatoms selected from nitrogen, oxygen or sulphur, phenyl or said heteroaryl, substituted with R7 and optionally substituted on the (hetero)aromatic ring with one or two substitutes selected from halogen, nitro, trifluoromethyl and (1-4C)alkyl; R7 denotes H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R8R9-amino, R10R11-aminocarbonyl, R12R13-amino(1-4C)alkylcarbonyl-amino, R14R15-amino(1-4C)alkyl, R16-oxy, R17R18-aminocarbonyl (1-4C)alkoxy, R19-oxy(1-4C)alkyl, R19-oxycarbonyl(1-4C)alkyl, R20R21-aminosulphonyl, R20-oxysulphonyl, aminoiminomethyl, (di)(1-4C)alkylaminoiminomethyl, morpholinyliminomethyl, trifluoromethylsulphonyl; R23-oxycarbonyl, or R23R24-aminocarbonyl; R8 denotes H or (1-4C)alkyl; R9 denotes (1-4C)alkylsulphonyl, (1-6C)alkylcarbonyl, (2-6C)alkenylcarbonyl, (3-6C)cycloalkylcarbonyl, (1-4C)alkoxycarbonyl, (3-4C)alkenyloxycarbonyl, (di)(1-4C)alkylaminocarbonyl, piperazinylcarbonyl, (5-8C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl or phenylcarbonyl, furylcarbonyl, thiophenylsulphonyl, 5-member heteraryl(1-4C)alkyl, having one or two nitrogen atoms, optionally substituted on the heteroaromatic ring with one, two or three substitutes selected from hydroxy, amino, halogen, nitro, trifluoromethyl, (1-4C)alkoxy; R10 denotes H or (1-4C)alkyl; R11 denotes hydroxy(2-4C)alkyl, (1-4C)alkoxy(2-4C)alkyl; R12, R13 independently denote H, (1-6C)alkyl, (3-6C)-cycloalkyl, (1-4C)alkoxy(2-4C)alkyl, (3-6C)cycloalkyl-(1-4C)alkyl, pyrrolidinyl(1-4C)alkyl, amino(2-4C)alkyl, (di)(1-4C)-alkylamino(2-4C)alkyl or phenyl(1-4C)alkyl, pyridinyl (1-4C)alkyl; or R12R13 in R12R13-amino(1-4C)alkylcarbonylamino can be bonded together with the nitrogen atom to which they are bonded into a (5-6C)heterocycloalkyl ring, having one or two nitrogen atoms, optionally substituted with hydroxy(1-4C)alkyl; R14, R15 independently denote H, (1-6C)alkyl, (1-6C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyridinyl(1-4C)alkyl, optionally substituted on the aromatic ring with one substitute selected from halogen; or R16 denotes (di)(1-4C)alkylamino(2-4C)alkyl, hydroxycarbonyl(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, phenyl(1-4C)alkyl or pyridinyl(1-4C)alkyl; R17, R18 independently denote H, (1-6C)alkyl, thiophenyl(1-4C)alkyl; or R17R18 in R17R18-aminocarbonyl(1-4C)alkoxy can be bonded into a morpholine or piperazine ring, R19 denotes H or (1-6C)alkyl; R20R21 independently denote H, (1-6C)alkyl or (1-4C)alkoxy(1-4C)alkyl; or R20R21 in R20R21-aminosulphonyl can be bonded into a morpholine ring; X denotes O or N-R22; Y denotes CH2 or C(O); Z denotes CN or NO2; R22 denotes H; R23, R24 independently denotes H; (1-4C)alkyl; or R23R24 in R23R24-aminocarbonyl can be bonded into a dihydropyridine ring; provided that compounds of formula I, in which X denotes O, R4 denotes phenyl and R7 is selected from H, (1-4C)alkylthio, (1-4C)alkylsulphonyl, R23-oxycarbonyl, and R23R24-aminocarbonyl, and compounds of formula I, in which X denotes O, R4 denotes (2-5C)heteroaryl and R7 denotes H are excluded. The invention also relates to use of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives to prepare a medicinal agent for treating sterility.

EFFECT: improved useful biological properties.

12 cl, 73 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for selective production of N-[3-(1,3,5-dithiazinan-5-yl)propyl]-N-[4-(1,3,5-dithiazinan-5-yl)butyl]amine and N1,N4-bis-[3-(1,3,5-dithiazinan-5-yl)propyl]-1,4-butane diamine which involves reaction of an amine with a hydrogen sulphide saturated aqueous solution of formaldehyde, where the amine used is polymethylenepolyamine (spermidine or spermine) in molar ratio polyamine: formaldehyde: hydrogen sulphide equal to 1:6:4 and the reaction is carried out at 20°C for 3 hours.

EFFECT: compounds can be used as selective sorbents and extraction agents of precious metals, special reagents for inhibiting bacterial activity in various media.

1 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: described are heterobicyclic derivatives of formula (I)

, in which V denotes -C(R7)-; W denotes a single bond or -C(R8R9)-; X denotes O, S, SO, SO2 or N(R10); Y denotes -C(R11R12)-, -C(R11R12)C(R13R14)C(R11R12)C(R13R14)C(R15R16)-, -C(R11R12)C(R13R14)C(R15R16)C(R17R18)- or- C(R11)=C(R12)-; R1, R2, R3, R4 and R5 independently denote hydrogen, halogen, (lower)alkyl, fluoro(lower)alkyl, (lower)alkoxy group, fluoro(lower)alkoxy group, NH2-C(O); R6 denotes a phenyl, pyridyl, pyrazolyl or thiazolyl group, where the group is optionally substituted with 1-4 substitutes selected from a group consisting of halogen, cyano group, (lower)alkyl, (lower)alkoxy group, COOH, 1H-tetrazol-5-yl, 5-oxo-4H-[1,2,4]oxadiazol-3-yl, where (lower)alkyl is optionally substituted with COOH. A pharmaceutical composition is also described.

EFFECT: said compounds inhibit L-CPT1 and can be used as medicinal agents.

27 cl, 120 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to derivatives of 2-pyridylmethylenecarboxamide of formula (I), where: -A represents a substituted or unsubstituted 5-member heterocyclyl group bound with carbonyl through carbon atom; -Z1 and Z2 which can be equal or different, represent hydrogen atom; C1-C5-alkyl; C5-alkoxycarbonyl; -Z3 represents substituted or unsubstituted C3-C7cycloalkyl; -Y represents C1-C5-halogenalkyl, containing to 5 halogen atoms which can be equal or different; X which can be equal or different, represents halogen atom, - n=0, 1, 2 or 3; and to their salts. Besides the invention describes a method of plant pathogenic fungi control with the use of such compounds.

EFFECT: there are prepared and described new derivatives of 2-pyridylmethylenecarboxamide which can be effective as fungicidal active agents.

8 cl, 96 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula: or to its pharmaceutically acceptable salt, where: Ar2 represents phenyl or pyridyl, each of which is substituted by 0-4 substituents, independently selected from R2; X and Z represent N; Y represents CRX; D represents N; F represents N, CH or carbon, substituted by substituent, representing R1 or R10; Rx in each case is independently selected from hydrogen, halogen, C1-C4alkyl, amino, cyano and mono- or di-(C1-C4alkyl)amino; R1 represents 0-3 substituents, independently selected from: (a) halogen, cyano and nitro; (b) groups of formula -Q-M-Ry; R10 represents one substituent, selected from: (a) groups of formula -Q-M-Ry; so that R10 is not hydroxy, amino or unsubstituted group, selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, C1-C6aloxy, C2-C6alkyl, ether, C2-C6alkanoyl, C3-C6alcanone, C1-C6halogenalkyl, C1-C6halogenoalkoxy, mono- or di-(C1-C6alkyl)amino, C1-C6alkylsulfonyl, mono- or di-(C1-C6alkyl)aminosulfonyl or mono- or di-(C1-C6alkyl)aminocarbonyl; each Q is independently selected from C0-C4alkylene; each M is independently absent or is selected from O, C(=O), OC(=O), C(=O)O, S(O)m, N(RZ), C(=O)N(Rz), C(=NH)N(Rz), N(Rz)C(=O), N(Rz)C(=NH), N(Rz)S(O)m, S(O)mN(Rz) and N[S(O)mRz]S(O)m, where m equals 2; and Rz in each case is independently selected from hydrogen, C1-C8alkyl and groups, which taken together with Ry, form possibly substituted (4-7)-member heterocycle; and each Ry independently represents hydrogen, C1-C8halogenalkyl, C1-C8alkyl, C2-C8alkenyl, (C3-C8carbocycle)C0-C4alkyl, ((4-7)-member heterocycle)C0-C4alkyl or taken together with Rz forms (4-7) member heterocycle, where each alkyl, carbocycle and heterocycle is substituted by 0-4 substituents, independently selected from hydroxy, halogen, amino, cyano, nitro, -COOH, aminocarbonyl, aminosulfonyl, C1-C6alkyl, C3-C7cecloalkyl, C2-C6alkyl ether, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C8alkoxy, C1-C8hydroxyalkyl, mono- and di-(C1-C6alkyl)aminocarbonyl, mono- and di-(C1-C6alkyl)aminosulfonyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkanoylamino and phenyl; so that Ry is not hydrogen, if Q represents C0alkyl and M is absent; each R2: (a) is independently selected from (1) hydroxyl, amino, cyano, halogen, -COOH, nitro and (2) C1-C6alkyl, (C3-C8cycloalkyl)C0-C4alkyl, C1-C6halogenalkyl; R3 is selected from: (1) hydrogen; (2) C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl; and (3) groups of formula: where L represents C0-C6alkylene; R5 and R6: (a) are independently selected from C1-C12alkyl, (C3-C8cycloalkyl)C0-C4alkyl; or (b) are combined with formation of (4-6)-member heterocycle, containing one or two heteroatoms independently selected from O and N; and where each of (2) and (3) is substituted by 0-4 substituents, independently selected from: C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl, each of which is substituted by 0-4 secondary substituents, independently selected from hydroxy, C1-C4alkyl and C1-C4alkoxy; and R4 represents 0-2 substituents, independently selected from C1-C3alkyl.

EFFECT: claimed are pharmaceutical compositions for modulation of capsaicin receptor activity and methods of applying said compounds for treatment of such disorders as pain, itch, cough, hiccup, urinary incontinence or obesity.

65 cl, 1 tbl, 10 ex

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