JP2008137997A - Medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having a broad treatment spectrum and can exhibit a satisfactory treatment effect in a short period. <P>SOLUTION: The medicine comprises a pyrrolidine compound represented by formula (1) (wherein R<SP>101</SP>and R<SP>102</SP>are the same or different and each a phenyl group, a pyridyl group or the like and the phenyl group or pyridyl group of them may have one or more substituents selected from the group consisting of a halogen and a lower alkyl group which may be substituted with one or more halogens) or its salt. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel medicine.

  Three monoamines, known as serotonin, norepinephrine and dopamine, function as neurotransmitters in vivo, so drugs that have reuptake inhibitory action of these monoamines can treat diseases related to the central or peripheral nervous system. Widely used as a medicine.

To date, many of the drugs used to treat depression are those that selectively inhibit norepinephrine or serotonin reuptake. Examples of such drugs include imipramine (first generation antidepressant), maprotiline (second generation antidepressant), and selective serotonin uptake inhibitors (SSRI, third, typified by fluoxetine). Generation antidepressants), serotonin and / or norepinephrine reuptake inhibitors (SNRI, fourth generation antidepressants) represented by venlafaxine (Non-patent Document 1).

However, all of these drugs require a long period of 3 weeks or more until a therapeutic effect is exhibited, and cannot exhibit a sufficient therapeutic effect for depression patients of about 30% (non- Patent Document 2).
Miura Sadanori, Clinical Psychopharmacology, 2000, 3: 311-318 Phil Skolnick, European Journal of Pharmacology, 2001, 375: 31-40

  An object of the present invention is to provide a drug having a broad therapeutic spectrum as compared with known antidepressants and capable of exhibiting a sufficient therapeutic effect in a short period of time.

  As a result of intensive studies to solve the above problems, the present inventor has found that a pyrrolidine compound represented by the following general formula (1) can be used for the production of a desired drug. The present invention has been completed based on such findings.

  The present invention provides pharmaceuticals shown in the following items 1 to 10.

  Item 1. General formula (1)

[Wherein, R ¹⁰¹ and R ¹⁰² each independently represent any group represented by the following (1) to (86).
(1) phenyl group,
(2) a pyridyl group,
(3) benzothienyl group,
(4) Indolyl group,
(5) 2,3-dihydro-1H-indenyl group,
(6) naphthyl group,
(7) benzofuryl group,
(8) quinolyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(12) benzothiazolyl group,
(13) thieno [3,2-b] pyridyl group,
(14) thienyl group,
(15) a cycloalkyl group,
(16) tetrahydropyranyl group,
(17) pyrrolyl group,
(18) 2,4-dihydro-1,3-benzodioxinyl group,
(19) 2,3-dihydrobenzofuryl group,
(20) 9H-fluorenyl group,
(21) pyrazolyl group,
(22) pyridazinyl group,
(23) indolinyl group,
(24) thieno [2,3-b] pyridyl group,
(25) thieno [3,2-d] pyrimidinyl group,
(26) thieno [3,2-e] pyrimidinyl group,
(27) 1H-pyrazolo [3,4-b] pyridyl group,
(28) isoquinolyl group,
(29) 2,3-dihydro-1,4-benzoxazinyl group,
(30) quinoxalinyl group,
(31) quinazolinyl group,
(32) 1,2,3,4-tetrahydroquinolyl group,
(33) a cycloalkyl lower alkyl group,
(34) a lower alkylthio lower alkyl group,
(35) an amino-substituted lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(36) Phenoxy lower alkyl group,
(37) pyridyloxy lower alkyl group,
(38) a lower alkynyl group,
(39) phenyl lower alkenyl group,
(40) 1,3-benzodioxolyl group,
(41) 2,3-dihydro-1,4-benzodioxinyl group,
(42) 3,4-dihydro-1,5-benzodioxepinyl group,
(43) dihydropyridyl group,
(44) 1,2-dihydroquinolyl group,
(45) 1,2,3,4-tetrahydroisoquinolyl group,
(46) benzoxazolyl group,
(47) benzoisothiazolyl group,
(48) indazolyl group,
(49) Benzimidazolyl group,
(50) imidazolyl group,
(51) 1,2,3,4-tetrahydronaphthyl lower alkyl group,
(52) imidazo [1,2-a] pyridyl lower alkyl group,
(53) a thiazolyl lower alkyl group,
(54) tetrahydropyranyl lower alkyl group,
(55) piperidyl lower alkyl group,
(56) diphenyl lower alkoxy substituted lower alkyl group,
(57) a lower alkoxycarbonyl-substituted lower alkyl group,
(58) phenyl lower alkoxycarbonyl substituted lower alkyl group,
(59) a hydroxy-substituted lower alkyl group,
(60) a lower alkoxy lower alkyl group,
(61) a carboxy lower alkyl group,
(62) A carbamoyl-substituted lower alkyl group (on the carbamoyl group, a lower alkyl group has 1 to 1
2 may be substituted),
(63) a lower alkenyl group,
(64) morpholinylcarbonyl lower alkyl group,
(65) benzoyl lower alkyl group,
(66) phenylthio lower alkyl group,
(67) Naphthylthio lower alkyl group,
(68) cycloalkylthio lower alkyl group,
(69) pyridylthio lower alkyl group,
(70) pyrimidinylthio lower alkyl group,
(71) furylthio lower alkyl group,
(72) thienylthio lower alkyl group,
(73) 1,3,4-thiadiazolylthio lower alkyl group,
(74) benzimidazolylthio lower alkyl group,
(75) Benzthiazolylthio lower alkyl group,
(76) tetrazolylthio lower alkyl group,
(77) benzoxazolylthio lower alkyl group,
(78) thiazolylthio lower alkyl group,
(79) imidazolylthio lower alkyl group,
(80) amino-substituted lower alkylthio lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(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) a phenoxy-substituted lower alkylthio lower alkyl group, and
(86) a lower alkoxycarbonyl-substituted lower alkylthio-lower alkyl group;
Each of the groups represented by the above (1) to (32), (37), (39) to (56), (64) to (79), (81) to (83) and (85) is a cycloalkyl ring. The aromatic ring or heterocyclic ring may have one or more substituents selected from the following (1-1) to (1-37).

(1-1) a halogen atom,
(1-2) a lower alkylthio group optionally substituted with one or more halogen atoms,
(1-3) a lower alkyl group which may be substituted with one or more halogen atoms,
(1-4) a lower alkoxy group which may be substituted with one or more halogen atoms,
(1-5) Nitro group,
(1-6) a lower alkoxycarbonyl group,
(1-7) an amino group in which one or two lower alkyl groups may be substituted,
(1-8) a lower alkylsulfonyl group,
(1-9) cyano group,
(1-10) carboxy group,
(1-11) hydroxyl group,
(1-12) thienyl group,
(1-13) oxazolyl group,
(1-14) naphthyl group,
(1-15) benzoyl group,
(1-16) Phenoxy group (1 to 3 halogen atoms may be substituted on the phenyl ring),
(1-17) phenyl lower alkoxy group,
(1-18) a lower alkanoyl group,
(1-19) Phenyl group (on the phenyl ring, a halogen atom, a lower alkoxy group, a cyano group,
1 to 5 substituents selected from the group consisting of a lower alkanoyl group and a lower alkyl group may be substituted),
(1-20) phenyl lower alkyl group,
(1-21) cyano lower alkyl group,
(1-22) a sulfonyl group substituted with a 5- to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
(1-23) thiazolyl group (on the thiazole ring, 1 to 2 lower alkyl groups may be substituted),
(1-24) imidazolyl group,
(1-25) Amino lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(1-26) pyrrolidinyl lower alkoxy group,
(1-27) isoxazolyl group,
(1-28) cycloalkylcarbonyl group,
(1-29) naphthyloxy group,
(1-30) pyridyl group,
(1-31) furyl group,
(1-32) phenylthio group,
(1-33) oxo group,
(1-34) carbamoyl group,
(1-35) a 5- to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (on the saturated heterocyclic group, an oxo group A lower alkyl group; a lower alkanoyl group; a phenyl lower alkyl group; a phenyl group optionally having 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring; and a pyridyl group 1 to 3 substituents selected from the group may be substituted)
(1-36) an oxide group, and
(1-37) a lower alkoxide group;
However, R ¹⁰¹ and R ¹⁰² must not be an unsubstituted phenyl group at the same time. ]
A pharmaceutical comprising a pyrrolidine compound represented by the formula:

Item 2. R ¹⁰¹ is
(1) phenyl group,
(3) benzothienyl group,
(4) Indolyl group,
(5) 2,3-dihydro-1H-indenyl group,
(6) naphthyl group,
(7) benzofuryl group,
(8) quinolyl group,
(12) benzothiazolyl group,
(18) 2,4-dihydro-1,3-benzodioxinyl group,
(19) 2,3-dihydrobenzofuryl group,
(20) 9H-fluorenyl group,
(23) indolinyl group,
(28) isoquinolyl group,
(29) 2,3-dihydro-1,4-benzoxazinyl group,
(30) quinoxalinyl group,
(31) quinazolinyl group,
(32) 1,2,3,4-tetrahydroquinolyl group,
(40) 1,3-benzodioxolyl group,
(41) 2,3-dihydro-1,4-benzodioxinyl group,
(42) 3,4-dihydro-1,5-benzodioxepinyl group,
(44) 1,2-dihydroquinolyl group,
(45) 1,2,3,4-tetrahydroisoquinolyl group,
(46) benzoxazolyl group,
(47) benzoisothiazolyl group,
(48) an indazolyl group, or
(49) is a benzimidazolyl group,
Each of these groups may have 1 to 3 substituents selected from (1-1) to (1-37) defined in Item 1 on the aromatic ring or heterocyclic ring.
A pharmaceutical comprising the pyrrolidine compound represented by the general formula (1) according to Item 1 or a salt thereof.

Item 3. R ¹⁰¹ is (1) a phenyl group or (3) a benzothienyl group,
Substitution selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with 1 to 3 halogen atoms on the aromatic ring or heterocyclic ring of each group May have 1 to 3 groups,
A medicament comprising a pyrrolidine compound represented by the general formula (1) according to Item 2 or a salt thereof.

Item 4. R ¹⁰² is
(1) phenyl group,
(2) a pyridyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(14) thienyl group,
(48) indazolyl group,
(59) a hydroxy-substituted lower alkyl group, or
(60) a lower alkoxy lower alkyl group,
Each group represented by the above (1), (2), (9), (10), (11), (14) and (48) is defined in item 1 on the aromatic ring or heterocyclic ring (1 -1) to (1-37) may have 1 to 3 substituents selected from,
A pharmaceutical comprising the pyrrolidine compound represented by the general formula (1) according to Item 3 or a salt thereof.

Item 5. R ¹⁰¹ is a monohalophenyl group, a dihalophenyl group or a phenyl group substituted with one halogen atom and one lower alkyl group;
R ¹⁰² is
(1) phenyl group,
(2) a pyridyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(14) thienyl group,
(48) indazolyl group,
(59) a hydroxy-substituted lower alkyl group, or
(60) a lower alkoxy lower alkyl group,
Each of the groups represented by the above (1), (2), (9), (10), (11), (14) and (48) is a (1-1) halogen atom on the aromatic ring or heterocyclic ring, (1-3) one or more substituents selected from the group consisting of a lower alkyl group which may be substituted with one or more halogen atoms and (1-9) a cyano group may be present,
A pharmaceutical comprising the pyrrolidine compound represented by the general formula (1) according to Item 4 or a salt thereof.

Item 6. A pharmaceutical comprising a pyrrolidine compound represented by the general formula (1) according to item 5 or a salt thereof selected from the following group:
(3-chloro-4-fluorophenyl) -3-thienyl- (S) -pyrrolidin-3-ylamine,
(4-chlorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
(4-fluorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
(3,4-difluorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
Bis (4-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3,4-difluorophenyl)-(4-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-yl-p-tolylamine,
4-[(S)-(4-fluoro-3-methylphenyl) pyrrolidin-3-ylamino] benzonitrile bis (3-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(4-fluorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl) pyrimidin-5-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyrazin-2-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyridin-2-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
(3,4-dichlorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-ylthiophen-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
(4-Fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S)
-Pyrrolidin-3-ylamine,
2-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) ethanol,
1-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) -2-methylpropan-2-ol,
(3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S) -pyrrolidin-3-ylamine,
3-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) propan-1-ol,
(3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S) -pyrrolidin-3-ylamine,
Benzo [b] thiophen-6-yl- (S) -pyrrolidin-3-ylthiophen-3-ylamine and benzo [b] thiophen-5-yl- (S) -pyrrolidin-3-ylthiophen-3-ylamine .

  Item 7. Item 7. A pharmaceutical composition comprising the pharmaceutical according to any one of Items 1 to 6 and a pharmaceutically acceptable carrier.

  Item 8. Item 7. A preventive and / or therapeutic agent for a disorder associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine, comprising the pharmaceutical according to any one of items 1 to 6 as an active ingredient.

Item 9. Disability is hypertension; depression; generalized anxiety disorder; fear; post-traumatic stress syndrome; acute stress syndrome; avoidance personality disorder; body deformity injury; premature ejaculation; eating disorder; obesity; alcohol, cocaine, Chemical dependence on heroin, phenobarbital, nicotine and benzodiazepines; cluster headache; migraine; pain; Alzheimer's disease; obsessive-compulsive disorder; panic disorder; memory disorder; Parkinson's disease; endocrine disorder; Gastrointestinal tract disorder; negative syndrome of schizophrenia; premenstrual syndrome; fibromyalgia syndrome; tension urinary incontinence; towlet syndrome; hair loss; stealing; male impotence; attention deficit hyperactivity disorder (ADHD); Selected from the group consisting of migraine; chronic fatigue; weakness; sleep apnea syndrome;
Item 9. The preventive and / or therapeutic agent according to Item 8.

Item 10. Item 9. The preventive and / or therapeutic agent according to item 8, wherein the disorder is selected from the following group;
Major Depressive Disorder; Bipolar I Disorder; Bipolar Type II Disorder; Mixed State; Mood Modulation Disorder; Rapid Cycler; Atypical Depression; Seasonal Emotion Disorder; Postpartum Depression; Mild Depression; Recurrent Short-Term Depression Morbidity disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety depression disorder; Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea / milk Depression associated with physical disease selected from the group consisting of secretion syndrome, Parkinson's disease, Alzheimer's disease, cerebral hemorrhage, diabetes, chronic fatigue syndrome and cancer; middle age depression; old age depression; childhood / pubertal depression Interferon-induced depression; and depression associated with adaptation disorders and anxiety associated with adaptation disorders; and various diseases [eg, neurological disorders (head trauma, brain infections and inner ear disorders), heart blood Disorders (heart failure, arrhythmias), endocrine disorders (adrenal hyperthyroidism, hyperthyroidism), respiratory disorders (asthma, chronic obstructive pulmonary disease) anxiety selected from the group consisting of anxiety caused by.

  A preferred embodiment of the pyrrolidine compound (1) includes a pharmaceutical comprising the compound represented by the general formula (1) or a salt thereof.

[Wherein R ¹⁰¹ is
(1) phenyl group,
(3) benzothienyl group,
(4) Indolyl group,
(5) 2,3-dihydro-1H-indenyl group,
(6) naphthyl group,
(7) benzofuryl group,
(8) quinolyl group,
(12) benzothiazolyl group,
(18) 2,4-dihydro-1,3-benzodioxinyl group,
(19) 2,3-dihydrobenzofuryl group,
(20) 9H-fluorenyl group,
(23) indolinyl group,
(28) isoquinolyl group,
(29) 2,3-dihydro-1,4-benzoxazinyl group,
(30) quinoxalinyl group,
(31) quinazolinyl group,
(32) 1,2,3,4-tetrahydroquinolyl group,
(40) 1,3-benzodioxolyl group,
(41) 2,3-dihydro-1,4-benzodioxinyl group,
(42) 3,4-dihydro-1,5-benzodioxepinyl group,
(44) 1,2-dihydroquinolyl group,
(45) 1,2,3,4-tetrahydroisoquinolyl group,
(46) benzoxazolyl group,
(47) benzoisothiazolyl group,
(48) an indazolyl group, or
(49) represents a benzimidazolyl group.

On the aromatic ring or heterocyclic ring of each group, 1 to 5 substituents selected from the following (1-1) to (1-37) are contained.
You may have (preferably 1-3 pieces).

(1-1) a halogen atom,
(1-2) a lower alkylthio group in which one or more (preferably 1 to 3) halogen atoms may be substituted,
(1-3) a lower alkyl group in which one or more (preferably 1 to 3) halogen atoms may be substituted,
(1-4) a lower alkoxy group in which one or more (preferably 1 to 4) halogen atoms may be substituted,
(1-5) Nitro group,
(1-6) a lower alkoxycarbonyl group,
(1-7) an amino group in which one or two lower alkyl groups may be substituted,
(1-8) a lower alkylsulfonyl group,
(1-9) cyano group,
(1-10) carboxy group,
(1-11) hydroxyl group,
(1-12) thienyl group,
(1-13) oxazolyl group,
(1-14) naphthyl group,
(1-15) benzoyl group,
(1-16) Phenoxy group (1 to 3 halogen atoms may be substituted on the phenyl ring),
(1-17) phenyl lower alkoxy group,
(1-18) a lower alkanoyl group,
(1-19) Phenyl group (on the phenyl ring, a halogen atom, a lower alkoxy group, a cyano group,
1 to 5 (preferably 1 to 3) substituents selected from the group consisting of a lower alkanoyl group and a lower alkyl group may be substituted),
(1-20) phenyl lower alkyl group,
(1-21) cyano lower alkyl group,
(1-22) a sulfonyl group (preferably a piperidylsulfonyl group) substituted with a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms,
(1-23) thiazolyl group (on the thiazole ring, 1 to 2 lower alkyl groups may be substituted),
(1-24) imidazolyl group,
(1-25) Amino lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(1-26) pyrrolidinyl lower alkoxy group,
(1-27) isoxazolyl group,
(1-28) cycloalkylcarbonyl group,
(1-29) naphthyloxy group,
(1-30) pyridyl group,
(1-31) furyl group,
(1-32) phenylthio group,
(1-33) oxo group,
(1-34) carbamoyl group,
(1-35) a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms (preferably pyrrolidinyl, piperazinyl or piperidyl) (on the saturated heterocyclic group, an oxo group; a lower alkyl group; An alkanoyl group; a phenyl lower alkyl group; a phenyl group optionally having 1 to 3 groups selected from the group consisting of halogen atoms and lower alkoxy groups on the phenyl ring; and a group consisting of pyridyl groups 1 to 3 substituents may be substituted)
(1-36) an oxide group, and
(1-37) a lower alkoxide group;
However, R ¹⁰¹ and R ¹⁰² must not be an unsubstituted phenyl group at the same time. ]

A more preferred embodiment of the pyrrolidine compound (1) includes a pharmaceutical comprising the compound represented by the general formula (1) or a salt thereof.

[Wherein R ¹⁰¹ represents (1) a phenyl group or (3) a benzothienyl group. Substitution selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with 1 to 3 halogen atoms on the aromatic ring or heterocyclic ring of each group You may have 1 or 2 groups. R ¹⁰² is
(1) phenyl group,
(2) a pyridyl group,
(3) benzothienyl group,
(4) Indolyl group,
(5) 2,3-dihydro-1H-indenyl group,
(6) naphthyl group,
(7) benzofuryl group,
(8) quinolyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(12) benzothiazolyl group,
(13) thieno [3,2-b] pyridyl group,
(14) thienyl group,
(15) a cycloalkyl group,
(16) tetrahydropyranyl group,
(17) pyrrolyl group,
(18) 2,4-dihydro-1,3-benzodioxinyl group,
(19) 2,3-dihydrobenzofuryl group,
(20) 9H-fluorenyl group,
(21) pyrazolyl group,
(22) pyridazinyl group,
(23) indolinyl group,
(24) thieno [2,3-b] pyridyl group,
(25) thieno [3,2-d] pyrimidinyl group,
(26) thieno [3,2-e] pyrimidinyl group,
(27) 1H-pyrazolo [3,4-b] pyridyl group,
(28) isoquinolyl group,
(29) 2,3-dihydro-1,4-benzoxazinyl group,
(30) quinoxalinyl group,
(31) quinazolinyl group,
(32) 1,2,3,4-tetrahydroquinolyl group,
(40) 1,3-benzodioxolyl group,
(41) 2,3-dihydro-1,4-benzodioxinyl group,
(42) 3,4-dihydro-1,5-benzodioxepinyl group,
(43) dihydropyridyl group,
(44) 1,2-dihydroquinolyl group,
(45) 1,2,3,4-tetrahydroisoquinolyl group,
(46) benzoxazolyl group,
(47) benzoisothiazolyl group,
(48) indazolyl group,
(49) Benzimidazolyl group,
(50) imidazolyl group,
(59) a hydroxy-substituted lower alkyl group, or
(60) represents a lower alkoxy lower alkyl group. Each group represented by the above (1) to (50) has 1 to 5 substituents (preferably 1) selected from the following (1-1) to (1-37) on an aromatic ring or a heterocyclic ring. ~ 3).

(1-1) a halogen atom,
(1-2) a lower alkylthio group in which one or more (preferably 1 to 3) halogen atoms may be substituted,
(1-3) a lower alkyl group in which one or more (preferably 1 to 3) halogen atoms may be substituted,
(1-4) a lower alkoxy group in which one or more (preferably 1 to 4) halogen atoms may be substituted,
(1-5) Nitro group,
(1-6) a lower alkoxycarbonyl group,
(1-7) an amino group in which one or two lower alkyl groups may be substituted,
(1-8) a lower alkylsulfonyl group,
(1-9) cyano group,
(1-10) carboxy group,
(1-11) hydroxyl group,
(1-12) thienyl group,
(1-13) oxazolyl group,
(1-14) naphthyl group,
(1-15) benzoyl group,
(1-16) Phenoxy group (1 to 3 halogen atoms may be substituted on the phenyl ring),
(1-17) phenyl lower alkoxy group,
(1-18) a lower alkanoyl group,
(1-19) Phenyl group (on the phenyl ring, a halogen atom, a lower alkoxy group, a cyano group,
1 to 5 (preferably 1 to 3) substituents selected from the group consisting of a lower alkanoyl group and a lower alkyl group may be substituted),
(1-20) phenyl lower alkyl group,
(1-21) cyano lower alkyl group,
(1-22) a sulfonyl group (preferably a piperidylsulfonyl group) substituted with a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms,
(1-23) thiazolyl group (on the thiazole ring, 1 to 2 lower alkyl groups may be substituted),
(1-24) imidazolyl group,
(1-25) Amino lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(1-26) pyrrolidinyl lower alkoxy group,
(1-27) isoxazolyl group,
(1-28) cycloalkylcarbonyl group,
(1-29) naphthyloxy group,
(1-30) pyridyl group,
(1-31) furyl group,
(1-32) phenylthio group,
(1-33) oxo group,
(1-34) carbamoyl group,
(1-35) a 5- to 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms (preferably pyrrolidinyl, piperazinyl or piperidyl) (on the saturated heterocyclic group, an oxo group; a lower alkyl group; An alkanoyl group; a phenyl lower alkyl group; a phenyl group optionally having 1 to 3 groups selected from the group consisting of halogen atoms and lower alkoxy groups on the phenyl ring; and a group consisting of pyridyl groups 1 to 3 substituents may be substituted)
(1-36) an oxide group, and
(1-37) a lower alkoxide group;
However, R ¹⁰¹ and R ¹⁰² must not be an unsubstituted phenyl group at the same time. ]

A particularly preferred embodiment of the pyrrolidine compound (1) includes a pharmaceutical comprising the compound represented by the general formula (1) or a salt thereof.

[Wherein R ¹⁰¹ is selected from the group consisting of (1) (1-1) halogen atom and (1-3) lower alkyl group optionally substituted with 1 to 3 halogen atoms on the phenyl ring. The substituted substituent represents a phenyl group substituted by 1 to 2 groups.
R ¹⁰² is
(1) phenyl group,
(2) a pyridyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(14) thienyl group,
(48) indazolyl group,
(59) a hydroxy-substituted lower alkyl group, or
(60) represents a lower alkoxy lower alkyl group. Each of the groups represented by the above (1), (2), (9), (10), (11), (14) and (48) is a (1-1) halogen atom on the aromatic ring or heterocyclic ring, (1-3) 1 to 2 substituents selected from the group consisting of a lower alkyl group which may be substituted with 1 to 3 halogen atoms and a (1-9) cyano group may be included. .

Particularly preferred are medicaments comprising the following pyrrolidine compounds;
(3-chloro-4-fluorophenyl) -3-thienyl- (S) -pyrrolidin-3-ylamine,
(4-chlorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
(4-fluorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
(3,4-difluorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
Bis (4-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3,4-difluorophenyl)-(4-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-yl-p-tolylamine,
4-[(S)-(4-fluoro-3-methylphenyl) pyrrolidin-3-ylamino] benzonitrile bis (3-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(4-fluorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl) pyrimidin-5-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyrazin-2-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyridin-2-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
(3,4-dichlorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-ylthiophen-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
(4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
2-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) ethanol,
1-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) -2-methylpropan-2-ol,
(3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S) -pyrrolidin-3-ylamine,
3-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) propan-1-ol,
(3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S) -pyrrolidin-3-ylamine,
Benzo [b] thiophen-6-yl- (S) -pyrrolidin-3-ylthiophen-3-ylamine and benzo [b] thiophen-5-yl- (S) -pyrrolidin-3-ylthiophen-3-ylamine .

More specifically, each group shown in the general formula (1) is as follows.

  As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are shown.

The lower alkylthio group which may be substituted with one or more halogen atoms includes a linear or branched alkylthio group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms, Specific examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, isopentylthio, neopentylthio, n-hexylthio, isohexylthio. 3-methylpentylthio, trifluoromethylthio, trichloromethylthio, chloromethylthio, bromomethylthio, fluoromethylthio, iodomethylthio, difluoromethylthio, dibromomethylthio, 2-chloroethylthio, 2,2,2-trifluoroethylthio, 2 , 2,2-Trichrome Ethylthio, 3-chloropropylthio, 2,3-dichloropropylthio, 4,4,4-trichlorobutylthio, 4-fluorobutylthio, 5-chloropentylthio, 3-chloro-2-methylpropylthio, 5- Examples thereof include bromohexylthio and 5,6-dibromohexylthio group.

  The lower alkyl group that may be substituted with one or more halogen atoms includes a linear or branched alkyl group having 1 to 6 carbon atoms that may be substituted with 1 to 4 halogen atoms, and Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, trifluoro Methyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2 , 3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl 5- chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromo-hexyl, can be exemplified 1,1,2,2-tetrafluoroethyl group.

  Examples of the lower alkoxy group which may be substituted with one or more halogen atoms include linear or branched alkoxy groups having 1 to 6 carbon atoms which may be substituted with 1 to 4 halogen atoms, Specific examples thereof include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy , Isohexyloxy, 3-methylpentyloxy, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy 2,2,2-trichloroethoxy, 3 Chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 5-bromohexyloxy, 5,6-dibromo Examples include hexyloxy and 1,1,2,2-tetrafluoroethoxy groups.

  The lower alkoxycarbonyl group includes an alkoxycarbonyl group in which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, Isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, 3-methylpentyloxy A carbonyl group etc. can be mentioned.

  The lower alkyl group includes a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec- Examples include butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and 3-methylpentyl group.

  The lower alkanoyl group includes a linear or branched alkanoyl group having 1 to 6 carbon atoms, and specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group and the like. Can be mentioned.

  The lower alkylsulfonyl group includes a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, and specific examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, Examples thereof include isobutylsulfonyl, tert-butylsulfonyl, sec-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 3-methylpentylsulfonyl group and the like.

  Examples of the phenoxy group (which may be substituted with 1 to 3 halogen atoms on the phenoxy ring) include, for example, phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-chlorophenoxy, 3 -Chlorophenoxy, 4-chlorophenoxy, 2-bromophenoxy, 3-bromophenoxy, 4-bromophenoxy, 2-iodophenoxy, 3-iodophenoxy, 4-iodophenoxy, 2,3-difluorophenoxy, 3,4- Difluorophenoxy, 3,5-difluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3,5-dichlorophenoxy, 2,4-dichloro Phenoxy, 2,6-dichlorophenoxy, 3 4,5-trifluorophenoxy, 3,4,5-trichlorophenoxy, 2,4,6-trifluorophenoxy, 2,4,6-trichlorophenoxy, 2-fluoro-4-bromophenoxy, 4-chloro-3 -Fluorophenoxy, 2,3,4-trichlorophenoxy group and the like can be exemplified.

  The phenyl lower alkoxy group includes a phenylalkoxy group in which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples thereof include benzyloxy, 2-phenylethoxy, 1-phenylethoxy. 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, 2-methyl-3-phenylpropoxy group and the like.

  The phenyl lower alkyl group includes a phenylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include benzyl, 1-phenethyl, 2-phenethyl, 3- Phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 4-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 1,1-dimethyl-2-phenylethyl group, etc. It can be illustrated.

  The cyano lower alkyl group includes a cyanoalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3- Examples include cyanopropyl, 4-cyanobutyl, 1,1-dimethyl-2-cyanoethyl, 5-cyanopentyl, 6-cyanohexyl, 1-cyanoisopropyl, 2-methyl-3-cyanopropyl group, and the like.

  The thiazolyl group (which may be substituted with 1 to 2 lower alkyl groups on the thiazole ring) is 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms on the thiazole ring. Including thiazolyl groups which may have a specific number, and specific examples thereof include (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- or 5-) thiazolyl, 4-n-hexyl- (2- or 5-) thiazolyl, 2,4-dimethyl-5-thiazolyl group and the like can be exemplified.

  An amino lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted) is an aminoalkyl in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Group (on the amino group, one or two linear or branched alkyl groups having 1 to 6 carbon atoms may be substituted). Specific examples thereof include aminomethyl, 2- Aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylamino Methyl, 2-ethylaminoethyl, 3-propylaminopropyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, 2- Methylaminoethyl, 2-diisopropylaminopropyl, 3-dimethylaminopropyl, diisopropylaminomethyl, 3-diisopropylaminopropyl, (N-ethyl-N-propylamino) methyl, 2- (N-methyl-N-hexylamino) A methyl group etc. can be illustrated.

  The pyrrolidinyl lower alkoxy group includes a pyrrolidinylalkoxy group in which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples thereof include (1-, 2- or 3-). Pyrrolidinylmethoxy, 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-[(1-, 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 group etc. can be illustrated .

  The cycloalkyl group includes a cycloalkyl group having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

  The cycloalkylcarbonyl group includes a cycloalkylcarbonyl group in which the cycloalkyl part is a cycloalkyl group having 3 to 8 carbon atoms, and specific examples thereof include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptyl. Examples include carbonyl and cyclooctylcarbonyl groups.

  The lower alkoxy group includes a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, Examples thereof include sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy group and the like.

  The lower alkylthio group includes a linear or branched alkylthio group having 1 to 6 carbon atoms. Specific examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio. Sec-butylthio, n-pentylthio, isopentylthio, neopentylthio, n-hexylthio, isohexylthio, 3-methylpentylthio group and the like.

  The phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring is a halogen atom and a straight chain having 1 to 6 carbon atoms as a substituent on the phenyl ring. Or a phenyl group which may have 1 to 3 groups selected from the group consisting of branched alkoxy groups, and specific examples thereof include phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- Methoxylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3, 4-diethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3 4,5-trimethoxyphenyl, 2-methoxy-4-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3 -Fluorophenyl, 2-fluorophenyl, 3-bromophenyl, 4-iodophenyl, 2-bromophenyl, 4-bromophenyl, 3,5-dichlorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 3 -Chlorophenyl, 4-chlorophenyl, 2 Iodophenyl, 3-iodophenyl, 2,3-dibromophenyl, 2,4-di-iodophenyl, may be exemplified 2,4,6-trichlorophenyl group.

  Specific examples of the 5- to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom include pyrrolidinyl, piperazinyl, piperidinyl, morpholino, Examples include thiomorpholino, homopiperazinyl, homopiperidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl and the like.

  An oxo group as a substituent; a lower alkyl group; a lower alkanoyl group; a phenyl lower alkyl group; a phenyl group optionally having 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring; The above heterocyclic group having 1 to 3 groups selected from the group consisting of pyridyl groups is an oxo group as a substituent; a linear or branched alkyl group having 1 to 6 carbon atoms; A chain or branched alkanoyl group; a phenylalkyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a halogen atom and a straight chain having 1 to 6 carbon atoms as substituents on the phenyl ring; A phenyl group that may have 1 to 3 groups selected from the group consisting of chain or branched alkoxy groups, and the above heterocyclic group that has 1 to 3 groups selected from the group consisting of pyridyl groups, Specific examples and 2-oxo- (1-, 3-, 4- or 5-) pyrrolidinyl, 2-oxo- (1-, 3-, 4-, 5- or 6-) piperazinyl, 4-methyl- (1 -, 2- or 3-) piperazinyl, 4-acetyl- (1-, 2- or 3-) piperazinyl, 4-ethyl- (1-, 2- or 3-) piperazinyl, 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-) piperazinyl, 4-acetyl-3-methyl- (1-, 2-, 3-, 5- or 6-) piperazinyl, -Methyl- (2-, 3-, 4-, 5- or 6-) morpholino, 2-acetyl- (2-, 3-, 4-, 5- or 6-) morpholino, 4- (2-phenylethyl) )-(1-, 2- or 3-) piperazinyl, 4- (3,4-dichlorophenyl)-(1-, 2-, 3- or 4-) piperazinyl, 4- (4-methoxyphenyl)-(1 -, 2- or 3-) piperazinyl, 4- (2-chlorophenyl)-(1-, 2- or 3-) piperazinyl, 4-[(2-, 3- or 4-) pyridyl]-(1-, 2- or 3-) piperazinyl, 4-phenyl- (1-, 2- or 3-) piperazinyl, 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 Examples include 6-) piperazinyl, 4-[(2-, 3- or 4-) pyridyl] -2-acetyl- (1-, 2-, 3-, 5- or 6-) piperazinyl.

  The cycloalkyl lower alkyl group includes a cycloalkylalkyl group in which the cycloalkyl part is a cycloalkyl group having 3 to 8 carbon atoms and the alkyl part is a linear or branched alkyl group having 1 to 6 carbon atoms, Specific examples thereof include cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, cyclopentylmethyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl, 6-cyclooctylhexyl, Examples include 1,1-dimethyl-2-cyclohexylethyl, 2-methyl-3-cyclopropylpropyl group, and the like.

  Lower alkylthio Lower alkyl group is an alkylthioalkyl in which the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methylthiomethyl, 2-methylthioethyl, 1-ethylthioethyl, 2-ethylthioethyl, 3-n-butylthiopropyl, 4-n-propylthiobutyl, 1,1- Examples thereof include dimethyl-2-n-pentylthioethyl, 5-n-hexylthiopentyl, 6-methylthiohexyl, 1-ethylthioisopropyl, 2-methyl-3-methylthiopropyl group and the like.

  The phenoxy lower alkyl group includes a phenoxyalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include phenoxymethyl, 1-phenoxyethyl, and 2-phenoxyethyl. , 3-phenoxypropyl, 2-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 4-phenoxypentyl, 6-phenoxyhexyl, 2-methyl-3-phenoxypropyl, 1,1-dimethyl-2-phenoxyethyl Etc. can be illustrated.

  The pyridyloxy lower alkyl group includes a pyridyloxyalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include [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-] pyridyloxy] 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] propi , 1,1-dimethyl-2- [2-, 3-, or 4-] can be exemplified pyridyloxy] ethyl, and the like.

  The lower alkynyl group includes a linear or branched alkynyl group having 2 to 6 carbon atoms, and specific examples thereof include ethynyl, (1- or 2-) propynyl, 1-methyl- (1- or 2- ) Propynyl, 1-ethyl- (1- or 2-) propynyl, (1-, 2- or 3-) butynyl, (1-, 2-, 3- or 4-) pentynyl, (1-, 2-, 3-, 4- or 5-) hexynyl group and the like can be exemplified.

  The phenyl lower alkenyl group is a linear or branched alkenyl group having 2 to 6 carbon atoms in the alkenyl moiety, and includes a phenyl alkenyl group containing 1 to 3 double bonds. Specific examples thereof include: Styryl, 3-phenyl-2-propenyl (common name: cinnamyl), 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 6- Examples thereof include phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl, 4-phenyl-1,3-butadienyl, 6-phenyl-1,3,5-hexatrienyl and the like. .

  The cycloalkyl lower alkyl group is a cycloalkyl moiety in which the cycloalkyl moiety is a cycloalkyl group having 3 to 8 carbon atoms as exemplified above and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above. Contains an alkylalkyl group.

  In the lower alkylthio-lower alkyl group, the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. An alkylthioalkyl group that is an alkyl group is included.

  The amino-substituted lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted) is a linear or branched alkyl group having an alkyl moiety of 1 to 6 carbon atoms as exemplified above And an amino-substituted alkyl group which may be substituted with one or two linear or branched alkyl groups having 1 to 6 carbon atoms on the amino group.

  The phenoxy lower alkyl group includes a phenoxyalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The pyridyloxy lower alkyl group includes a pyridyloxyalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The 1,2,3,4-tetrahydronaphthyl lower alkyl group is a 1,2,3,4-tetrahydronaphthylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above. including.

  The imidazo [1,2-a] pyridyl lower alkyl group includes an imidazo [1,2-a] pyridylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above. .

  The thiazolyl lower alkyl group includes a thiazolylalkyl group in which the alkyl portion is the above-exemplified linear or branched alkyl group having 1 to 6 carbon atoms.

  The tetrahydropyranyl lower alkyl group includes a tetrahydropyranylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The piperidyl lower alkyl group includes a piperidylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  In the diphenyl lower alkoxy substituted lower alkyl group, the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. It includes a diphenylalkoxy-substituted alkyl group that is a chain alkyl group.

  In the lower alkoxycarbonyl-substituted lower alkyl group, the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. An alkoxycarbonyl-substituted alkyl group which is a chain alkyl group is included.

  In the phenyl lower alkoxycarbonyl-substituted lower alkyl group, the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. It includes a phenylalkoxycarbonyl-substituted alkyl group which is a branched alkyl group.

  The hydroxy-substituted lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above, and includes an alkyl group substituted with 1 to 3 hydroxy groups. Specific examples thereof include , Hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 5-hydroxypentyl, 4- Examples include hydroxypentyl, 6-hydroxyhexyl, 2,2-dimethyl-3-hydroxypropyl, 1,1-dimethyl-2-hydroxyethyl, 2,3,4-trihydroxybutyl group and the like.

  In the lower alkoxy lower alkyl group, the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. Specific examples include alkoxyalkyl groups which are alkyl groups, and specific examples thereof include methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 4 Examples include -methoxybutyl, 3-methoxybutyl, 5-methoxypentyl, 4-ethoxypentyl, 6-methoxyhexyl, 2,2-dimethyl-3-methoxypropyl, 1,1-dimethyl-2-methoxyethyl group and the like. .

  The carboxy lower alkyl group includes a carboxyalkyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The carbamoyl-substituted lower alkyl group (on the carbamoyl group, 1 to 2 lower alkyl groups may be substituted) is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above. A carbamoyl-substituted alkyl group (wherein the carbamoyl group may be substituted by 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms as exemplified above).

  The morpholinylcarbonyl lower alkyl group includes a morpholinylcarbonylalkyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The benzoyl lower alkyl group includes a benzoylalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The phenylthio lower alkyl group includes a phenylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The naphthylthio lower alkyl group includes a naphthylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The cycloalkylthio lower alkyl group includes a cycloalkylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The pyridylthio lower alkyl group includes a pyridylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The pyrimidinylthio lower alkyl group includes a pyrimidinylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The furylthio lower alkyl group includes a furylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The thienylthio lower alkyl group includes a thienylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  1,3,4-thiadiazolylthio lower alkyl group is a 1,3,4-thiadiazolylthioalkyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above including.

  The benzimidazolylthio lower alkyl group includes a benzimidazolylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The benzthiazolylthio lower alkyl group includes a benzthiazolylthioalkyl group in which the alkyl portion is the above-exemplified linear or branched alkyl group having 1 to 6 carbon atoms.

  The tetrazolylthio lower alkyl group includes a tetrazolylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The benzoxazolylthio lower alkyl group includes a benzoxazolylthioalkyl group in which the alkyl portion is the above-exemplified linear or branched alkyl group having 1 to 6 carbon atoms.

  The thiazolylthio lower alkyl group includes a thiazolylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The imidazolylthio lower alkyl group includes an imidazolylthioalkyl group in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  In the amino-substituted lower alkylthio lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted), the alkylthio moiety is linear or branched having 1 to 6 carbon atoms as exemplified above An amino-substituted alkylthioalkyl group, which is an alkylthio group and the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above (on the amino group, a linear or branched group having 1 to 6 carbon atoms); 1 to 2 branched alkyl groups may be substituted).

  In the phenyl-substituted lower alkylthio lower alkyl group, the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. It includes a phenyl-substituted alkylthioalkyl group which is a chain alkyl group.

  In the furyl-substituted lower alkylthio lower alkyl group, the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. A furyl-substituted alkylthioalkyl group that is a chain alkyl group is included.

  In the pyridyl-substituted lower alkylthio lower alkyl group, the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. It includes a pyridyl-substituted alkylthioalkyl group that is a chain alkyl group.

  In the hydroxy-substituted lower alkylthio lower alkyl group, the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. A hydroxy-substituted alkylthioalkyl group that is a chain alkyl group is included.

In the phenoxy-substituted lower alkylthio lower alkyl group, the alkylthio moiety is a linear or branched alkylthio group having 1 to 6 carbon atoms as exemplified above, and the alkyl moiety is a linear or branched chain having 1 to 6 carbon atoms as exemplified above. A phenoxy-substituted alkylthioalkyl group that is a chain alkyl group is included.

  In the lower alkoxycarbonyl-substituted lower alkylthio-lower alkyl group, the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms as exemplified above, and the alkylthio moiety is a straight chain having 1 to 6 carbon atoms as exemplified above or It is a branched alkylthio group, and includes an alkoxycarbonyl-substituted alkylthioalkyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms as exemplified above.

  The lower alkenyl group includes a linear or branched alkenyl group having 2 to 6 carbon atoms. Specific examples thereof include vinyl, 1-propenyl, allyl, 1-methylallyl, (1-, 2- or 3- Examples thereof include butenyl, (1-, 2-, 3- or 4-) pentenyl, (1-, 2-, 3-, 4- or 5-) hexenyl groups.

  Specific examples of the sulfonyl group substituted with a 5- to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom include pyrrolidinyl Sulfonyl, piperazinylsulfonyl, piperidinylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, homopiperazinylsulfonyl, homopiperidinylsulfonyl, imidazolidinylsulfonyl, thiazolidinylsulfonyl, isothiazolidinylsulfonyl, oxazolyl Examples thereof include dinylsulfonyl, isoxazolidinylsulfonyl, isothiazolidinylsulfonyl, pyrazolidinylsulfonyl and the like.

  The lower alkoxide group includes a linear or branched alkoxide group having 1 to 6 carbon atoms, and specific examples thereof include methoxide and ethoxide.

  The pyrrolidine compound represented by the general formula (1) can be produced by various methods. For example, the pyrrolidine compound can be produced by the method represented by the following reaction formula-1.

  [Reaction Formula-1]

[Wherein, R ¹⁰¹ and R ¹⁰² are the same as described above. R ¹¹² represents an amino protecting group. ]
Pyrrolidine compound (1) is produced by subjecting compound (2) to an amino protecting group removal reaction.

  Here, examples of the protecting group for the amino group include a lower alkoxycarbonyl group, a lower alkanoyl group, an aryloxycarbonyl group, and an aryl-substituted lower alkyl group.

The lower alkoxycarbonyl group includes a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxy. Examples include carbonyl and hexyloxycarbonyl groups.

  The lower alkanoyl group includes a linear or branched alkanoyl group having 1 to 6 carbon atoms, and specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl group and the like. Can be mentioned.

  Specific examples of the aryloxycarbonyl group include a phenoxycarbonyl group which may have 1 to 3 substituents, a naphthyloxycarbonyl group which may have 1 to 3 substituents, and the like. . Examples of the substituent for the aryl group 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-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxy Isopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2, 2,2-trichloroe , 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6 A straight-chain or branched chain having 1 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of halogen atoms and hydroxyl groups as substituents such as dichlorohexyl and 3-hydroxy-2-chloropropyl groups Alkyl group; methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxy Ethoxy, 5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, trifluoromethoxy, trichloromethoxy, chloromethoxy, Bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 5-bromohexyloxy, 5,6-dichlorohexyloxy, 3-hydroxy-2- Chloropropo A linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of a halogen atom and a hydroxyl group as a substituent such as a xyl group; a fluorine atom, a bromine atom, chlorine Examples thereof include halogen atoms such as atoms and iodine atoms. When there are two or more substituents, these substituents may be the same or different.

  Examples of the aryl-substituted lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 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- 1 to 6 carbon-containing linear or branched alkyl groups substituted with 1 to 3 phenyl groups which may have 1 to 3 substituents such as naphthyl) propyl group, 1 to 3 substituents There such a linear or branched alkyl group having 1 to 6 carbon atoms can be mentioned also a naphthyl group was substituted. Examples of the substituent for the aryl group 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-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxy Isopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2, 2,2-trichloroe , 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6 A straight-chain or branched chain having 1 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of halogen atoms and hydroxyl groups as substituents such as dichlorohexyl and 3-hydroxy-2-chloropropyl groups Alkyl group; methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxy Ethoxy, 5,5,4-trihydroxypentyloxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 1-hydroxyisopropoxy, 2-methyl-3-hydroxypropoxy, trifluoromethoxy, trichloromethoxy, chloromethoxy, Bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 5-bromohexyloxy, 5,6-dichlorohexyloxy, 3-hydroxy-2- Chloropropo A linear or branched alkoxy group having 1 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of a halogen atom and a hydroxyl group as a substituent such as a xyl group; a fluorine atom, a bromine atom, chlorine Examples thereof include halogen atoms such as atoms and iodine atoms. When there are two or more substituents, these substituents may be the same or different.

  The reaction for producing the compound (1) from the compound (2) is carried out in a suitable solvent or in the absence of a solvent in the presence of an acid or a basic compound. This reaction is hereinafter referred to as “Reaction A”.

  Examples of the solvent to be used 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; Fatty acids such as formic acid; Esters such as methyl acetate and ethyl acetate; Halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane and carbon tetrachloride; N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl Examples include amides such as pyrrolidone; dimethyl sulfoxide; hexamethylphosphoric triamide or a mixed solvent thereof.

  Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

  Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide. be able to.

The amount of the acid or basic compound used is usually at least about 1 mol, preferably about 1 to 10 mol, relative to 1 mol of compound (2), but the acid is in large excess relative to compound (2). It may be used.

  This reaction normally proceeds suitably at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 10 minutes to 30 hours.

In the case of the compound (2) in which R ¹¹² represents an aryl-substituted lower alkyl group, the compound (1) can also be produced by reducing the compound (2).

  This reduction reaction is performed, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst.

  Examples of the solvent used 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 ethylene glycol dimethyl ether; ethyl acetate And esters such as methyl acetate; aprotic polar solvents such as dimethylformamide or a mixed solvent thereof.

  Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and a mixture thereof. The catalyst is generally used in an amount of about 0.02 to 1 times the weight of the compound (2).

  The reaction temperature of the reduction reaction is usually around −20 to 100 ° C., preferably around 0 to 80 ° C., and the hydrogen pressure is usually 1 to 10 atm. The reaction is generally completed in about 0.5 to 20 hours.

When R ¹¹² is an aryl-substituted lower alkyl group (2), (i) the compound (2) is treated with a dealkylating agent in an appropriate solvent, and (ii) the resulting compound is It can lead to a compound (1) by the process heated in a solvent.

As the solvent used in the reaction of step (i), any of the same solvents as those used in the above reaction A can be used.

  Examples of the dealkylating agent include formic acid esters such as 1-chloroethyl chloroformate, ethyl chloroformate, and tert-butyl chloroformate. The dealkylating agent is generally used in an amount of at least about 1 mol, preferably about 1 to 10 mol, per 1 mol of compound (2).

  The reaction normally proceeds suitably at about 0 to 150 ° C., preferably at room temperature to about 100 ° C., and is generally completed in about 1 to 25 hours.

  Examples of the solvent used in step (ii) include alcohols such as methanol, ethanol and isopropanol. The heating temperature is usually about 0 to 150 ° C, preferably room temperature to about 100 ° C, and it is preferable to heat for about 1 to 10 hours.

  The compound of the general formula (2) used as the starting material can be easily produced, for example, by the method shown in Reaction Scheme-2.

  [Reaction Formula-2]

[Wherein, R ¹⁰¹ , R ¹⁰² and R ¹¹² are the same as above. ]
The reaction between the compound (3) and the compound (4) is performed, for example, in the absence of a solvent or in a suitable solvent in the presence of a reducing agent.

  In this reaction, compound (4) is usually used in an amount of at least about 1 mol, preferably 1 mol to a large excess with respect to 1 mol of compound (3).

  Examples of the solvent used in this reaction include water; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; acetonitrile; fatty acids such as formic acid and acetic acid; diethyl ether, tetrahydrofuran, dioxane, Examples include ethers such as monoglyme and diglyme; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, or mixed solvents thereof.

  Examples of the reducing agent include fatty acid such as formic acid; fatty acid alkali metal salt such as sodium formate; hydrogen reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, lithium aluminum hydride, etc. Or a mixture of these hydrogenation reducing agents, a catalytic hydrogen reducing agent such as palladium-black, palladium-carbon, platinum oxide, platinum black, Raney nickel, and the like can be exemplified.

  When a fatty acid and a fatty acid alkali metal salt are used as the reducing agent, the reaction temperature is usually from room temperature to 200 ° C, and preferably from about 50 to 150 ° C. The reaction is generally completed in about 10 minutes to 10 hours. The fatty acid or fatty acid alkali metal salt is preferably used in a large excess with respect to the compound (3).

  When a hydrogenation reducing agent is used as the reducing agent, the reaction temperature is usually about −80 to 100 ° C., preferably about −80 to 70 ° C. The reaction is generally completed in about 30 minutes to 60 hours. The hydrogenation reducing agent is generally used in an amount of about 1 mol to 20 mol, preferably about 1 mol to 6 mol, per 1 mol of compound (3). In particular, when lithium aluminum hydride is used as the hydrogenation reducing agent, the solvent is an ether such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, or a mixed solvent thereof. It is preferred to use. In the reaction system, amines such as trimethylamine, triethylamine, N-ethyldiisopropylamine, or molecular sieves such as type 3A molecular sieves (MS-3A) or type 4A molecular sieves (MS-4A) are added. May be.

When a catalytic hydrogen reducing agent is used as the reducing agent, the reaction is usually carried out in a hydrogen atmosphere at about normal pressure to 20 atm, preferably about 10 to 10 atm, or formic acid, ammonium formate, cyclohexene, hydrazine hydrate. In the presence of a hydrogen donor such as, it is usually performed at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C. The reaction is generally completed in about 1 to 12 hours. The catalytic hydrogen reducing agent is generally used in an amount of about 0.1 to 40% by weight, preferably about 1 to 20% by weight, based on the compound (3).

  [Reaction Formula-3]

[Wherein, R ¹⁰¹ , R ¹⁰² and R ¹¹² are the same as above. R ¹¹³ represents a lower alkylsulfonyloxy group, a phenylsulfonyloxy group which may be substituted with one or more lower alkyl groups on the phenyl ring, or a halogen atom. ]
The lower alkylsulfonyloxy group is a group composed of an alkyl group having 1 to 6 carbon atoms and a sulfonyloxy group, such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, or a butanesulfonyloxy group. , Pentanesulfonyloxy group, hexanesulfonyloxy group and the like.

  Examples of the phenylsulfonyloxy group optionally substituted by one or more lower alkyl groups on the phenyl ring include a benzenesulfonyloxy group, an o-toluenesulfonyloxy group, an m-toluenesulfonyloxy group, and a p-toluenesulfonyl group. Oxy group, 2-ethylbenzenesulfonyloxy group, 3-ethylbenzenesulfonyloxy group, 4-ethylbenzenesulfonyloxy group, 2-propylbenzenesulfonyloxy group, 3-propylbenzenesulfonyloxy group, 4-propylbenzenesulfonyloxy group, 2, 1-3 linear or branched alkyl groups having 1 to 6 carbon atoms such as 3-dimethylbenzenesulfonyloxy group, 2,4-dimethylbenzenesulfonyloxy group, 2,4,6-trimethylbenzenesulfonyloxy group, etc. It may be replaced It can be exemplified benzene sulfonyloxy group.

  Examples of the halogen atom include a fluorine atom, a bromine atom, a chlorine atom, and an iodine atom.

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

  Examples of the inert solvent used include water; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, monoglyme and diglyme; dichloromethane, dichloroethane and chloroform Halogenated hydrocarbons such as carbon tetrachloride; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and ethylene glycol; fatty acids such as acetic acid; esters such as ethyl acetate and methyl acetate; acetone and methyl ethyl ketone Ketones such as acetonitrile, pyridine, N-methylpyrrolidone, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide or a mixed solvent thereof. .

  Examples of basic compounds include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; phosphoric acid Phosphates such as potassium and sodium phosphate; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metals such as potassium and sodium; sodium amide; sodium methylate, sodium ethylate, sodium n-butoxide, sodium Metal alcoholates such as tert-butoxide and potassium tert-butoxide; pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-diazabicyclo [2.2.2] Mention may be made of organic bases such as octane (DABCO) or mixtures thereof.

  Compound (5) is generally used in an amount of at least about 0.1 mol, preferably about 0.1 to 10 mol, per 1 mol of compound (4).

  The basic compound is generally used in an amount of at least about 1 mol, preferably about 1 to 10 mol, per 1 mol of compound (4).

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

  In the reaction system of this reaction, an alkali metal halogen compound such as sodium iodide or potassium iodide may be added.

  The reaction is usually performed at about 0 to 200 ° C., preferably about 0 to 150 ° C., and the reaction is generally completed in about 5 minutes to 80 hours.

  [Scheme-4]

[Wherein, R ¹⁰¹ , R ¹⁰² and R ¹¹² are the same as above. X represents a halogen atom. ]
The reaction between the compound (6) and the compound (7) and the reaction between the compound (8) and the compound (9) are the same reaction conditions as the reaction between the compound (5) and the compound (4) in the reaction formula-3. Done below.

When R ¹⁰¹ or R ¹⁰² is a compound (6) showing any one of the groups represented by the above (1) to (14), (17) to (32) and (40) to (50), The reaction of 6) and compound (7) can be carried out in a suitable solvent in the presence of a basic compound and a catalyst. R ¹⁰¹ or R ¹⁰² is a compound (1) to (14), (17) to (32) or any one of the groups represented by (40) to (50) (
Similarly, in the case of 8), the reaction between the compound (8) and the compound (9) can be carried out in a suitable solvent in the presence of a basic compound and a catalyst.

  As the solvent and basic compound used in these reactions, the same solvent and basic compound as the solvent and basic compound used in the reaction of compound (5) and compound (4) in the above Reaction Scheme-3 are used. be able to.

Examples of the catalyst include palladium acetate, bis (tributyltin) / bis (dibenzylideneacetone) palladium, copper iodide / 2,2′-bipyridyl, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium. , [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium, and other palladium compounds; R-2,2′-bis (diphenylphosphino) -1, 1'-binaphthyl (R-BINAP), S-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (S-BINAP), RAC-2,2'-bis (diphenylphosphino)- Binaphthyl compounds such as 1,1′-binaphthyl (RAC-BINAP); 4,5-bis (diphenyl) Xanthene compounds such as Sufino) -9,9-dimethylxanthene; borates such as tritert-butylphosphine tetrafluoroborate; 2,2-bis (diphenylimidazolidinylidene) or a mixture thereof. .

  The basic compound is usually used in an amount of at least about 0.5 mol, preferably about 0.5 to 40 times mol, per 1 mol of compound (6) or (8).

  The catalyst is used in a usual catalytic amount relative to compound (6) or (8).

  Compounds (7) and (9) are usually used in an amount of at least about 0.5 mol, preferably about 0.5 to 3 mol, per 1 mol of compound (6) or (8).

  These reactions usually proceed suitably at about room temperature to about 200 ° C., preferably at about room temperature to about 150 ° C., and are generally completed in about 0.5 to 20 hours.

In the case where R ¹⁰¹ or R ¹⁰² is a compound (6) having any one of the groups represented by the above (1) to (14), (17) to (32) and (40) to (50), The reaction of 6) and compound (7) can be carried out in a suitable solvent in the presence of a basic compound, copper iodide and ethylene glycol. The same applies to the compound (8) in which R ¹⁰¹ or R ¹⁰² is any one of the groups represented by the above (1) to (14), (17) to (32) and (40) to (50). In addition, the reaction of the compound (8) and the compound (9) can be carried out in a suitable solvent in the presence of a basic compound, copper iodide and ethylene glycol.

  As the solvent and basic compound used in the reaction, the same solvent and basic compound as the solvent and basic compound used in the reaction of the compound (5) and the compound (4) in the reaction formula-3 are used. Can do.

  Copper iodide and ethylene glycol are each usually used in an amount of about 0.01 to 3 mol, preferably about 0.05 to 1 mol, per 1 mol of compound (6) or (7).

  Compounds (7) and (9) are generally used in an amount of at least about 1 mol, preferably about 1 mol to 2 mol, per 1 mol of compound (6) or (8).

  These reactions usually proceed suitably at about room temperature to 200 ° C., preferably at about room temperature to 150 ° C., and are generally completed in about 0.5 to 50 hours.

In the case where R ¹⁰¹ or R ¹⁰² is a compound (6) having any one of the groups represented by the above (1) to (14), (17) to (32) and (40) to (50), The reaction between 6) and compound (7) can be carried out in a suitable solvent in the presence of a silane compound such as sodium bis (trimethylsilyl) amide. Also, R ¹⁰¹ or R ¹⁰² is the above (1) to (14), (17) to (32) and (40) to (50).
Similarly, in the case of the compound (8) showing any of the groups represented by the above, the reaction between the compound (8) and the compound (9) is carried out in the presence of a silane compound such as bis (trimethylsilyl) amido sodium in an appropriate solvent. Can be done below.

  As the solvent used in the reaction, the same solvent as the solvent used in the reaction of the compound (5) and the compound (4) in the reaction formula-3 can be used.

  The silane compound is generally used in an amount of about 0.1 to 3 mol, preferably about 0.1 to 2 mol, per 1 mol of compound (6) or (7).

  Compounds (7) and (9) are usually used in an amount of at least about 1 mol, preferably about 1 to 2 mol, per 1 mol of compound (6) or (8).

  These reactions usually proceed suitably at about 0 to 200 ° C, preferably around 0 to 150 ° C, and are generally completed in about 0.5 to 20 hours.

  In the reaction of the compound (6) and the compound (7), depending on the type of the compound (7) used, the compound (10) shown below is produced instead of the compound (8).

[Wherein, R ¹⁰¹ and R ¹¹² are the same as above. ]
[Reaction Formula-5]

[Wherein, R ¹⁰¹ and X are the same as defined above. R ¹⁰⁸ represents any group represented by (1-1) to (1-37) defined in the general formula (1). R ¹¹⁰ and R ¹¹¹ each contain one nitrogen atom which may have one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, together with the nitrogen atom to which they are bonded. A 7-membered saturated heterocyclic group (selected from the group consisting of an oxo group; a lower alkyl group; a lower alkanoyl group; a phenyl lower alkyl group; a halogen atom and a lower alkoxy group on the phenyl ring; A phenyl group optionally having 1 to 3 groups; and 1 to 3 substituents selected from the group consisting of a pyridyl group may be substituted. b 'shows the integer of 0-3. ]
As the 5- to 7-membered saturated heterocyclic group containing one nitrogen atom which may have one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, specifically, Pyrrolidinyl, piperazinyl, piperidinyl, morpholino, thiomorpholino, homopiperazinyl, homopiperidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl and the like.

  An oxo group as a substituent; a lower alkyl group; a lower alkanoyl group; a phenyl lower alkyl group; a phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group as a substituent on the phenyl ring. In addition, the above heterocyclic group having 1 to 3 groups selected from the group consisting of pyridyl groups includes, as a substituent, an oxo group; a linear or branched alkyl group having 1 to 6 carbon atoms; A linear or branched alkanoyl group; a phenylalkyl group in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms; a halogen atom as a substituent on the phenyl ring and a carbon number of 1 to 6 A phenyl group that may have 1 to 3 groups selected from the group consisting of linear or branched alkoxy groups, and the above heterocyclic group that has 1 to 3 groups selected from the group consisting of pyridyl groups, Specific examples of 2-oxo- (1-, 3-, 4- or 5-) pyrrolidinyl, 2-oxo- (1-, 3-, 4-, 5- or 6-) piperazinyl, 4-methyl -(1-, 2- or 3-) piperazinyl, 4-acetyl- (1-, 2- or 3-) piperazinyl, 4-ethyl- (1-, 2- or 3-) piperazinyl, 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-) piperazinyl, 4-acetyl-3-methyl- (1-, 2-, 3-, 5- or 6-) pi Razinyl, 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-) piperazinyl, 4- (3,4-dichlorophenyl)-(1-, 2-, 3- or 4-) piperazinyl, 4- (4-methoxyphenyl) -(1-, 2- or 3-) piperazinyl, 4- (2-chlorophenyl)-(1-, 2- or 3-) piperazinyl, 4-[(2-, 3- or 4-) pyridyl]-( 1-, 2- or 3-) piperazinyl, 4-phenyl- (1-, 2- or 3-) piperazinyl, 4-benzyl- (1-, 2- or 3-) piperidinyl, 4- (3,4- Dichlorophenyl)-(1-, 2- or 3-) morpholino, 2- (4-methoxypheny) )-(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-) piperazinyl, 4-[(2-, 3- or 4-) pyridyl] -2-acetyl- (1-, 2-, 3-, 5- or 6-) piperazinyl group, etc. Can be illustrated.

  The reaction between the compound (11) and the compound (12) is performed under the same reaction conditions as the reaction between the compound (6) and the compound (7) in the above Reaction Scheme-4.

  [Reaction Formula-6]

[Wherein R ¹⁰¹ , R ¹⁰⁸ , b ′ and X are the same as above. ]
Compound (14) is produced by reacting compound (11) with a metal cyano compound in a suitable solvent in the presence of a catalyst.

  Examples of the metal cyano compound include sodium cyano, cyano potassium, cyano zinc, cyano copper and the like.

  As the solvent and the catalyst used here, any of the solvent and the catalyst used in the reaction of the compound (6) and the compound (7) in the reaction formula-4 can be used. The catalyst is used in a usual catalytic amount relative to compound (11).

  The metal cyano compound is generally used in an amount of at least about 1 mol, preferably about 1 to 3 mol, per 1 mol of compound (11).

  The reaction normally proceeds suitably at about room temperature to about 200 ° C, preferably at about room temperature to about 150 ° C, and is generally completed in about 0.5 to 20 hours.

  [Reaction Formula-7]

[Wherein R ¹⁰¹ , R ¹⁰⁸ , b ′ and X are the same as above. R ¹¹⁴ represents (1-3), (1-12), (1-14), (1-19), (1-23), (1-30) and (1-31) in the general formula (1). ) Is selected. ]
The reaction between the compound (11) and the compound (15) is performed under the same reaction conditions as the reaction between the compound (6) and the compound (7) in the above Reaction Scheme-4.

  [Reaction Formula-8]

[Wherein, R ¹⁰¹ and R ¹¹² are the same as above. R ¹¹⁵ is a phenyl group, a phenyl lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a lower alkylthio lower alkyl group, an amino-substituted lower alkyl group (on the amino group, 1 to 2 lower alkyl groups are substituted). Phenoxy lower alkyl group or pyridyl lower alkyl group. R ¹¹⁶ represents a hydrogen atom or a lower alkyl group. R ¹¹⁵ and R ¹¹⁶ may be bonded to each other to form a cycloalkyl group. However, the total number of carbon atoms in the CH (R ¹¹⁶ ) (R ¹¹⁵ ) moiety in the side chain of the compound (18) — (R ¹⁰¹ ) CH (R ¹¹⁶ ) (R ¹¹⁵ ) shall not exceed 6. ]
The reaction of compound (8) and compound (17) is the same as in reaction formula-2 except that compound (17) is usually used in an amount of at least 1 mol (preferably 1 to 5 mol) relative to 1 mol of compound (8). The reaction is carried out under the same reaction conditions as in the reaction between compound (3) and compound (4).

  [Reaction Formula-9]

[Wherein, R ¹⁰¹ and R ¹¹² are the same as above. a 'shows the integer of 0-4. R ¹⁰³ represents any group represented by (1-1) to (1-37) in the general formula (1). R ¹¹⁷ represents a lower alkoxycarbonyl group. R ¹¹⁸ represents a carboxy group. ]
Compound (20) is produced by hydrolyzing compound (19).

  The hydrolysis of compound (19) is performed in the presence of an acid or a basic compound in a suitable solvent or without a solvent.

  Examples of the solvent used here 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; dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide or These mixed solvents can be mentioned.

  Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, sulfonic acid such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. These acids are used singly or in combination of two or more.

  Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; calcium hydroxide and the like Examples include alkaline earth metal hydroxides. These basic compounds are used singly or in combination of two or more.

  The hydrolysis reaction proceeds normally at about 0 to 200 ° C., preferably about 0 to 150 ° C., and is generally completed in about 10 minutes to 30 hours.

Compound (19) includes compound (20) and general formula (21)
R ¹¹⁹ OH (21)
[Wherein, R ¹¹⁹ represents a lower alkyl group. ]
It is manufactured by making it react with the compound represented by these.

  For the reaction between the compound (20) and the compound (21), reaction conditions for usual esterification reaction can be applied. For example, the reaction between the compound (20) and the compound (21) is performed in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, or phosphorus trichloride. Compound (21) is used in a large excess relative to compound (20). The reaction normally proceeds suitably at about 0 to 150 ° C., preferably about 50 to 100 ° C., and is generally completed in about 1 to 10 hours.

  [Reaction Formula-10]

[Wherein, R ¹⁰¹ , R ¹⁰³ , a ′ and R ¹¹² are the same as above. R ¹²⁰ represents a lower alkylthio group. R ¹²¹ represents a lower alkylsulfonyl group. ]
The reaction for converting compound (22) to compound (23) is carried out in a suitable solvent in the presence of an oxidizing agent.

  Examples of the solvent used here include water; fatty acids such as formic acid, acetic acid and trifluoroacetic acid; alcohols such as methanol and ethanol; halogenated hydrocarbons such as chloroform and dichloromethane; and mixed solvents thereof. It can be illustrated.

  Examples of the oxidizing agent used include peracids such as formic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, and o-carboxyperbenzoic acid; hydrogen peroxide; metaperiodic acid Sodium dichromate; dichromates such as dichromic acid, sodium dichromate and potassium dichromate; permanganates such as permanganate, sodium permanganate and potassium permanganate; lead salts such as lead tetraacetate Etc.

  The oxidizing agent is usually used in an amount of at least about 2 mol, preferably about 2 to 4 mol, per 1 mol of compound (22).

  The reaction is usually performed at about −10 to 150 ° C., preferably around −10 to 100 ° C., and is generally completed in about 1 to 10 hours.

  [Reaction Formula-11]

[Wherein, R ¹⁰¹ and R ¹¹² are the same as above. R ¹²² represents a lower alkyl group having one or more halogen atoms. ^R123 represents an amino-substituted lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted). R ^123a represents an amino group (on the amino group, 1 to 2 lower alkyl groups may be substituted). ]
The reaction between the compound (24) and the compound (25) is performed under the same reaction conditions as the reaction between the compound (5) and the compound (4) in the above Reaction Scheme-3.

  Compounds (7) and (9) used as starting materials are easily produced, for example, by the method shown in the following reaction formula.

  [Reaction formula-12]

[Wherein X is the same as defined above. R ¹²⁴ represents a lower alkyl group having one or more halogen atoms. ]
The reaction between the compound (27) and the compound (28) is performed under the same reaction conditions as the reaction between the compound (5) and the compound (4) in the above Reaction Scheme-3.

  The starting compound (8) can be produced, for example, by the method shown in the following Reaction Scheme-13.

  [Reaction Formula-13]

[Wherein, R ¹⁰³ , a ′, X and R ¹¹² are the same as described above. ]
The reaction for producing the compound (31) from the compound (30) is performed, for example, in the absence of a solvent or in a suitable solvent in the presence of a reducing agent.

  Examples of the solvent used here include water; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; acetonitrile; fatty acids such as formic acid and acetic acid; diethyl ether, tetrahydrofuran, dioxane, and monoglyme. And ethers such as diglyme; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, or a mixed solvent thereof.

  Examples of the reducing agent include catalytic hydrogen reducing agents such as palladium-black, palladium-carbon, platinum oxide, platinum black, and Raney nickel.

  The catalytic hydrogen reducing agent is usually used in an amount of about 0.1 to 40% by weight, preferably about 0.1 to 20% by weight, based on the compound (30).

  When a basic compound such as sodium hydroxide is added to the reaction system of this reaction, the reaction proceeds advantageously.

  The reaction is usually carried out in a hydrogen atmosphere at about normal pressure to 20 atm, preferably about 10 to 10 atm, usually at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C. The reaction is generally completed in about 1 to 12 hours.

  Compounds (3), (5) and (6) used as starting materials are easily produced by, for example, the method shown in the following reaction formula.

  [Reaction formula-14]

[Wherein R ¹¹² and X are the same as defined above. R ¹²⁵ represents an oxo group, a group —R ¹¹³ or an amino group. Here, R ¹¹³ is the same as described above. ]
The reaction between the compound (32) and the compound (33) is performed under the same reaction conditions as the reaction between the compound (5) and the compound (4) in the above Reaction Scheme-3.

  Compound (4) used as a starting material is easily produced, for example, by the method shown in the following reaction formula.

  [Reaction formula-15]

[Wherein, R ¹⁰¹ , R ¹⁰² and X are the same as above. ]
The reaction between the compound (35) and the compound (9) is performed under the same reaction conditions as the reaction between the compound (6) and the compound (7) in the above Reaction Scheme-4.

Compounds (3), (5), (6), (8), (11), (19), (20), (22) or (3) used as starting materials in the reactions shown in Reaction Formulas 2 to 11 The compound in which R ¹¹² in 24) is converted to a hydrogen atom is used as a starting material, and the compound is reacted under the same reaction conditions as in the reactions shown in Reaction Formulas 2 to 11, whereby R ¹¹² is a hydrogen atom. The compound (2), (8), (13), (14), (16), (18), (19), (20), (23) or (26) is produced.

  Optical activity as a starting material (compound (5), (6), (8), (11), (19), (20), (22) or (24)) in each reaction shown in Reaction Formulas 3 to 11 When the compound is used, the compound (2), (8), (13), (14) of the optically active substance is reacted by reacting the compound under the same reaction conditions as the reactions shown in Reaction Formulas 3 to 11. ), (16), (18), (19), (20), (23) or (26).

  Compounds (2), (8), (13), (14), (16), (18), (19), (20), (23) produced in each reaction shown in Reaction Formulas 2 to 11 Alternatively, the compound (1) of the present invention can also be produced by directly using the compound (26) as a starting material for the reaction shown in the following reaction formula-1 without isolation.

  Each target compound obtained in each reaction formula shown above is prepared by cooling the reaction mixture, for example, and then separating the crude reaction product by an isolation operation such as filtration, concentration, extraction, etc., and column chromatography, recrystallization The reaction mixture can be isolated and purified by a conventional purification operation such as

  The compound represented by the general formula (1) of the present invention includes stereoisomers and optical isomers.

  Among the starting material of the present invention and the target pyrrolidine compound, a compound having a basic group can easily form a salt with a normal pharmacologically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, apple Examples thereof include organic acids such as acid and lactic acid.

Of the starting material of the present invention and the target pyrrolidine compound, a compound having an acidic group can be easily formed into a salt by acting a pharmaceutically acceptable basic compound. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

  Furthermore, compounds in the form of solvates (for example, hydrates, ethanol solvates, etc.) added to the starting materials and target compounds shown in each reaction formula are also included in each general formula.

  A medical preparation containing the compound of the present invention as an active ingredient will be described.

  The above-mentioned medical preparation is prepared by formulating the compound of the present invention in the form of a normal medical preparation, and is usually used as a filler, a bulking agent, a binder, a moistening agent, a disintegrant, a surfactant, and a lubricant. Etc. and are prepared using diluents and / or excipients.

  Such a medical preparation can be selected from various forms depending on the purpose of treatment, and representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories. Agents, injections (solutions, suspensions, etc.) and the like.

  As the carrier used for molding into a tablet form, known ones can be widely used, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, hydrogen carbonate Sodium, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors, quaternary ammonium Group, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Lubricants and the like.

  Furthermore, the tablets can be coated with a normal coating material as necessary, and can be, for example, sugar coatings, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  As the carrier used for forming into a pill form, known ones can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.

  As the carrier used for forming into a suppository form, known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. As the diluent used for forming these liquids, emulsions and suspensions, known ones that are widely used can be used, for example, water, ethanol, propylene glycol, ethoxy Isooxyaryl stearate, polyoxygenated isostearyl alcohol, polyoxyethylene sorbetane fatty acid esters and the like. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizer, buffer, soothing agent, etc. If necessary, colorants, preservatives, fragrances, flavors, sweeteners, and / or other pharmaceuticals may be included.

  The amount of the compound of the present invention contained in the medical preparation is not particularly limited and can be appropriately selected from a wide range. Usually, the compound of the present invention is contained in an amount of about 1 to 70% by weight in the medical preparation. preferable.

  There is no restriction | limiting in particular as the administration method of the medical formulation which concerns on this invention, It administers by the method according to various formulation forms, a patient's age, sex, a disease state, and other conditions. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of injections, they are administered alone or mixed with normal fluids such as glucose and amino acids and administered intravenously, and further, if necessary, alone intramuscularly, intradermally, subcutaneously or intraperitoneally. Can be administered. In the case of a suppository, it is administered intrarectally.

  The dosage of the above-mentioned medical preparation may be appropriately selected according to usage, patient age, sex, disease level, and other conditions, and is usually about 0.001 to 100 mg per 1 kg body weight per day, preferably Is administered in an amount of about 0.001 to 50 mg divided into 1 to several times.

  Since the dosage varies depending on various conditions, a dosage smaller than the above range may be sufficient, or a dosage exceeding the above range may be necessary.

  The pyrrolidine compound of the present invention has a reuptake inhibitory action of one, two or three monoamines (serotonin, norepinephrine, dopamine).

  The pyrrolidine compound of the present invention has an uptake inhibitory activity in an in vitro test or an uptake inhibitory activity in an Ex vivo test for any one of the three types of monoamines, compared to existing compounds having monoamine uptake inhibitory activity. Remarkably strong. Further, in the microdialysis study in the brain, the pyrrolidine compound of the present invention is remarkably strong against the increase of any one of the three types of monoamines as compared with the existing compounds having monoamine uptake inhibitory activity. Shows activity.

  The pyrrolidine compound of the present invention has a broad therapeutic spectrum compared to known antidepressants.

  The pyrrolidine compound of the present invention exhibits a sufficient therapeutic effect even when administered for a short period of time.

  The pyrrolidine compound of the present invention is excellent in bioavailability, has weak metabolic enzyme inhibitory activity in the liver, has few side effects, and is excellent in safety.

  The pyrrolidine compound of the present invention exhibits strong activity in the mouse forced swimming test and tail suspension test used for screening for depression. The pyrrolidine compound of the present invention also exhibits strong activity in the rat forced swimming test used for screening for depression. In addition, the pyrrolidine compound of the present invention exhibits a strong activity in a reserpine-induced hypothermia test used for screening for depression.

  The pyrrolidine compound of the present invention expresses a strong activity in a mouse marble filling behavior test and a fear conditioned stress model, which are anxiety or stress disease models.

The pyrrolidine compound of the present invention comprises one, two or three monoamines (serotonin,
Norepinephrine and dopamine) are effective in treating various disorders associated with decreased neurotransmission of serotonin, norepinephrine or dopamine.

  Such disorders include hypertension, depression (eg, major depressive disorder; bipolar type I disorder; bipolar type II disorder; mixed condition; mood modulation disorder; rapid cycler; atypical depression; seasonal feelings Disorders; postpartum depression; mild depression; recurrent short-term depression disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing syndrome, hypothyroidism , Hyperparathyroidism, Addison's disease, amenorrhea / milk secretion syndrome, Parkinson's disease, Alzheimer's disease, cerebral hemorrhage, diabetes, chronic fatigue syndrome, depression associated with various body diseases such as cancer; middle-aged depression; Geriatric depression; depression in children and adolescents; drug-induced depression such as interferon; depression associated with adaptation disorder; anxiety due to adaptation disorder; anxiety associated with various diseases [eg neuropathy (extracranial) , Brain infection and inner ear disorders); cardiovascular disorders (heart failure, arrhythmia); endocrine disorders (adrenal hyperactivity, hyperthyroidism); respiratory disorders (asthma, chronic obstructive pulmonary disease)], generalized anxiety Disability, fear (eg, agoraphobia, social phobia and simple phobia), post-traumatic stress syndrome, acute stress syndrome, avoidance personality disorder, body deformity disorder, premature ejaculation, eating disorders (eg nerve Anorexia and nervous eating), obesity, chemical dependence (eg, addiction to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive Disability, panic disorder, memory impairment (eg dementia, amnestic disorder and age-related cognitive decline (ARCD)), Parkinson's disease (eg in Parkinson's disease) Dementia, neuroleptic-induced parkinsonism and late-onset dyskinesia), endocrine disorders (eg hyperprolactinemia), vasospasm (especially in the cerebral vasculature), cerebellar ataxia, gastrointestinal disorders (motor and secretion disorders) Changes), negative syndrome of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, tension urinary incontinence, Toulette syndrome, hair loss, stealing, male impotence, attention deficit hyperactivity disorder (ADHD), chronic seizure These include migraine, chronic fatigue, weakness, sleep apnea syndrome and headache (related to vascular disorders).

  The formulation examples, reference examples, examples and pharmacological test examples are given below.

Formulation Example 1
100 g of the compound of the present invention, 40 g of Avicel (trade name, manufactured by Asahi Kasei Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate were mixed and polished, and then tableted using a R10 mm kinematic tablet. The obtained tablets were coated with a film coating agent consisting of 10 g of TC-5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropylmethylcellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil and an appropriate amount of ethanol, A film coating tablet having the above composition was produced.

Reference example 1
Synthesis of 3-[(3,4-dichlorophenyl)-(4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 0.19 g of sodium hydride (60% oily) was added to 10 ml of dimethyl sulfoxide (DMSO) In addition, the mixture was stirred at 60 ° C. for 1 hour. Next, 1.0 g of (3,4-dichlorophenyl)-(4-fluorophenyl) -amine was added to the mixture, and the mixture was stirred at 60 ° C. for 1 hour. A DMSO solution containing 2.0 g of 3- (toluene-4-sulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture, and the mixture was stirred at 60 ° C. for 15 hours. Ethyl acetate was added to the reaction solution. The solution was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1). The solvent was distilled off under reduced pressure to give 3-[(3,4-
0.29 g of (dichlorophenyl)-(4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.74-1.92 (1H, m), 2.04-2.22 (1H, m), 3.10-3.35 (3H, m), 3. 61-3.85 (1H, m), 4.31-4.48 (1H, m), 6.42 (1H, dd, J = 2.9 Hz, J = 8.9 Hz), 6.67 (1H , D, J = 2.8 Hz), 6.90-7.22 (5H, m).

Reference example 2
Synthesis of 3 (S)-[(3,4-dichlorophenyl) phenylamino] pyrrolidine-1-carboxylic acid tert-butyl ester Stir for 1 hour at ° C. Next, 2.0 g of 3,4-dichlorophenyl-phenylamine was added to the mixture, and the mixture was stirred at 60 ° C. for 1 hour. A DMSO solution containing 1.5 g of 3 (R) -methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester was gradually added to the mixture, followed by stirring at 60 ° C. for 15 hours. Ethyl acetate was added to the reaction solution, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1). The solvent was distilled off under reduced pressure to obtain 0.13 g of light brown amorphous solid 3 (S)-[(3,4-dichlorophenyl) phenylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.42 (9H, s), 1.73-1.93 (1H, m), 2.05-2.23 (1H, m), 3.10-3.36 (3H, m), 3. 61-3.83 (1H, m), 4.33-4.50 (1H, m), 6.48 (1H, dd, J = 2.9 Hz, J = 10.3 Hz), 6.74 (1H , D, J = 2.8 Hz), 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-benzylpyrrolidin-3-yl)-(3-fluorophenyl) amine (S) -1-benzylpyrrolidin-3-ylamine 2.2 g (12.5 mmol), 3-bromofluoro Benzene 2.2 g (12.5 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP) 0.31 g (0.51 mmol), bis (dibenzylideneacetone) palladium ( A toluene solution containing 0.14 g (0.22 mmol) of Pd (dba) ₂ ) and 1.3 g (13.2 mmol) of sodium t-butoxide was heated to reflux for 3 hours under a nitrogen stream. The reaction solution was filtered to remove insoluble materials, and ethyl acetate and water were added to the filtrate for liquid separation. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1 → 1: 1). The solvent was distilled off under reduced pressure to obtain 3.0 g of colorless oily ((S) -1-benzylpyrrolidin-3-yl)-(3-fluorophenyl) amine.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.59-1.78 (2H, m), 2.21-2.38 (1H, m) 2.39-2.50 (1H, m), 2.55 (1H, dd, J = 3. 3 Hz, J = 9.7 Hz), 2.61-2.85 (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-benzylpyrrolidin-3-yl) phenylamine Using (S) -1-benzylpyrrolidin-3-ylamine and bromobenzene in the same manner as in Reference Example 3, ((S) -1 -Benzylpyrrolidin-3-yl) phenylamine was synthesized.
Brown oil
¹ H-NMR (CDCl ₃ ) δ ppm:
1.56-1.78 (2H, m), 2.22-2.39 (1H, m), 2.41-2.58 (1H, m), 2.70-2.84 (2H, m) ), 3.63 (2H, s), 4.01 (1H, s), 6.57 (2H, d, J = 8.5 Hz), 6.64-6.73 (1H, m), 7. 11-7.19 (2H, m), 7.21-7.36 (5H, m).

Reference Example 5
Synthesis of ((S) -1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl) amine ((S) -1-benzylpyrrolidin-3-yl)-(3 -Fluorophenyl) amine 0.7 g (2.6 mmol), 4-bromobenzotrifluoride 0.59 g (2.6 mmol), BINAP 65 mg (0.1 mmol), palladium acetate 23 mg (0.1 mmol) and A toluene solution containing 0.28 g (2.9 mmol) of sodium t-butoxide was heated to reflux for 3 hours under a nitrogen stream. The reaction solution was filtered to remove insoluble materials, and ethyl acetate and water were added to the filtrate for liquid separation. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1 → 10: 1). The solvent was distilled off under reduced pressure to obtain 0.48 g of colorless oily ((S) -1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl) amine.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.82-2.01 (1H, m), 2.17-2.31 (1H, m), 2.61-2.78 (3H, m), 3.45 (1H, d, J = 12) .9 Hz), 3.64 (1 H, d, J = 12.9 Hz), 4.55 (1 H, m), 6.78-6.86 (3 H, m), 6.88-6.96 (2 H) , M), 7.19-7.36 (6H, m).

Reference Example 6
Synthesis of 3 (S)-(3-chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester 5.0 g (27 mmol) of 3 (S) -aminopyrrolidine-1-carboxylic acid tert-butyl ester ), 4-bromo-2-chloro-1-fluorobenzene in a toluene solution (50 ml) containing 5.7 g (27 mmol) of BINAP (1.7 g, 2.7 mmol) and palladium acetate (0.30 g, 1.3 mmol). ) And 3.5 g (36 mmol) of sodium tert-butoxide. The mixture was heated to reflux for 8 hours under a nitrogen atmosphere and then cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to give 3 (S)-(3-chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester as a white powder. 76 g was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m), 3. 11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (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
3 (S)-(3-Chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acid t
Synthesis of ert-butyl ester 15.0 g (80.5 mmol) of 3 (S) -aminopyrrolidine-1-carboxylic acid tert-butyl ester and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96. 7 ml) was added 1.54 g (8.1 mmol) of copper (I) iodide, 9.0 ml (10.1 mmol) of ethylene glycol and 34.2 g (161 mmol) of potassium phosphate. In addition, the mixture was heated to reflux for 46 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered through celite. The residue was washed with ethyl acetate, the washings and the filtrate were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to give 3 (S)-(3-chloro-4-fluorophenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester as a white powder. 9 g was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.47 (9H, s), 1.78-1.96 (1H, m), 2.10-2.28 (1H, m), 2.10-2.28 (1H, m), 3. 11-3.30 (1H, m), 3.30-3.56 (2H, m), 3.57-3.79 (2H, m), 3.85-4.03 (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 3 (S)-(3-cyanophenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester 2.82 g (15 mmol) of 3 (S) -aminopyrrolidine-1-carboxylic acid tert-butyl ester and 3- To a toluene solution (7 ml) containing 1.82 g (10 mmol) of bromo-benzonitrile, 68.5 mg (0.11 mmol) of BINAP, 22.5 mg (0.1 mmol) of palladium acetate and 3.91 g (12 mmol) of cesium carbonate Was added. This mixture was heated to reflux for 8 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. After drying over sodium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The purified product was concentrated to dryness under reduced pressure to obtain 1.56 g of 3 (S)-(3-cyanophenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow powder.
¹ H-NMR (CDCl ₃ ) δ ppm:
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), 6.99 (1H, d, J = 7.6 Hz) ), 7.23 (1H, dd, J = 7.6 Hz, J = 8.4 Hz).

Reference Example 9
Synthesis of 3 (S)-(3-chloro-4-methoxyphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S) -Aminopyrrolidine-1-carboxylic acid tert-butyl ester 0.20 g (1. 1 mmol) and 2-chloro-3-bromoanisole 0.238 g (1.1 mmol) in toluene solution (5 ml), BINAP 67.0 mg (0.11 mmol), tris (dibenzylideneacetone) dipalladium 24 mg (0 0.027 mmol) and 144 mg (1.5 mmol) sodium tert-butoxide. The mixture was heated to reflux at 100 ° C. for 1 hour under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1 → 3: 1). The purified product was concentrated to dryness under reduced pressure to obtain 0.28 g of light yellow amorphous solid 3 (S)-(3-chloro-4-methoxyphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester. .
¹ H-NMR (CDCl ₃ ) δ ppm:
1.47 (9H, s), 1.80-1.90 (1H, m), 2.10-2.20 (1H, m), 3.10-3.25 (1H, m), 3. 38-3.75 (3H, m), 3.83 (3H, s), 3.92-3.96 (1H, m), 6.47 (1H, dd, J = 2.8 Hz, J = 8 .8 Hz), 6.67 (1H, d, J = 2.8 Hz), 6.81 (1H, d, J = 8.8 Hz).

Reference Example 10
Synthesis of 3 (S)-(4-methoxyphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-(3-chloro-4-methoxyphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester To an ethanol solution (10 ml) containing 0.28 g, 0.2 ml of 5N sodium hydroxide solution and 0.1 g of 10% palladium carbon were added. Catalytic reduction was performed at room temperature and normal pressure. The reaction solution was filtered through celite and concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated to dryness under reduced pressure to obtain 0.25 g of yellow amorphous solid 3 (S)-(4-methoxyphenylamino) pyrrolidine-1-carboxylic acid tert-butyl ester.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.46 (9H, s), 1.79-1.88 (1H, m), 2.10-2.22 (1H, m), 3.12-3.25 (1H, m), 3. 30-3.52 (3H, m), 3.60-3.75 (4H, m), 3.88-4.00 (1H, m), 6.50-6.58 (2H, m), 6.72-6.80 (2H, m).

Reference Example 11
Synthesis of 3 (S)-[bis- (3-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 1.0 g of 3 (S) -aminopyrrolidine-1-carboxylic acid tert-butyl ester (5. 3 mg) and toluene solution (10 ml) containing 2.3 g (13 mmol) of 3-bromo-1-fluorobenzene, 32 mg (0.11 mmol) of tritert-butylphosphine tetrafluoroborate, 24 mg of palladium acetate ( 0.11 mmol) and 1.5 g (16 mmol) sodium tert-butoxide were added. This mixture was heated to reflux for 8 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The purified product was concentrated to dryness under reduced pressure to obtain 1.56 g of 3 (S)-[bis- (3-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.78-1.95 (1H, m), 2.02-2.26 (1H, m), 3.12-3.39 (3H, m), 3. 65-3.83 (1H, m), 4.35-4.51 (1H, m), 6.61 (2H, dt, J = 2.1 Hz, J = 11.0 Hz), 6.61-6 .68 (2H, m), 6.77 (2H, t, J = 8.0 Hz), 7.18-7.31 (2H, m).

Reference Example 12
Synthesis of 3 (S)-[(3,4-dichlorophenyl) thiazol-2-ylamino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-(3,4-dichlorophenylamino) pyrrolidine-1-carboxylic acid To a toluene solution (150 ml) containing 20.0 g (60.4 mmol) of tert-butyl ester and 15.0 g (91.5 mmol) of 2-bromothiazole, 1.86 g of tritert-butylphosphine tetrafluoroborate ( 6.4 mmol), 2.88 g (3.15 mmol) tris (dibenzylideneacetone) dipalladium and 11.6 g (120 mmol) sodium tert-butoxide were added. The mixture was heated to reflux for 9 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered through celite. Water was added to the filtrate and extracted with ethyl acetate. After drying over sodium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The purified product was concentrated to dryness under reduced pressure to obtain 7.94 g of 3 (S)-[(3,4-dichlorophenyl) -thiazol-2-ylamino] pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow powder. It was.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.83 to 2.03 (1H, m), 2.11-2.35 (1H, m), 3.18-3.42 (3H, m), 3. 73-3.87 (1H, m), 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, brs), 7.39 (1H, d, J = 2.5 Hz), 7.56 (1H, brd, J = 8.5 Hz).

Reference Example 13
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl) pyridin-3-ylamino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-(3-Chloro-4-fluorophenylamino) 9,9-dimethyl-4,5 was added to a toluene solution (10 ml) containing 1.0 g (3.2 mmol) of pyrrolidine-1-carboxylic acid tert-butyl ester and 0.75 g (4.75 mmol) of 3-bromopyridine. -50 mg (0.09 mmol) of bis (diphenylphosphino) xanthene (XANTPHOS), 21.4 mg (0.10 mmol) of palladium acetate and 11.6 g (120 mmol) of sodium tert-butoxide were added. The mixture was heated to reflux for 9 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and filtered through Celite. Water was added to the filtrate and extracted with ethyl acetate. After drying over sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). The purified product was concentrated under reduced pressure to give 1.14 g of 3 (S)-[(3-chloro-4-fluorophenyl) pyridin-3-ylamino] pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil. Obtained. ¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.79-1.98 (1H, m), 2.08-2.29 (1H, m), 3.12-3.41 (3H, m), 3. 65-3.85 (1H, m), 4.38-4.51 (1H, m), 6.83-6.91 (1H, m), 7.00-7.23 (4H, m [7 .04 ppm (including dd, J = 2.7 Hz, J = 6.4 Hz)], 8.14 (1H, s), 8.22 (1H, d, J = 4.4 Hz).

Reference Example 14
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl) cyclohexylamino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(3-chloro-4-fluorophenyl) amino] pyrrolidine An acetic acid solution (3 ml) containing 0.60 g (1.9 mmol) of -1-carboxylic acid tert-butyl ester and 0.56 g (5.7 mmol) of cyclohexanone was stirred overnight at room temperature. To this mixture was added 1.21 g (5.7 mmol) of sodium triacetoxyborohydride and then stirred at room temperature for 8 hours. Dichloromethane was added to the reaction solution, washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1). The solvent was distilled off from the purified product under reduced pressure to give 0.24 g of colorless oily 3-[(S)-(3-chloro-4-fluorophenyl) cyclohexylamino] pyrrolidine-1-carboxylic acid tert-butyl ester. Obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
0.81-1.32 (6H, m), 1.44 (9H, s), 1.60-2.00 (6H, m), 2.79-2.93 (1H, m), 2. 98-3.10 (1H, m), 3.16-
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 3 (S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(3-chloro-4- 6 ml of 5N sodium hydroxide solution was added to an ethanol solution containing 1.7 g (3.7 mmol) of fluorophenyl)-(4-ethoxycarbonylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester, and the mixture was stirred at room temperature for 15 minutes. Stir for hours. Dichloromethane and acetic acid were added to the reaction solution to make it acidic. This was washed three times with water and once with a saturated aqueous sodium hydrogen carbonate solution, and then the solvent was distilled off under reduced pressure to obtain 3 (S)-[(4-carboxyphenyl)-(3- 1.50 g of chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.33 (9H, s), 1.72-1.88 (1H, m), 2.06-2.26 (1H, m), 2.99-3.23 (3H, m), 3. 61 (1H, dd, J = 6.4 Hz, J = 11.3 Hz), 4.53-4.69 (1H, m), 6.57-6.65 (2H, m), 7.19-7 .28 (1H, m), 7.46-7.58 (2H, m), 7.68-7.78 (2H, m), 12.3 (1H, brs).

Reference Example 16
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(3-chloro-4 -Fluorophenyl)-(4-methylsulfanylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane solution containing 0.45 g (1.0 mmol) at 0 ° C., 0.54 g (3 0.1 mmol) and then stirred at 0 ° C. for 2 hours. The reaction solution was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Next, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 1: 1). The solvent was distilled off from the purified product under reduced pressure, and the pale yellow oily 3 (S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl) amino] pyrrolidine-1-carboxylic acid tert- 0.42 g of butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.80-1.91 (1H, m), 2.11-2.29 (1H, m), 3.01 (3H, s), 3.16-3. 40 (3H, m), 3.70-3.86 (1H, m), 4.49-4.61 (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), 7.19-7.23 (1H, m) , 7.24-7.31 (1H, m), 7.66-7.74 (2H, m).

Reference Example 17
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(6- Bromopyridin-2-yl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 500 mg (1.06 mmol), zinc cyanate 250 mg (2.12 mmol) and tetrakis ( 122 mg (0.106 mmol) of triphenylphosphine) palladium was suspended in 8 ml of dimethylformamide (DMF), and then stirred at 110 ° C. for 9 hours under a nitrogen stream. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the layers. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1 → 3: 1). The solvent was distilled off from the purified product under reduced pressure to give colorless oily 3 (S)-[(3-chloro-4-fluorophenyl)-(6-cyanopyridin-2-yl) amino] pyrrolidine-1-carboxyl. 398 mg of acid tert-butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.44 (9H, s), 1.74-1.84 (1H, m), 2.03-2.24 (1H, m), 3.08-3.32 (3H, m), 3. 76-3.86 (1H, m), 5.28-5.38 (1H, m), 6.21 (1H, d, J = 8.7 Hz), 7.04-7.11 (2H, m ), 7.23-7.42 (3H, m).

Reference Example 18
Synthesis of 3 (S)-{(3-chloro-4-fluorophenyl)-[5- (4-fluorophenyl) pyridin-2-yl] -amino} pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S )-[(5-Bromopyridin-2-yl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 300 mg (0.64 mmol), 4-fluorophenylboric acid 98 mg (0.7 mmol), tetrakis (triphenylphosphine) palladium 23 mg (0.02 mmol) and 2M-sodium carbonate aqueous solution 0.83 ml were added to 3 ml of toluene, and then stirred at 100 ° C. for 10 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the layers. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1). The solvent was distilled off from the purified product under reduced pressure to obtain 3 (S)-{(3-chloro-4-fluorophenyl)-[5- (4-fluorophenyl) pyridin-2-yl] amino} as a white solid. 255 mg of pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.44 (9H, s), 1.78-1.89 (1H, m), 2.05-2.23 (1H, m), 3.07-3.31 (3H, m), 3. 85 (1H, dd, J = 7.1, 10.8 Hz), 5.31-5.42 (1H, m), 6.08 (1H, d, J = 8.8 Hz), 7.06-7 .14 (3H, m), 7.20-7.28 (2H, m), 7.41-7.50 (3H, m), 8.37-8.41 (1H, m).

Reference Example 19
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl)-(4-thiophen-3-ylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(4- 3 (S)-[((Bromophenyl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester and 3-thiophene boric acid were used in the same manner as in Reference Example 9. 3-Chloro-4-fluorophenyl)-(4-thiophen-3-ylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester was synthesized.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.83 to 1.88 (1H, m), 2.05-2.20 (1H, m), 3.18-3.31 (3H, m), 3. 63-3.84 (1H, m), 4.40-4.51 (1H, m), 6.71-6.80 (1H, m), 6.85-6.88 (2H, m), 6.94 (1H, dd, J = 2.8 Hz, J = 6.4 Hz), 7.05-7.10 (1H, m), 7.30-7.45 (3H, m), 7.50 -7.55 (2H, m).

Reference Example 20
Synthesis of (S)-{(3-chloro-4-fluorophenyl)-[6- (4-methylpiperazin-1-yl) pyridin-2-yl] amino} pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(6-Bromopyridin-2-yl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 200 mg (0.43 mmol), 1-methylpiperazine 0.61 ml (0.55 mmol), 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (XANTPHOS) 12 mg (0.02 mmol), tris (dibenzylideneacetone) dipalladium 9 mg (.0. 01 mmol) and 61 mg (0.63 mmol) sodium t-butoxide in 5 ml toluene, And stirred at 100 ° C. for 8 hours under a nitrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The solvent was distilled off from the purified product under reduced pressure to give colorless oily (S)-{(3-chloro-4-fluorophenyl)-[6- (4-methylpiperazin-1-yl) pyridin-2-yl. ] 102 mg of amino} pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.44 (9H, s), 1.74-1.89 (1H, m), 2.03-2.21 (1H, m), 2.36 (3H, s), 2.51-2. 55 (4H, m), 3.08-3.31 (3H, m), 3.54 (4H, brs), 3.64-3.90 (1H, m), 5.10-5.23 ( 1H, m), 5.32 (1H, d, J = 8.1 Hz), 6.01 (1H, d, J = 8.1 Hz), 7.03-7.08 (1H, m), 7. 19-7.25 (3H, m).

Reference Example 21
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl)-(4-piperidin-1-ylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(4- Bromophenyl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester and piperidine and 3 (S)-[(3-chloro- 4-Fluorophenyl)-(4-piperidin-1-ylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester was synthesized.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.55-1.62 (2H, m), 1.68-1.73 (4H, m), 1.74-1.90 (1H, m), 2. 02-2.18 (1H, m), 3.16-3.29 (7H, m), 3.61-3.81 (1H, m), 4.23-4.38 (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 3 (S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(3- Chloro-4-fluorophenyl) -amino] pyrrolidine-1-carboxylic acid tert-butyl ester 0.50 g (1.6 mmol) and 2-chloro-4-fluorobenzonitrile 0.30 g (1.9 mmol) 1.45 ml of a tetrahydrofuran solution containing sodium (1.1M) bis (trimethylsilyl) amide was added to the anhydrous toluene solution using a syringe. The mixture was heated to reflux for 8 hours under a nitrogen atmosphere and cooled to room temperature. Water was added to the reaction solution and extracted with diethyl ether. After drying over sodium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). The purified product was concentrated to dryness under reduced pressure to give white amorphous solid 3 (S)-[(3-chloro-4-cyanophenyl)-(3-chloro-4-fluorophenyl) amino] pyrrolidine-1- 0.56 g of carboxylic acid tert-butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.43 (9H, s), 1.76-1.93 (1H, m), 2.11-2.27 (1H, m), 3.15-3.39 (3H, m), 3. 66-3.87 (1H, m), 4.39-4.55 (1H, m), 6.42 (1H, dd, J = 2.5 Hz, J = 9.0 Hz), 6.57 (1H , D, J = 2.5 Hz), 6.98-7.04 (1H, m), 7.20 (1H, dd, J = 2.5 Hz, J = 6.5 Hz), 7.23-7. 32 (1H, m), 7.40 (1H, d, J = 8.5 Hz).

Reference Example 23
Synthesis of 2- (4-chlorobutoxy) pyridine To a DMF solution (110 ml) containing 10 g (105 mmol) of 2-pyridinol and 36 ml (315 mmol) of 1-bromo-4-chlorobutane, 16 g (116 mmol) of potassium carbonate was added. Subsequently, it stirred at room temperature for 8 hours. 300 ml of water was added to the reaction solution, and extracted with 300 ml of ethyl acetate. The organic layer was washed twice with water (300 ml) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1). The purified product was concentrated under reduced pressure to obtain 3.32 g of colorless oily 2- (4-chlorobutoxy) pyridine.

Reference Example 24
Synthesis of 3 (S)-[4- (pyridin-2-yloxy) butylamino] pyrrolidine-1-carboxylic acid tert-butyl ester 0.93 g of 3 (S) -aminopyrrolidine-1-carboxylic acid tert-butyl ester 5.0 mmol), 0.93 g (5.0 mmol) of 2- (4-chlorobutoxy) pyridine, 0.83 g (6.0 mmol) of potassium carbonate and 0.83 g (5.5 mmol) of sodium iodide. It was suspended in 20 ml of acetonitrile and heated to reflux for 24 hours. After cooling to room temperature, 50 ml of water was added to the reaction solution, and extracted with 50 ml of ethyl acetate. The organic layer was washed twice with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1). The purified product was concentrated under reduced pressure to obtain 372 mg of colorless oily 3 (S)-[4- (pyridin-2-yloxy) butylamino] pyrrolidine-1-carboxylic acid tert-butyl ester.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.46 (9H, s), 1.5-1.9 (6H, m), 1.95-2.15 (1H, m), 2.68 (2H, t, J = 7 Hz), 2. 95-3.15 (1H, m), 3.25-3.65 (4H, m), 4.30 (2H, t, J = 6.5 Hz), 6.71 (1H, d, J = 8) .5 Hz), 6.85 (1 H, dd, J = 5.5 Hz, J = 6.5 Hz), 7.5-7.65 (1 H, m), 8.14 (1 H, dd, J = 2 Hz, J = 5 Hz).

Reference Example 25
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(3-chloro-4- Fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 g (9.5 mmol), 4.7 ml (48 mmol) 1-bromo-3-chloropropane and 1.97 g (14.3 mmol) potassium carbonate. It was suspended in 15 ml of N-methylpyrrolidone (NMP) and then stirred at 100 ° C. for 8 hours. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), and the purified product was concentrated under reduced pressure to give colorless oily 3 (S)-[(3-chloro-4-fluorophenyl )-(3-Chloropropyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 1.0 g was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.46 (9H, s), 1.7-2.1 (4H, m), 3.1-3.35 (4H, m), 3.35-3.7 (4H, m), 3. 8-4.1 (1H, m), 6.7-6.9 (1H, m), 6.9-7.1 (2H, m).

Reference Example 26
Synthesis of 3 (S)-[(3-chloro-4-fluorophenyl)-(3-dimethylaminopropyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester 3 (S)-[(3-chloro-4 -Fluorophenyl)-(3-chloropropyl) -amino] pyrrolidine-1-carboxylic acid tert-butyl ester 0.5 g (1.24 mmol), 50% aqueous dimethylamine solution 1 ml and sodium iodide 0.37 g (2. 5 mmol) was suspended in 3 ml DMF and then stirred at 60 ° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and then the purified product was concentrated under reduced pressure to give colorless oily 3 (S)-[(3-chloro-4-fluorophenyl)-(3- 0.36 g of dimethylaminopropyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.46 (9H, s), 1.5-1.75 (4H, m), 1.75-2.1 (2H, m), 2.19 (6H, s), 3.0-3. 3 (4H, m), 3.3-3.75 (2H, m), 3.8-4.2 (1H, m), 6.6-6.8 (1H, m), 6.8- 7.1 (2H, m).

  In the same manner as in the above Reference Example, the compounds shown in the following table were produced.

Example 1
Synthesis of (3,4-dichlorophenyl) phenylpyrrolidin-3-ylamine dihydrochloride, including 0.67 g of 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester and 0.94 g of (3,4-dichlorophenyl) phenylamine The acetic acid solution (15 ml) was stirred at room temperature overnight. To this mixture was added 1.5 g of sodium triacetoxyborohydride and then stirred at room temperature for 8 hours. Dichloromethane was added to the reaction solution, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1). The solvent was distilled off from the purified product under reduced pressure, and the residue was dissolved in 1N hydrochloric acid-ethanol and heated to reflux for 1 hour. The reaction solution was concentrated to dryness to obtain 50 mg of (3,4-dichlorophenyl) phenylpyrrolidin-3-ylamine dihydrochloride as a brown amorphous solid.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.74-2.90 (1H, m), 3.02-3.22 (2H, m ), 3.51-3.66 (1H, m), 4.61-4.79 (1H, m), 6.58 (1H, dd, J = 2.9 Hz, J = 9.0 Hz), 6 .87 (1H, d, J = 2.9 Hz), 7.13-7.19 (2H, m), 7.29-7.44 (2H, m), 7.45-7.54 (2H, m), 9.03 (2H, brs).

Example 2
Synthesis of 3 (S)-(3,4-dichlorophenyl) phenylpyrrolidin-3-ylamine dihydrochloride 3 (S)-[(3,4-dichlorophenyl) phenylamino] pyrrolidine-1-carboxylic acid tert-butyl ester 0.13 g was dissolved in 1N hydrochloric acid-ethanol and heated to reflux for 1 hour. The reaction solution was concentrated to dryness to obtain 0.11 g of brown amorphous solid 3 (S)-(3,4-dichlorophenyl) phenylpyrrolidin-3-ylamine hydrochloride.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.50-1.68 (1H, m), 2.10-2.29 (1H, m), 2.75-2.90 (1H, m), 3.02-3.23 (2H, m ), 3.51-3.65 (1H, m), 4.60-4.80 (1H, m), 6.58 (1H, dd, J = 2.9 Hz, J = 9.0 Hz), 6 .87 (1H, d, J = 2.9 Hz), 7.12-7.19 (2H, m), 7.29-7.44 (2H, m), 7.45-7.54 (2H, m), 9.05 (2H, brs).

Example 3
Synthesis of (3-fluorophenyl)-(S) -pyrrolidin-3-yl- (4-trifluoromethylphenyl) amine difumarate ((S) -1-benzylpyrrolidin-3-yl)-(3 1-chloroethyl chloroformate 0.82 g (5.8 mmol) was added to a 1,2-dichloromethane solution (1 ml) containing 0.48 g (1.1 mmol) of -fluorophenyl)-(4-trifluoromethylphenyl) amine. added. The mixture was stirred at room temperature for 15 hours and heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, 5 ml of methanol was added to the residue, and the mixture was heated to reflux for 3 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, and 128 mg (1.1 mmol) of fumaric acid was added to make a homogeneous solution. The solvent was distilled off under reduced pressure, dichloromethane was added to the residue, and the precipitated crystals were separated by filtration, dried, and (3-fluorophenyl)-(S) -pyrrolidin-3-yl)- 0.24 g of (4-trifluoromethylphenyl) amine difumarate was obtained.
Melting point: 144.0-146.2 ° C.

Example 4
Synthesis of (3-Chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S) -pyrrolidin-3-ylamine hydrochloride 3 (S)-[(3-Chloro-4-fluorophenyl)- (4-Methanesulfonylphenyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester (0.42 g, 0.9 mmol) was added to 4N hydrochloric acid / ethyl acetate, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain 0.35 g of (3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S) -pyrrolidin-3-ylamine hydrochloride as white powder. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.56-1.68 (1H, m), 2.19-2.29 (1H, m), 2.82-2.94 (1H, m), 3.08 (3H, s), 3. 10-3.20 (2H, m), 3.57-3.68 (1H, m), 4.70-4.85 (1H, m), 6.69-6.75 (2H, m), 7.32-7.37 (1H, m), 7.58-7.64 (1H, m), 7.65-7.69 (3H, m), 9.10-9.45 (2H, m) ).

Example 5
(3-Chloro-4-fluorophenyl)-[4- (pyridin-2-yloxy) butyl]
Synthesis of-(S) -pyrrolidin-3-ylamine difumarate 3 (S)-[4- (Pyridin-2-yloxy) butylamino] pyrrolidine-1-carboxylic acid tert-butyl ester 0.2 g (0 .6 mmol) and 4-bromo-2-chloro-1-fluorobenzene in a toluene solution (4 ml) containing 0.8 ml (0.65 mmol) of tritert-butylphosphine tetrafluoroborate 14 mg (0.05 Mmol), 11 mg (0.012 mmol) of tris (dibenzylideneacetone) dipalladium and 110 mg (1.2 mmol) of sodium tert-butoxide were added, and the mixture was heated to reflux for 12 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1). The solvent was distilled off from the purified product under reduced pressure. The residue was dissolved in 0.4 ml of dichloromethane, 0.06 ml (0.8 mmol) of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. Concentrated under reduced pressure and the residue was purified by HPLC. The desired fractions were combined, the solvent was distilled off under reduced pressure, 10% aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and an ethanol solution containing 8.1 mg of fumaric acid was added to the residue (ethanol solution) to obtain a uniform solution. After concentration under reduced pressure, 3 ml of water was added to the residue, then lyophilized to give (3-chloro-4-fluorophenyl)-[4- (pyridin-2-yloxy) butyl]-(S) as a white solid 19 mg of pyrrolidin-3-ylamine difumarate were obtained.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.45-1.55 (2H, m), 1.65-1.8 (2H, m), 1.8-1.95 (1H, m), 2.05-2.15 (1H, m) ), 2.6-4.05 (11H, m), 4.25 (2H, t, J = 6.5 Hz), 4.3-4.4 (1H, m), 6.55 (4H, s) ), 6.77 (1H, d, J = 8.5 Hz), 6.8-6.9 (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), 7.65-7.7 (1H, m), 8.1-8.15 ( 1H, m).

Example 6
Synthesis of (3-chloro-4-fluorophenyl)-(3-methylsulfanylpropyl)-(S) -pyrrolidin-3-ylamine hydrochloride hydrochloride 3 (S)-[(3-chloro-4-fluorophenyl) amino An acetic acid solution (3 ml) containing 0.60 g (1.9 mmol) of pyrrolidine-1-carboxylic acid tert-butyl ester and 0.6 g (5.7 mmol) of 3-methylthiopropionaldehyde was stirred overnight at room temperature. To this mixture, 0.81 g (3.8 mmol) of sodium triacetoxyborohydride was added and then stirred at room temperature for 15 hours. Dichloromethane was added to the reaction solution, washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 10 ml of 1N hydrochloric acid-ethanol and heated to reflux for 1 hour. The reaction solution was concentrated to dryness to give 0.16 g of (3-chloro-4-fluorophenyl)-(3-methylsulfanylpropyl)-(S) -pyrrolidin-3-ylamine hydrochloride as a yellow amorphous solid. It was.
¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.52-1.70 (2H, m), 1.80-2.18 (5H, m [including 2.07 ppm (s)]), 2.40-2.51 (2H, m), 2 84-3.49 (6H, m), 4.29-4.49 (1H, m), 6.85-6.95 (1H, m), 7.05-7.35 (2H, m) , 9.30-9.79 (2H, m).

Example 7
Synthesis of (3-chloro-4-fluorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine dimethanesulfonate 3 (S)-[(3-chloro-4-fluorophenyl) pyridine To a dichloromethane solution (100 ml) containing 16.0 g (41 mmol) of -3-ylamino] pyrrolidine-1-carboxylic acid tert-butyl ester was added 20 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was made alkaline by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (dichloromethane: methanol = 10: 1). The solvent was distilled off from the purified product under reduced pressure, 9.2 g of methanesulfonic acid was added to the ethanol solution containing the residue, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 16.9 g of (3-chloro-4-fluorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine dimethanesulfonate as white powder.
Melting point 194.0-195.0 ° C.

Using corresponding appropriate starting materials, the compounds of Examples 8 to 1180 shown in the following table were produced in the same manner as in the above Examples. In these tables, for example, compounds having physical properties such as crystal form, mp (melting point), salt, ¹ H-NMR and MS (mass spectrum) were actually produced.

Pharmacological test 1
Measurement of Serotonin (5-HT) Uptake Inhibitory Activity of Test Compound by Rat Brain Synaptosome Male Wistar rats were decapitated, the brain was removed, and the frontal cortex was excised. The separated frontal cortex was placed in a 0.32 molar (M) sucrose solution 20 times the weight and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g and 4 ° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g and 4 ° C. for 20 minutes. The pellet was suspended in an incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride and 1.5 mM calcium chloride), and the crude synaptosome fraction was suspended. Used as minutes.

Using each well of a 96 well-round bottom plate, the uptake reaction was performed with a total volume of 200 μl of a solution containing pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml).

  That is, solvent, unlabeled 5-HT, and serially diluted test compound were added to each well, and a synaptosomal fraction of one-tenth of the final volume was added to each well. After preincubation at 37 ° C. for 10 minutes, tritium label 5 -HT solution (final concentration 8 nM) was added and the uptake reaction started at 37 ° C. The uptake reaction was terminated after 10 minutes by suction filtration through a 96-well glass fiber filter plate. Further, the filter was washed with cold physiological saline, and then sufficiently dried. Microcinch 0 (Perkin Elmer) was added, and the residual radioactivity on the filter was measured.

  The uptake value when only the solvent was added was 100%, and the uptake value (non-specific uptake value) when unlabeled 5-HT (final concentration 10 μM) was added was 0%. A 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 160.

Pharmacological test 2
Measurement of Norepinephrine (NE) Uptake Inhibitory Activity of Test Compound by Rat Brain Synaptosome Male Wistar rats were decapitated, the brain was taken out, and the hippocampus was cut out. The separated hippocampus was placed in a 0.32 molar (M) sucrose solution 20 times the weight and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g and 4 ° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g and 4 ° C. for 20 minutes. The pellet was suspended in an incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride and 1.5 mM calcium chloride), and the crude synaptosome fraction was suspended. Used as minutes.

Using each well of a 96 well-round bottom plate, the uptake reaction was performed with a total volume of 200 μl of a solution containing pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml).

That is, solvent, unlabeled NE, and serially diluted test compound were added to each well, and a synaptosomal fraction of one-tenth the final volume was added to each well. After preincubation at 37 ° C. for 10 minutes, tritium-labeled NE solution ( The final concentration of 12 nM) was added to start the uptake reaction at 37 ° C. The uptake reaction was terminated after 10 minutes by suction filtration through a 96-well glass fiber filter plate. Further, the filter was washed with cold physiological saline, and then sufficiently dried. Microcinch 0 (Perkin Elmer) was added, and the residual radioactivity on the filter was measured.

  The uptake value when only the solvent was added was 100%, and the uptake value (nonspecific uptake value) when unlabeled NE (final concentration 10 μM) was added was 0%. A 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 161.

Pharmacological test 3
Measurement of Dopamine (DA) Uptake Inhibitory Activity of Test Compounds by Rat Brain Synaptosomes Male Wistar rats were decapitated, the brain was removed, and the striatum was excised. The separated striatum was placed in a 0.32 molar (M) sucrose solution 20 times the weight and homogenized with a potter type homogenizer. The homogenate was centrifuged at 1000 g and 4 ° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g and 4 ° C. for 20 minutes. The pellet was suspended in an incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride and 1.5 mM calcium chloride), and the crude synaptosome fraction was suspended. Used as minutes.

Using each well of a 96 well-round bottom plate, the uptake reaction was performed with a total volume of 200 μl of a solution containing pergelin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / ml).

  That is, a solvent, unlabeled DA and serially diluted test compound were added to each well, and a synaptosomal fraction of 1/10 of the final volume was added to each well. After preincubation at 37 ° C. for 10 minutes, a tritium-labeled DA solution ( The final concentration of 2 nM) was added and the uptake reaction was started at 37 ° C. The uptake reaction was terminated after 10 minutes by suction filtration through a 96-well glass fiber filter plate. Further, the filter was washed with cold physiological saline, and then sufficiently dried. Microcinch 0 (Perkin Elmer) was added, and the residual radioactivity on the filter was measured.

  The uptake value when only the solvent was added was 100%, and the uptake value (non-specific uptake value) when unlabeled DA (final concentration 10 μM) was added was 0%. A 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 162.

Pharmacological test 4
Forced swimming test This test was performed by the method of Porsolt et al. (Porsolt, RD, et al., Behavioral despair in
mice: A primary screening test for antidepressants. Arch. int. Pharmacodyn., 229, pp 327-336 (1977)).

  The test compound was suspended in 5% gum arabic / physiological saline solution (w / v) and orally administered to male ICR (ICR) mice (CLEA Japan (JCL), 5-6 weeks old). One hour later, the mouse was placed in a water tank with a water depth of 9.5 cm and a water temperature of 21 to 25 ° C., and a swimming trial was conducted immediately after that for 6 minutes. Then, the time during which the mouse did not move during the last 4 minutes (immobility time) was measured. For measurement and analysis of immobility time, a Scannet MV-20AQ (SCANET MV-20 AQ) system manufactured by Melquest was used.

  In this experiment, animals treated with test compounds showed a reduction in immobility time. From this it is clear that the test compound is useful as an antidepressant.

Claims (10)

General formula (1)

[Wherein, R ¹⁰¹ and R ¹⁰² each independently represent any group represented by the following (1) to (86).
(1) phenyl group,
(2) a pyridyl group,
(3) benzothienyl group,
(4) Indolyl group,
(5) 2,3-dihydro-1H-indenyl group,
(6) naphthyl group,
(7) benzofuryl group,
(8) quinolyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(12) benzothiazolyl group,
(13) thieno [3,2-b] pyridyl group,
(14) thienyl group,
(15) a cycloalkyl group,
(16) tetrahydropyranyl group,
(17) pyrrolyl group,
(18) 2,4-dihydro-1,3-benzodioxinyl group,
(19) 2,3-dihydrobenzofuryl group,
(20) 9H-fluorenyl group,
(21) pyrazolyl group,
(22) pyridazinyl group,
(23) indolinyl group,
(24) thieno [2,3-b] pyridyl group,
(25) thieno [3,2-d] pyrimidinyl group,
(26) thieno [3,2-e] pyrimidinyl group,
(27) 1H-pyrazolo [3,4-b] pyridyl group,
(28) isoquinolyl group,
(29) 2,3-dihydro-1,4-benzoxazinyl group,
(30) quinoxalinyl group,
(31) quinazolinyl group,
(32) 1,2,3,4-tetrahydroquinolyl group,
(33) a cycloalkyl lower alkyl group,
(34) a lower alkylthio lower alkyl group,
(35) an amino-substituted lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(36) Phenoxy lower alkyl group,
(37) pyridyloxy lower alkyl group,
(38) a lower alkynyl group,
(39) phenyl lower alkenyl group,
(40) 1,3-benzodioxolyl group,
(41) 2,3-dihydro-1,4-benzodioxinyl group,
(42) 3,4-dihydro-1,5-benzodioxepinyl group,
(43) dihydropyridyl group,
(44) 1,2-dihydroquinolyl group,
(45) 1,2,3,4-tetrahydroisoquinolyl group,
(46) benzoxazolyl group,
(47) benzoisothiazolyl group,
(48) indazolyl group,
(49) Benzimidazolyl group,
(50) imidazolyl group,
(51) 1,2,3,4-tetrahydronaphthyl lower alkyl group,
(52) imidazo [1,2-a] pyridyl lower alkyl group,
(53) a thiazolyl lower alkyl group,
(54) tetrahydropyranyl lower alkyl group,
(55) piperidyl lower alkyl group,
(56) diphenyl lower alkoxy substituted lower alkyl group,
(57) a lower alkoxycarbonyl-substituted lower alkyl group,
(58) phenyl lower alkoxycarbonyl substituted lower alkyl group,
(59) a hydroxy-substituted lower alkyl group,
(60) a lower alkoxy lower alkyl group,
(61) a carboxy lower alkyl group,
(62) A carbamoyl-substituted lower alkyl group (one to two lower alkyl groups may be substituted on the carbamoyl group),
(63) a lower alkenyl group,
(64) morpholinylcarbonyl lower alkyl group,
(65) benzoyl lower alkyl group,
(66) phenylthio lower alkyl group,
(67) Naphthylthio lower alkyl group,
(68) cycloalkylthio lower alkyl group,
(69) pyridylthio lower alkyl group,
(70) pyrimidinylthio lower alkyl group,
(71) furylthio lower alkyl group,
(72) thienylthio lower alkyl group,
(73) 1,3,4-thiadiazolylthio lower alkyl group,
(74) benzimidazolylthio lower alkyl group,
(75) Benzthiazolylthio lower alkyl group,
(76) tetrazolylthio lower alkyl group,
(77) benzoxazolylthio lower alkyl group,
(78) thiazolylthio lower alkyl group,
(79) imidazolylthio lower alkyl group,
(80) amino-substituted lower alkylthio lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(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) a phenoxy-substituted lower alkylthio lower alkyl group, and
(86) a lower alkoxycarbonyl-substituted lower alkylthio-lower alkyl group;
Each of the groups represented by the above (1) to (32), (37), (39) to (56), (64) to (79), (81) to (83) and (85) is a cycloalkyl ring. The aromatic ring or heterocyclic ring may have one or more substituents selected from the following (1-1) to (1-37).
(1-1) a halogen atom,
(1-2) a lower alkylthio group optionally substituted with one or more halogen atoms,
(1-3) a lower alkyl group which may be substituted with one or more halogen atoms,
(1-4) a lower alkoxy group which may be substituted with one or more halogen atoms,
(1-5) Nitro group,
(1-6) a lower alkoxycarbonyl group,
(1-7) an amino group in which one or two lower alkyl groups may be substituted,
(1-8) a lower alkylsulfonyl group,
(1-9) cyano group,
(1-10) carboxy group,
(1-11) hydroxyl group,
(1-12) thienyl group,
(1-13) oxazolyl group,
(1-14) naphthyl group,
(1-15) benzoyl group,
(1-16) Phenoxy group (1 to 3 halogen atoms may be substituted on the phenyl ring),
(1-17) phenyl lower alkoxy group,
(1-18) a lower alkanoyl group,
(1-19) phenyl group (on the phenyl ring, 1 to 5 substituents selected from the group consisting of a halogen atom, a lower alkoxy group, a cyano group, a lower alkanoyl group and a lower alkyl group may be substituted. ),
(1-20) phenyl lower alkyl group,
(1-21) cyano lower alkyl group,
(1-22) a sulfonyl group substituted with a 5- to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
(1-23) thiazolyl group (on the thiazole ring, 1 to 2 lower alkyl groups may be substituted),
(1-24) imidazolyl group,
(1-25) Amino lower alkyl group (on the amino group, 1 to 2 lower alkyl groups may be substituted),
(1-26) pyrrolidinyl lower alkoxy group,
(1-27) isoxazolyl group,
(1-28) cycloalkylcarbonyl group,
(1-29) naphthyloxy group,
(1-30) pyridyl group,
(1-31) furyl group,
(1-32) phenylthio group,
(1-33) oxo group,
(1-34) carbamoyl group,
(1-35) a 5- to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (on the saturated heterocyclic group, an oxo group A lower alkyl group; a lower alkanoyl group; a phenyl lower alkyl group; a phenyl group optionally having 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring; and a pyridyl group 1 to 3 substituents selected from the group may be substituted)
(1-36) an oxide group, and
(1-37) a lower alkoxide group;
However, R ¹⁰¹ and R ¹⁰² must not be an unsubstituted phenyl group at the same time. ]
A pharmaceutical comprising a pyrrolidine compound represented by the formula: R ¹⁰¹ is
(1) phenyl group,
(3) benzothienyl group,
(4) Indolyl group,
(5) 2,3-dihydro-1H-indenyl group,
(6) naphthyl group,
(7) benzofuryl group,
(8) quinolyl group,
(12) benzothiazolyl group,
(18) 2,4-dihydro-1,3-benzodioxinyl group,
(19) 2,3-dihydrobenzofuryl group,
(20) 9H-fluorenyl group,
(23) indolinyl group,
(28) isoquinolyl group,
(29) 2,3-dihydro-1,4-benzoxazinyl group,
(30) quinoxalinyl group,
(31) quinazolinyl group,
(32) 1,2,3,4-tetrahydroquinolyl group,
(40) 1,3-benzodioxolyl group,
(41) 2,3-dihydro-1,4-benzodioxinyl group,
(42) 3,4-dihydro-1,5-benzodioxepinyl group,
(44) 1,2-dihydroquinolyl group,
(45) 1,2,3,4-tetrahydroisoquinolyl group,
(46) benzoxazolyl group,
(47) benzoisothiazolyl group,
(48) an indazolyl group, or
(49) is a benzimidazolyl group,
Each of these groups may have 1 to 3 substituents selected from (1-1) to (1-37) defined in Item 1 on the aromatic ring or heterocyclic ring.
A pharmaceutical comprising the pyrrolidine compound represented by the general formula (1) according to claim 1 or a salt thereof. R ¹⁰¹ is (1) a phenyl group or (3) a benzothienyl group,
Substitution selected from the group consisting of (1-1) halogen atoms and (1-3) lower alkyl groups optionally substituted with 1 to 3 halogen atoms on the aromatic ring or heterocyclic ring of each group May have 1 to 3 groups,
A pharmaceutical comprising the pyrrolidine compound represented by the general formula (1) according to claim 2 or a salt thereof. R ¹⁰² is
(1) phenyl group,
(2) a pyridyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(14) thienyl group,
(48) indazolyl group,
(59) a hydroxy-substituted lower alkyl group, or
(60) a lower alkoxy lower alkyl group,
Each group represented by the above (1), (2), (9), (10), (11), (14) and (48) is defined in item 1 on the aromatic ring or heterocyclic ring (1 -1) to (1-37) may have 1 to 3 substituents selected from,
A medicament comprising the pyrrolidine compound represented by the general formula (1) according to claim 3 or a salt thereof. R ¹⁰¹ is a monohalophenyl group, a dihalophenyl group or a phenyl group substituted with one halogen atom and one lower alkyl group;
R ¹⁰² is
(1) phenyl group,
(2) a pyridyl group,
(9) thiazolyl group,
(10) pyrimidinyl group,
(11) pyrazinyl group,
(14) thienyl group,
(48) indazolyl group,
(59) a hydroxy-substituted lower alkyl group, or
(60) a lower alkoxy lower alkyl group,
Each of the groups represented by the above (1), (2), (9), (10), (11), (14) and (48) is a (1-1) halogen atom on the aromatic ring or heterocyclic ring, (1-3) one or more substituents selected from the group consisting of a lower alkyl group which may be substituted with one or more halogen atoms and (1-9) a cyano group may be present,
A pharmaceutical comprising the pyrrolidine compound represented by the general formula (1) according to claim 4 or a salt thereof. A medicament comprising a pyrrolidine compound represented by the general formula (1) according to claim 5 or a salt thereof selected from the following group:
(3-chloro-4-fluorophenyl) -3-thienyl- (S) -pyrrolidin-3-ylamine,
(4-chlorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
(4-fluorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
(3,4-difluorophenyl) phenyl- (S) -pyrrolidin-3-ylamine,
Bis (4-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3,4-difluorophenyl)-(4-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-yl-p-tolylamine,
4-[(S)-(4-fluoro-3-methylphenyl) pyrrolidin-3-ylamino] benzonitrile bis (3-fluorophenyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(4-fluorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl)-(S) -pyrrolidin-3-ylthiazol-2-ylamine,
(3,4-dichlorophenyl) pyrimidin-5-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyrazin-2-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-chloropyridin-2-yl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyridin-2-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(6-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
(3,4-dichlorophenyl) pyridin-3-yl- (S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(S) -pyrrolidin-3-ylthiophen-3-ylamine,
(3-chloro-4-fluorophenyl)-(5-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
(4-fluoro-3-methylphenyl)-(5-fluoropyridin-3-yl)-(S) -pyrrolidin-3-ylamine,
2-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) ethanol,
1-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) -2-methylpropan-2-ol,
(3-chloro-4-fluorophenyl)-(2-methoxyethyl)-(S) -pyrrolidin-3-ylamine,
3-[(S)-(3-chloro-4-fluorophenyl) pyrrolidin-3-ylamino) propan-1-ol,
(3-chloro-4-fluorophenyl)-(3-methoxypropyl)-(S) -pyrrolidin-3-ylamine,
(3-chloro-4-fluorophenyl)-(1-methyl-1H-indazol-5-yl)-(S) -pyrrolidin-3-ylamine,
Benzo [b] thiophen-6-yl- (S) -pyrrolidin-3-ylthiophen-3-ylamine and benzo [b] thiophen-5-yl- (S) -pyrrolidin-3-ylthiophen-3-ylamine .   A pharmaceutical composition comprising the pharmaceutical according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.   A preventive and / or therapeutic agent for a disorder associated with a decrease in neurotransmission of serotonin, norepinephrine or dopamine, comprising the medicine according to any one of claims 1 to 6 as an active ingredient. Disability is hypertension; depression; generalized anxiety disorder; fear; post-traumatic stress syndrome; acute stress syndrome; avoidance personality disorder; body deformity injury; premature ejaculation; eating disorder; obesity; alcohol, cocaine, Chemical dependence on heroin, phenobarbital, nicotine and benzodiazepines; cluster headache; migraine; pain; Alzheimer's disease; obsessive-compulsive disorder; panic disorder; memory disorder; Parkinson's disease; endocrine disorder; Gastrointestinal tract disorder; negative syndrome of schizophrenia; premenstrual syndrome; fibromyalgia syndrome; tension urinary incontinence; towlet syndrome; hair loss; stealing; male impotence; attention deficit hyperactivity disorder (ADHD); Selected from the group consisting of migraine; chronic fatigue; weakness; sleep apnea syndrome;
The preventive and / or therapeutic agent according to claim 8. The preventive and / or therapeutic agent according to claim 8, wherein the disorder is selected from the following group;
Major Depressive Disorder; Bipolar I Disorder; Bipolar Type II Disorder; Mixed State; Mood Modulation Disorder; Rapid Cycler; Atypical Depression; Seasonal Emotion Disorder; Postpartum Depression; Mild Depression; Recurrent Short-Term Depression Morbidity disorder; refractory depression / chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety depression disorder; Cushing syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea / milk Depression associated with physical disease selected from the group consisting of secretion syndrome, Parkinson's disease, Alzheimer's disease, cerebral hemorrhage, diabetes, chronic fatigue syndrome and cancer; middle age depression; old age depression; childhood / pubertal depression Interferon-induced depression; and depression associated with adaptation disorders and anxiety associated with adaptation disorders; and various diseases [eg, neurological disorders (head trauma, brain infections and inner ear disorders), heart blood Disorders (heart failure, arrhythmias), endocrine disorders (adrenal hyperthyroidism, hyperthyroidism), respiratory disorders (asthma, chronic obstructive pulmonary disease) anxiety selected from the group consisting of anxiety caused by.