JP2002338466A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal composition useful as a prophylactic or therapeutic agent of penile impotentia erigendi or the like because of exhibiting excellent selective PDE V (cGMP-specific phosphodiesterase)-inhibiting activities. SOLUTION: This medicinal composition contains an aromatic nitrogen- containing six-membered ring compound represented by general formula (I) [wherein, ring A is a nitrogen-containing heterocyclic group which may be substituted; R<1> is a lower alkyl group which may be substituted, a group represented by the formula: -NH-Q-R<3> (wherein, R<3> is a nitrogen-containing heterocyclic group which may be substituted; and Q is a lower alkylene group or a single bond) or a group represented by the formula: -NH-R<4> (wherein, R<4> is a cycloalkyl group which may be substituted); R<2> is an aryl group which may be substituted; one of Y and Z is a group represented by the formula: =CH-, and the other is a group represented by the formula: =N-] or a pharmacologically acceptable salt thereof as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[0002]

2. Description of the Related Art In general, cGMP, which is a second intracellular messenger, is degraded and inactivated by PDE having affinity for cGMP among phosphodiesterases (PDEs) widely distributed in tissues in a living body. P
It is known that when DE activity is inhibited, the concentration of intracellular cGMP increases, and as a result, various pharmacological actions such as a vascular smooth muscle relaxing action, a bronchial smooth muscle relaxing action, a platelet aggregation inhibitory action and the like are expressed. ing. In addition, such cG
Among PDEs having affinity for MP, an inhibitory effect on cGMP-specific PDE (PDE V) (ie, PDE
V inhibitory compound), various diseases caused by dysfunction of cGMP signaling, for example, hypertension,
Angina, myocardial infarction, chronic and acute heart failure, pulmonary hypertension
(WO96 / 05176, etc.), prostate hypertrophy (Australian Patent Publication No. 9955977), etc., are known to be useful, and further, female sexual dysfunction [Vemulapalli]
Et al., Life Sciences, Vol. 67, Nos. 23-29
(2000) (Life Sciences)], diabetic gastroparesis [Watkins et al., Journal of Clinical Investigation, Vol. 106, pp. 373-384.
(2000) (J. Clin. Invest.)), Achalasia (Bor
Tolotti et al., Gastroenterology, Vol. 118, pp. 253-257 (2000) (Gastroenterolog
y)), diarrhea [Mule et al., British Journal
Of Pharmacology, Vol. 127, 514-52
0 (1999) (Br. J. Pharmacol.)), Constipation [Bakr
e et al., Journal of Cellular Biochemistry, Vol. 77, pp. 159-167 (2000) (J. Ce)
ll. Biochem.)), asthma (Turner et al., British
Journal of Pharmacology, Vol. 111, pp. 1198-1204 (1994) (Br. J. Pharmaco
l.)] has also been reported.

[0003] Further, 1- has a PDEV inhibitory action.
[4-ethoxy-3- (6,7-dihydro-1-methyl-
7-oxo-3-propyl-1H-pyrazolo [4,3-
d] pyrimidin-5-yl) phenylsulfonyl] -4
-Methylpiperazine [generic name: sildenafil (Sildenafil)
fil)] has also been reported to be useful in treating diseases such as penile erectile dysfunction [Boolell et al., The Journal of Urology Supplements, Vol. 155, No. 5, 495A, p. 739 (1996). ) (The Journal of Urol
ogy, Supplement), Terrett et al., Bioorganic
And Medicinal Chemistry Letters, 6
Vol. 15, No. 1819 (1996) (Bioorgani
c & Medicinal Chemistry Letters) and Ballard et al.
British Journal of Pharmacology
Proceeding Supplement, Vol. 118, 153
P (1996) (British Journal of Pharmacology,
Proceeding Supplement)].

[0004] However, it has also been reported that sildenafil has side effects such as headache, flushing of the face, gastrointestinal tract disorders, rhinitis, abnormal color vision and persistent erection [Irwin
Et al., The New Ingrad Journal of Medicine, Vol. 338, No. 20, 1397-1404
P. (1998) (The New England Journal of Medici
ne), Morales et al., International Journal
Of Impotence Research, Vol. 10, No. 2, pp. 69-73 (1998) (International Journal o
f Impotence Research) and Goldenberg, Clinical Therapeutics, Volume 20, Issue 6, 1033
-1048 (1998) (Clinical Therapeutic
s)].

In dog experiments, it has been reported that sildenafil correlates with the PDE VI inhibitory effect on the effect of retinal light response [Morales
Et al., International Journal of Impotence Research, Vol. 10, No. 2, pp. 69-73.
(1998) (International Journal of Impotence R
esearch)] On the other hand, it has also been reported that PDE VI of the retina plays an important role in visual function [Mo
rales et al., International Journal of Impotence Research, Vol. 10, No. 2, 69-7
3 pages (1998) (International Journal of Impoten
ce Research) and Estrade et al., European Journal of Pharmacology, 352, 157.
-163 (1998) (European Journal of Pharma
cology)).

[0006]

SUMMARY OF THE INVENTION The present invention provides an excellent PD
The present invention relates to a pharmaceutical composition comprising, as an active ingredient, a novel aromatic nitrogen-containing six-membered ring compound which has an EV inhibitory action and is useful as a prophylactic / therapeutic agent for penile erectile dysfunction with few side effects.

[0007]

The present invention provides a compound represented by the general formula (I):

Embedded image (Wherein, ring A is an optionally substituted nitrogen-containing heterocyclic group, R ¹ is an optionally substituted lower alkyl group, formula: —NH—Q—R ³ (wherein, R ³ is substituted A nitrogen-containing heterocyclic group which may be
Group or the formula Q is represented by representing) a lower alkylene group or a single bond: -NH-R ⁴ (wherein the groups represented by R ⁴ represents a cycloalkyl group which may be substituted), R ² is One of the optionally substituted aryl groups, Y and Z, has the formula: ＣＨCH- and the other has the formula: ＮN-), or a pharmacologically acceptable aromatic nitrogen-containing six-membered ring compound thereof. A pharmaceutical composition comprising a salt which can be used as an active ingredient.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Compounds as active ingredients of the present invention
In (I), the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” for ring A includes 5 to 5
10-membered monocyclic or bicyclic nitrogen-containing heterocyclic group, more specifically, a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group and 8 to
Examples thereof include a 10-membered bicyclic nitrogen-containing heterocyclic group, and more specifically, a 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group such as a pyrrolidinyl group, a piperazinyl group, a piperidyl group, and a morpholino group. 5 to 6 such as a formula group, an imidazolyl group and a pyrrolyl group
Membered aromatic monocyclic nitrogen-containing heterocyclic group, 6,7-dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl group, 5,
6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl group, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl group, 1,2,3,4 -Tetrahydro-2-isoquinolinyl group, 1H-2,3,4,5,6,7-
Hexahydropyrazolo [4,3-c] pyridin-5-yl group, 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-6-yl group, 5,6,7,8 -Tetrahydropyrido [4,3-d] pyrimidin-6-yl group, 4,5,6,7-
Tetrahydro-3H-imidazo [4,5-c] pyridine-
Examples include a bicyclic nitrogen-containing heterocyclic group such as a 3-yl group.

The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for R ³ includes:
Examples thereof include a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, and specifically, a morpholinyl group, a piperazinyl group, a piperidyl group, a thiadiazolyl group, A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group such as a dihydropyrimidinyl group or a dihydropyrazolyl group;
5- or 6-membered aromatic monocyclic nitrogen-containing heterocyclic group such as pyrimidinyl group, pyridazinyl group, pyridyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyrazinyl group, benzothiazolyl group, quinolyl group, dihydrobenzo Examples thereof include 8- to 10-membered bicyclic nitrogen-containing heterocyclic groups such as oxazolyl groups.

The substituents of the "optionally substituted nitrogen-containing heterocyclic group" represented by rings A and R ³ include (1) a lower alkyl group, (2) a hydroxyl-substituted lower alkyl group, and (3) Formyl group, (4) oxo group, (5) amino group, (6) di-lower alkylamino group, (7) hydroxyl group, (8) lower alkoxy group,
(9) a lower alkoxycarbonyl group, (10) a lower alkoxy-substituted lower alkanoyl group, (11) a lower alkanoyl group, (12) a cyano-substituted lower alkyl group, and (13)
(i) a benzylamino group substituted by a halogen atom and a lower alkoxy group; and (ii) a pyrimidinyl group substituted by a hydroxyl-substituted cycloalkylcarbamoyl group.

The aryl group of the "optionally substituted aryl group" for R ² includes a 5- to 10-membered monocyclic or bicyclic aromatic hydrocarbon group.
Examples include a phenyl group and a naphthyl group.

Examples of the substituent of the "optionally substituted aryl group" for R ² include a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group and the like.

The substituents of the "optionally substituted lower alkyl group" for R ¹ and the "optionally substituted cycloalkyl group" for R ⁴ include a lower alkoxy group, a hydroxyl group and a morpholinyl group. A lower alkylsulfonyl group, a di-lower alkylphosphino group, a di-lower alkylamino group, a pyrimidinyl-substituted lower alkylamino group,
A pyridyl group, a pyridylamino group, a lower alkyl group-substituted piperazinyl group and a pyrimidinyloxy group.

Throughout this specification, a lower alkyl group is
It means a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy and the like. Cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
It means a cycloalkyl group having 3 to 8 carbon atoms such as cycloheptyl. The lower alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms such as methylene, ethylene and trimethylene. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Among the compounds (I) which are the active ingredients of the present invention, preferred compounds include those in the "optionally substituted nitrogen-containing heterocyclic group" represented by ring A in the general formula (I). The nitrogen heterocyclic group has the formula: A monocyclic or bicyclic nitrogen-containing heterocyclic group represented by the above-mentioned "optionally substituted nitrogen-containing heterocyclic group"
Substituent is a group selected from a lower alkyl group, a hydroxyl-substituted lower alkyl group, an oxo group and an amino group, R ¹
Is a lower alkyl group which may be substituted with a group selected from a lower alkoxy group, a morpholinyl group, a pyrimidinyl group-substituted lower alkylamino group, a pyridyl group, a pyridylamino group and a lower alkyl group-substituted piperazinyl group, formula: -NH-Q- A group represented by R ³ or a group represented by the formula: —NH—R ⁴ , wherein the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula: : Wherein the substituent of the `` nitrogen-containing heterocyclic group which may be substituted '' is a lower alkyl group, a hydroxyl-substituted lower alkyl group, a cyano group-substituted lower alkyl group, an oxo group, an amino group, a di-lower alkyl group. Amino group, lower alkanoyl group,
A lower alkoxy group-substituted group selected from a lower alkanoyl group and a lower alkoxy group, R ⁴ is a cycloalkyl group substituted with a group selected from a hydroxyl group, a lower alkoxy group and a pyrimidinyloxy group, and R ² is a lower alkoxy group And a phenyl group substituted with a group selected from a halogen atom, a cyano group and a nitro group.

Compound (I) as an active ingredient of the present invention
Other preferred compounds include those represented by the general formula (I)
Represents an optionally substituted nitrogen-containing heterocyclic group represented by ring A
The nitrogen-containing heterocyclic group in the “cyclic group” has the formula:A monocyclic or bicyclic nitrogen-containing heterocyclic group represented by
And the above-mentioned "optionally substituted nitrogen-containing heterocyclic group"
Is a hydroxyl-substituted lower alkyl group or a formyl group
A group selected from¹Is substituted with a lower alkoxy group
An optionally substituted lower alkyl group of the formula: —NH—Q—R^Three Or a group represented by the formula: -NH-R^Four A group represented by^ThreeIs replaced with
Nitrogen-containing heterocyclic group "
But the formula:And the above-mentioned `` nitrogen-containing heterocyclic ring optionally substituted ''
Group is a lower alkyl group or a cyano group-substituted lower group
A group selected from alkyl groups,^FourIs hydroxyl group and low
Substituted with a group selected from lower alkoxy groups
A kill group, ^TwoIs lower alkoxy group and halogen atom
A phenyl group substituted with a group selected from the group consisting of
Compounds of the formula: = N- and Z is the formula: = CH-
I can do it.

Among the compounds (I) which are the active ingredients of the present invention, another preferable compound is a nitrogen-containing heterocyclic group which may be substituted and which is represented by a ring A in the general formula (I). Is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group; Substituents of the "good nitrogen-containing heterocyclic group" are (1) lower alkyl group, (2) hydroxyl-substituted lower alkyl group, (3) formyl group, (4) oxo group, (5) amino group, (6) Selected from a hydroxyl group, (7) a lower alkoxycarbonyl group, and (8) (i) a benzylamino group substituted with a halogen atom and a lower alkoxy group, and (ii) a pyrimidinyl group substituted with a hydroxy-substituted cycloalkylcarbamoyl group. a group, R ¹ is a lower alkoxy group, a hydroxyl group, a morpholinyl group A lower alkylsulfonyl group, a di-lower alkylphosphino group, a di-lower alkylamino group, a pyrimidinyl group-substituted lower alkylamino group, a pyridyl group, a lower optionally substituted by a group selected from a pyridylamino group and a lower alkyl group-substituted piperazinyl group; alkyl group, the formula: -NH-Q-R ³ in a group represented by or the formula: a group represented by -NH-R ^4, the "optionally substituted nitrogen-containing heterocyclic group" represented by R ³ Is a group selected from a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group; The substituent of the `` nitrogen-containing heterocyclic group which may be substituted '' is a lower alkyl group, a hydroxyl-substituted lower alkyl group, an oxo group, an amino group, a di-lower alkylamino group, a lower alkanoyl group and a cyano group-substituted lower alkyl group. A group selected from the group, R ⁴ is a hydroxyl group, a cycloalkyl group substituted by a group selected from a lower alkoxy group and a pyrimidinyloxy group, R ² is a lower alkoxy group, a halogen atom, a cyano group, a nitro group, Compounds that are phenyl groups substituted with a group selected from a hydroxyl group and a lower alkyl group are exemplified.

More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A has the formula:

Embedded image A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or
formula:

Embedded image 5 to 6-membered monocyclic nitrogen-containing heterocyclic group represented by
A bicyclic nitrogen-containing heterocyclic group in which a 6-membered ring is fused,
The nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” for R ³ has the formula:

Embedded image Or a non-aromatic nitrogen-containing heterocyclic group represented by the formula:

Embedded image And a compound which is an aromatic nitrogen-containing heterocyclic group represented by the formula:

Among the compounds (I) which are the active ingredients of the present invention, further preferred compounds include a nitrogen-containing heterocyclic group which may be substituted and which is represented by a ring A in the general formula (I). Is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group; The substituent of the `` good nitrogen-containing heterocyclic group '' is a group selected from a lower alkyl group, a hydroxyl-substituted lower alkyl group, a formyl group and an oxo group, and R ¹ is substituted with a group selected from a lower alkoxy group and a morpholinyl group. which may be a lower alkyl group, the formula: group, or the formula represented by -NH-Q-R ^3: a group represented by -NH-R ^4, which may be "substituted represented by R ³ contains Nitrogen heterocyclic group '' may be substituted with a lower alkyl group Monocyclic nitrogen-containing heterocyclic group 6-membered, cycloalkyl group substituted with a group R ⁴ is selected from hydroxyl and lower alkoxy group, R ² is a lower alkoxy group, a halogen atom and a cyano group And a phenyl group substituted with a group selected from the following.

More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A has the formula:

Embedded image A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula:

Embedded image Is a bicyclic nitrogen-containing heterocyclic group in which a 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is condensed with the 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by And the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula:

Embedded image Or a non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula:

Embedded image And a compound which is an aromatic monocyclic nitrogen-containing heterocyclic group represented by

More specifically, ring A has the formula:

Embedded image Wherein R ¹ is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a morpholinyl group-substituted lower alkyl group, a group represented by the formula: —NH—Q—R ³ or a formula: —NH—R ⁴ Wherein R ³ is a group represented by the formula:

Embedded image Wherein R ⁴ is a group represented by the formula:

Embedded image Wherein R ² is a group represented by the formula:

Embedded image The compound which is a group shown by these is mentioned.

Among the compounds (I) which are the active ingredients of the present invention, more preferred compounds include those in the "optionally substituted nitrogen-containing heterocyclic group" represented by ring A in the general formula (I). The nitrogen-containing heterocyclic group is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group; The substituent of the “nitrogen heterocyclic group” is a group selected from a lower alkyl group, a hydroxyl-substituted lower alkyl group, a formyl group and an oxo group, wherein R ¹ is a lower alkyl group substituted with a lower alkoxy group; A group represented by NH—Q—R ³ or a group represented by the formula: —NH—R ⁴ , wherein the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is substituted by a lower alkyl group monocyclic nitrogen-containing heterocyclic group which may 5-6 membered optionally be, R ⁴ is a hydroxyl group And R ² is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom.

More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A has the formula:

Embedded image A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula:

Embedded image Wherein the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula:

Embedded image Or a non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula:

Embedded image And a compound which is an aromatic monocyclic nitrogen-containing heterocyclic group represented by

More specifically, ring A has the formula:

Embedded image R ¹ is a lower alkyl group substituted with a lower alkoxy group, a group represented by the formula: —NH—QR ³ or a group represented by the formula: —NH—R ⁴ , ³ is the formula:

Embedded image Wherein R ⁴ is a group represented by the formula:

Embedded image Wherein R ² is a group represented by the formula:

Embedded image The compound which is a group shown by these is mentioned.

Among the compounds (I) which are the active ingredients of the present invention, more preferred compounds are those in the "optionally substituted nitrogen-containing heterocyclic group" represented by ring A in the general formula (I). The nitrogen-containing heterocyclic group is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group; nitrogen substituents of the heterocyclic group "is a hydroxyl group-substituted lower alkyl group, R ¹ has the formula: a group represented by -NH-Q-R ^3, may be" optionally substituted represented by R ³ contains nitrogen heterocyclic group "is substituted by a lower alkyl group is a monocyclic nitrogen-containing heterocyclic group which may 5-6 membered, substituted by a group R ² is selected from a lower alkoxy group and a halogen atom And a phenyl group.

More specifically, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A has the formula:

Embedded image A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula:

Embedded image Wherein the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula:

Embedded image Or a non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula:

Embedded image And a compound which is an aromatic monocyclic nitrogen-containing heterocyclic group represented by

More specifically, ring A has the formula:

Embedded image Wherein R ¹ is a group represented by the formula: —NH—Q—R ³ , and R ³ is a group represented by the formula:

Embedded image Wherein R ² is a group represented by the formula:

Embedded image The compound which is a group shown by these is mentioned.

Among the compounds (I) which are the active ingredients of the present invention, particularly preferred compounds are those wherein Y has the formula: = N-
And Z is a compound of the formula: = CH-.

Among the compounds (I) which are the active ingredients of the present invention, the compounds which are preferable in terms of pharmacological effect include compounds selected from the following group or pharmacologically acceptable salts thereof. (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (6 , 7-Dihydro-5H-pyrrolo
[3,4-b] pyridin-6-yl) -4- (3-cyano-
4- (methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,
7,8-tetrahydroimidazo [1,2-a] pyrazine-7
-Yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-methoxycyclohexyl) carbamoyl] pyrimidine; 2- (6,7-dihydro-
5H-pyrrolo [3,4-b] pyridin-6-yl) -4-
(3-cyano-4-methoxybenzylamino) -5- [N
-(Trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- (6,7-dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl) -4- (3-cyano-4-methoxybenzyl Amino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; (S) -2-
(2-Hydroxymethyl-1-pyrrolidinyl) -4- (3
-Chloro-4-methoxybenzylamino) -5- [N-
(2-morpholinoethyl) carbamoyl] pyrimidine; 2
-[(2S) -2-hydroxymethyl-1-pyrrolidinyl]
-4- (3-chloro-4-methoxybenzylamino) -5
-[N-[[(2R) -4-methyl-2-morpholinyl] methyl] carbamoyl] pyrimidine; 2-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-
4-methoxybenzylamino) -5- [N-[[(2S) -4
-Methyl-2-morpholinyl] methyl] carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- ( 4-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (4-methyl-3-oxo-1-
Piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- (4-formyl-1-piperazinyl) -4- (3 -Chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2-
(5,6,7,8-Tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxy Cyclohexyl) carbamoyl] pyrimidine; 2- [cis-
2,5-bis (hydroxymethyl) -1-pyrrolidinyl]-
4- (3-chloro-4-methoxybenzylamino) -5
[N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydroimidazo [1,2-
a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydro Imidazo [1,2-a] pyrazin-7-yl)-
4- (3-chloro-4-methoxybenzylamino) -5
[N- (2-morpholinoethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-acetyl Pyrimidine; (S)-
2- (2-hydroxymethyl-1-pyrrolidinyl) -4-
(3-chloro-4-methoxybenzylamino) -5- [N
-(4-pyridazinylmethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1
-Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyridylmethyl) carbamoyl] pyrimidine; (S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-Chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-1-
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-[(2-morpholinoethyl) carbonyl] pyrimidine; 2- (pyrrolidinyl) pyrazine; (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3
-Chloro-4-methoxybenzylamino) -5- [N-
[(4-Methyl-2-morpholinyl) methyl] carbamoyl] pyrimidine; (S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine; 2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (5,6,7,8 -Tetrahydroimidazo [1,2-a] pyrazin-7-yl) pyrazine; (S)-
2- (2-hydroxymethyl-1-pyrrolidinyl) -4-
(3-chloro-4-methoxybenzylamino) -5-[(2
-Methoxyethyl) carbonyl] pyrimidine; (S) -2-
(2-Hydroxymethyl-1-pyrrolidinyl) -4- (3
-Chloro-4-methoxybenzylamino) -5- [N-
(1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof.

Among the compounds (I), which are the active ingredients of the present invention, more preferable compounds in terms of pharmacological effect include compounds selected from the following group or pharmacologically acceptable salts thereof. (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; (S)- 2- (2-hydroxymethyl-1
-Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (4-methyl-3-oxo-
1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- (4-
Formyl-1-piperazinyl) -4- (3-chloro-4-
Methoxybenzylamino) -5- [N- (trans-4-
Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a]
Pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl)
Carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4-
(3-chloro-4-methoxybenzylamino) -5- [N
-(2-morpholinoethyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl ] Pyrimidine; (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- [N- (2-pyrimidinylmethyl) carbamoyl ] -3- (3-Chloro-4-
(Methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4
-Methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-
Methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof.

Among the compounds (I) which are the active ingredients of the present invention, the other preferable compounds for the pharmacological effect include compounds selected from the following group or pharmacologically acceptable salts thereof. (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; (S)- 2- (2-hydroxymethyl-1
-Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydroimidazo [1,2 -A] pyrazin-7-yl) -4- (3-
Chloro-4-methoxybenzylamino) -5- [N- (2
-Pyrimidinylmethyl) carbamoyl] pyrimidine; 2-
(5,6,7,8-tetrahydro-1,7-naphthyridine-
7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1
-Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-Chloro-4-methoxybenzylamino) -5- [2-hydroxymethyl-
1-pyrrolidinyl] pyrazine; (S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4
-Methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-
4-methoxybenzylamino) -5- [N- (1,3,5-
Trimethyl-4-pyrazolyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof.

Among the compounds (I) which are the active ingredients of the present invention, particularly preferred compounds for the pharmacological effect include the following compounds or pharmacologically acceptable salts thereof. (S) -2
-(2-hydroxymethyl-1-pyrrolidinyl) -4-
(3-chloro-4-methoxybenzylamino) -5- [N
-(2-pyrimidinylmethyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof, and 2- (5,
6,7,8-tetrahydro-1,7-naphthyridine-7-
Yl) -4- (3-Chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl]
Pyrimidine, or a pharmaceutically acceptable salt thereof, and
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
-4- (3-chloro-4-methoxybenzylamino) -5
-[N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof.

The compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has a ring A, R ¹ and / or R ² having an asymmetric atom. Although it may exist as isomers, the present invention includes both of these optical isomers and mixtures thereof.

The compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has an excellent selective PDEV inhibitory action, so that it does not substantially show side effects such as abnormal color vision, It can be used for prevention and treatment of erectile dysfunction.

The compound (I), which is an active ingredient of the present invention, can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use. Pharmaceutically acceptable salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate or hydrobromide, acetate, fumarate,
Organic acid salts such as oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate are exemplified.

The compound (I) or a salt thereof, which is an active ingredient of the present invention, includes any of internal salts and adducts, solvates and hydrates thereof.

The compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, can be administered orally or parenterally, and can be administered in the form of tablets, granules and fine granules. , Pills, capsules, powders, injections, inhalants, buccal preparations, sublingual preparations, syrups, dry syrups, jellies, suppositories, ointments, elixirs, liniments, lotions, drinks, It can be used as a conventional pharmaceutical preparation such as a nasal preparation, a transdermal preparation, and a rapidly disintegrating preparation in the oral cavity.
These pharmaceutical formulations contain pharmaceutically acceptable excipients, binders,
It is prepared by formulating in a conventional manner together with additives such as a wetting agent, a disintegrating agent and a bulking agent.

The dose of compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, varies depending on the administration method, age, weight, and condition of the patient. Usually about 0.001 to 100 mg / kg per day,
In particular, it is preferably about 0.1 to 10 mg / kg, and in the case of an oral preparation, usually about 0.1 to 200 mg / kg, particularly about 0.1 to 80 mg / kg per day.

The compound (I) which is the active ingredient of the present invention
Or a pharmacologically acceptable salt thereof is an excellent selective PD
Since it has an EV inhibitory action, in addition to erectile dysfunction as described above, various diseases caused by dysfunction of cGMP signaling (eg, pulmonary hypertension, diabetic gastroparesis, hypertension, angina pectoris, myocardial infarction) , Chronic and acute heart failure, female sexual dysfunction, prostatic hypertrophy, asthma, diarrhea, constipation, achalasia, etc.).

Compound (I) as an active ingredient of the present invention can be produced by the following [Method A] to [Method F].

[Method A] Compound (I) which is the active ingredient of the present invention
Wherein R ¹ is a group represented by the formula: —NH—Q—R ³ or —NH—R ⁴ , that is, a compound represented by the general formula (Ia):

Embedded image (Where R ¹¹ represents a group represented by the formula: —NH—Q—R ³ or —NH—R ⁴ , and other symbols have the same meanings as described above), and the compound represented by the general formula (II)

Embedded image (Provided that X ¹ is a halogen atom, R ⁵ is a protecting group for a carboxyl group, R ⁹ is an optionally substituted lower alkyl group or an optionally substituted aryl group, and other symbols are as defined above.) And a compound represented by the general formula (II)
I) reacting with a compound represented by R ² —CH ₂ —NH ₂ (III) (wherein the symbols have the same meanings as described above) to obtain a general formula (IV)

Embedded image (Wherein the symbols have the same meanings as above) by oxidizing the compound represented by the general formula (V)

Embedded image (Where n represents 1 or 2, and the other symbols have the same meanings as described above).
A compound represented by the general formula (VI):

Embedded image (Wherein the symbols have the same meanings as described above) or a salt thereof, and reacted with a compound of the general formula (VII)

Embedded image (Wherein the symbols have the same meanings as described above), and then the carboxyl-protecting group R ⁵ is removed to form a compound of the general formula (VIII)

Embedded image (Provided that the symbols have the same meanings as described above), and further represented by the general formula (IX-a) R ¹¹ -H (IX-a) (where R ¹¹ has the same meaning as described above) By reacting with the compound to be prepared.

Compound (Ia) is compound (VII)
I) is halogenated to form a compound of the general formula (X)

Embedded image (Where X ² represents a halogen atom, and other symbols have the same meanings as described above).
It can also be produced by reacting with (IX-a).

The compound (VII) has the general formula (X
I)

Embedded image (Wherein X ³ and X ⁴ represent a halogen atom, and other symbols have the same meanings as described above), and the resulting dihalogeno compound is treated with carbon dioxide to obtain a general formula (XII)

Embedded image (Wherein the symbols have the same meanings as described above) by protecting the carboxyl group of the compound represented by the general formula (XIII)

Embedded image (Wherein the symbols have the same meanings as described above), and then reacted with compound (III) to obtain a compound of the general formula (X
IV)

Embedded image (Provided that the symbols have the same meanings as described above), and the compound (VI) can be further produced.

The compound (XIV) is a compound (V)
Is obtained by hydrolysis of the general formula (XV)

Embedded image (Wherein the symbols have the same meanings as described above).

[Method B] Compound (I) which is the active ingredient of the present invention
Wherein R ¹ is a lower alkyl group which may be substituted, that is, a compound represented by the general formula (Ib):

Embedded image (Wherein R ¹² represents a lower alkyl group which may be substituted, and other symbols have the same meanings as described above). The compound represented by the general formula (X
VI)

Embedded image (Wherein the symbols have the same meanings as described above) by oxidizing the compound represented by the general formula (XVII)

Embedded image (Wherein the symbols have the same meanings as described above), and further oxidized to formula (XVIII)

Embedded image (Wherein the symbols have the same meanings as described above), and then reacted with compound (VI) to obtain a compound of the general formula (XI
X)

Embedded image (Wherein the symbols have the same meanings as described above), and a compound represented by the general formula (IX-b) R ¹² -H (IX-b) (where R ¹² has the same meanings as described above) Reacting with a metal salt of the compound represented by the general formula (XX)

Embedded image (Where the symbols have the same meanings as described above), and then can be produced by oxidation.

Compound (I) which is an active ingredient of the present invention
Among them, the group R ¹ is a lower alkoxy-substituted ethyl group, a morpholino-substituted ethyl group, a 4-lower alkylpiperazinyl-substituted ethyl group, a 3-pyridylamino-substituted ethyl group,
A compound which is a 2-pyridyl lower alkylamino group-substituted ethyl group, a di-lower alkylaminoethyl group or a hydroxyethyl group, that is, a compound represented by the general formula (Ic):

Embedded image (However, R ⁶ represents a lower alkoxy group, a morpholino group, a 4-lower alkylpiperazinyl group, a 3-pyridylamino group,
-Represents a pyrimidyl lower alkylamino group, a di-lower alkylamino group or a hydroxyl group, and the other symbols have the same meanings as described above) .The compound represented by the formula (XIX) and the formula CH ₂ ＣＨCHMgBr (XXI) General formula (XXII) obtained by reacting with a Grignard compound

Embedded image (Wherein the symbols have the same meanings as described above) to oxidize the compound represented by the general formula (XXIII)

Embedded image (Wherein the symbols have the same meanings as described above), and further reacted with a compound represented by the general formula (XXIV) R ⁶ -H (XXIV) (where the symbols have the same meanings as described above). It can also be manufactured by the following.

[Method C] The compound (Ia) is obtained by removing the carboxyl-protecting group R ⁵ of the compound (IV) by the general formula
(XXV)

Embedded image (Provided that the symbols have the same meanings as described above) and the compound (IX-a) to react with the compound represented by the general formula (XXVI)
-A)

Embedded image Wherein the symbols have the same meanings as described above, and further oxidized to give a compound of the general formula (XXVII-a)

Embedded image (Provided that the symbols have the same meanings as described above), and then reacted with compound (VI).

[Method D] Compound (Ib) was prepared from compound (XVI)
General formula (XXVIII) obtained by reacting I) with a metal salt of compound (IX-b)

Embedded image (Wherein the symbols have the same meanings as described above), and oxidized to give a compound of the general formula (XXVI-b)

Embedded image Wherein the symbols have the same meanings as described above, and further oxidized to give a compound of the general formula (XXVII-b)

Embedded image (Provided that the symbols have the same meanings as described above), and then reacted with compound (VI).

[Method E] The compound (Ib) comprises a dihalogeno compound (XI) and a compound represented by the general formula (XXIX) R ¹² -CHO (XXIX) (wherein the symbols have the same meanings as described above). General formula (XXX) obtained by reacting

Embedded image Wherein the symbols have the same meanings as described above, are oxidized to give a compound of the general formula (XXXI)

Embedded image (Wherein the symbols have the same meanings as described above), which is reacted with compound (III) to give a compound of the general formula
(XXXII)

Embedded image (Provided that the symbols have the same meanings as described above), and the compound (VI) is further reacted to produce the compound.

The compound (XXXII) is a compound
(XXX) is reacted with compound (III) to obtain a compound of the general formula (XXXIII)

Embedded image (However, the symbols have the same meanings as described above).

[Method F] Compound (Ia) was prepared from compound (XII)
I) and a compound represented by the general formula (XXXIV) RSH (XXXIV) (where R represents a lower alkyl group which may be substituted or an aryl group which may be substituted) XXXV)

Embedded image (Wherein the symbols have the same meanings as described above), and then reacted with compound (VI) or a salt thereof to obtain a compound of the general formula (XXXVI)

Embedded image (Wherein the symbols have the same meanings as described above), and then the carboxyl-protecting group R ⁵ is removed to form a compound of the general formula (XXXVII)

Embedded image (Wherein the symbols have the same meanings as described above), and further reacted with compound (IX-a) to obtain a compound of the general formula
(XXXIX)

Embedded image (Where the symbols have the same meanings as described above), and then oxidized to a sulfonyl or sulfinyl compound, followed by reaction with compound (III).

The above [Method A] to [Method F] can be carried out as follows.

[Method A] The reaction between compound (II) and compound (III) can be carried out in a solvent in the presence or absence of a deoxidizing agent. As the deoxidizing agent, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate, and sodium hydrogencarbonate are preferably used. it can. As the solvent, dimethyl sulfoxide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane,
Any solvent that does not inhibit the reaction, such as xylene and N, N-dimethylformamide, can be suitably used.
The present reaction suitably proceeds at -10 ° C to room temperature, particularly at 0 ° C to room temperature.

The reaction of oxidizing compound (IV) to give sulfonyl (or sulfinyl) compound (V) can be carried out in a solvent in the presence of an oxidizing agent. As oxidizing agents,
Peracids such as m-chloroperbenzoic acid and peracetic acid, manganese dioxide, sodium periodate, hydrogen peroxide, nitrous oxide, halogen, hydroperoxide, iodobenzene acetate, t-butyl hypochlorite, sulfuryl chloride And an inorganic oxidizing agent such as potassium peroxymonosulfate can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, methylene chloride, dichloroethane, and acetic acid, can be used as appropriate. The reaction is carried out at −78 ° C. to 50
C., especially at -10 to 10 C.

The reaction of compound (V) with compound (VI) or a salt thereof can be carried out in a solvent in the presence or absence of a deoxidizing agent. As the deoxidizing agent, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate, and sodium hydrogencarbonate are preferably used. it can. Compound
As the salt of (VI), an alkali metal salt such as a sodium salt and a potassium salt can be suitably used. As the solvent, any solvent that does not inhibit the reaction, such as N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane, and dimethylsulfoxide, can be suitably used. This reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 60 ° C.

Protecting group for carboxyl group of compound (VII)
R^FiveTo give compound (VIII)
A method generally used depending on the type of the protecting group for the sil group (additional method)
(Hydrolysis, catalytic reduction, etc.)
When the protecting group of the carboxyl group is eliminated by decomposition
Can be carried out, for example, in a solvent in the presence of a base.
Wear. As the base, sodium hydroxide, potassium hydroxide
Alkali metal hydroxides such as lithium hydroxide
Preferred are alkali metal carbonates such as thorium and potassium carbonate.
It can be used appropriately. As the solvent, water or methano
, Ethanol, tetrahydrofuran, dioxane,
N, N-dimethylformamide, dimethyl sulfoxide
And a mixed solvent of water and the like can be used as appropriate. Main reaction
Preferably proceeds at 0 to 80 ° C, particularly at 5 to 60 ° C.
You. The carboxyl protecting group R ^FiveAs a low grade
Alkaline groups, benzyl groups, etc.
A protecting group for a ruboxyl group can be used.

The reaction between compound (VIII) and compound (IX-a) can be carried out in a suitable solvent in the presence or absence of a condensing agent, a base or an activating agent. As the condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, diethylcyanophosphonate, and the like generally used in peptide synthesis can be suitably used. As the base, triethylamine,
An organic base such as N-methylmorpholine and a activating agent such as 1-hydroxybenzotriazole can be suitably used. As the solvent, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide,
Any solvent that does not inhibit the reaction, such as ethyl acetate, can be suitably used. The present reaction suitably proceeds at −30 to 50 ° C., particularly at −10 to 10 ° C.

As another method, compound (VIII) is converted into compound (X), and then compound (IX-a) is reacted with compound (VIII). Is reacted with a halogenating agent in the presence or absence of a compound (X), and then the compound (IX-a) is reacted.
The reaction of compound (VIII) with a halogenating agent can be carried out in a solvent. As the halogenating agent, for example, thionyl chloride, oxalyl chloride, phosphorus pentachloride and the like can be suitably used. As an activator,
Amide compounds such as N, N-dimethylformamide can be suitably used. As the solvent, methylene chloride,
Any solvent that does not inhibit the reaction, such as chloroform, tetrahydrofuran, benzene, toluene and dioxane, can be suitably used. The reaction is carried out at -30 to 100
C., especially at -5 to 10C.

The subsequent reaction with the compound (IX-a)
It can be carried out in a solvent in the presence of a deoxidizing agent. N, N-diisopropylethylamine, N
Organic bases such as methylmorpholine, triethylamine, pyridine and dimethylaminopyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium hydrogencarbonate can be suitably used. As the solvent, any solvent that does not inhibit the reaction, such as tetrahydrofuran, methylene chloride, chloroform, toluene, benzene, dioxane, and ethyl acetate, can be suitably used. The reaction is carried out at -30 to 100 ° C, especially at -5 to
Proceeds favorably at 10 ° C.

The reaction of treating the dihalogeno compound (XI) with carbon dioxide to obtain the compound (XII) can be carried out in a solvent in the presence of a base. As the base, lithium diisopropylamide, lithium 2,2,6,6-
An alkali metal salt of an organic base such as tetramethylpiperidide can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, or the like can be used as appropriate. This reaction suitably proceeds at -100 ° C to -30 ° C, particularly at -100 ° C to -70 ° C.

The reaction for obtaining the compound (XIII) by protecting the carboxyl group of the compound (XII) can be carried out by a conventional method. For example, when the protecting group is a lower alkyl group, the reaction of a base and a solvent may be carried out. It can be carried out by reacting with an alkylating agent in the presence. As the alkylating agent, a lower alkyl halide such as methyl iodide can be suitably used. As the base, an alkali metal bicarbonate such as sodium bicarbonate, and as the solvent,
Solvents that do not inhibit the reaction, such as N, N-dimethylformamide and tetrahydrofuran, can be suitably used. The reaction is carried out at 0 ° C to 100 ° C, especially at room temperature to 70 ° C.
The process proceeds favorably.

The reaction of reacting compound (XIII) with compound (III) to give compound (XIV) can be carried out in the same manner as in the reaction of compound (II) with compound (III). Compound (XIV) is reacted with compound (VI) to give compound (VII)
Can be carried out in the same manner as in the reaction of compound (V) with compound (VI).

The compound (V) is hydrolyzed to give a compound
The reaction for obtaining (XV) can be carried out in a solvent in the presence of a base. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate can be suitably used. As the solvent, water or a mixed solvent of methanol, ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethylsulfoxide, and the like and water can be used as appropriate. The reaction is carried out at -20 to 80 ° C, especially at -5 to 60 ° C.
The process proceeds favorably.

Compound (XV) is halogenated to give compound (X
The reaction for obtaining compound (IV) can be carried out in the same manner as the reaction for obtaining compound (X) by halogenating compound (VIII) with a halogenating agent.

[Method B] The compound (X) is obtained by reducing the compound (IV).
The reaction leading to VI) can be carried out in a suitable solvent in the presence of a reducing agent. As the reducing agent, an alkali metal aluminum hydride such as lithium aluminum hydride, an alkali metal borohydride such as lithium borohydride, or the like can be suitably used. As the solvent, tetrahydrofuran, dioxane, diethyl ether,
A solvent that does not inhibit the reaction, such as dimethoxyethane, can be suitably used. The present reaction suitably proceeds at -78 ° C to the boiling point of the solvent used, particularly at -10 ° C to room temperature.

Compound (XVI) is oxidized to give compound (XVI
The reaction leading to I) can be carried out in a solvent in the presence of an oxidizing agent. The oxidizing agent is not particularly limited as long as it can induce an alcohol to the corresponding carbonyl compound. For example, manganese dioxide, barium permanganate, potassium permanganate, 2,3-dichloro-5,6-
Dicyano-1,4-benzoquinone, pyridinium chlorochromate, pyridinium dichromate and the like can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, toluene, ethyl acetate, 1,2-dichloroethane, methylene chloride, and tetrahydrofuran, can be used as appropriate. This reaction is carried out at 0 ° C to 100 ° C,
In particular, it proceeds favorably at room temperature to 70 ° C.

Compound (XVII) is oxidized to give compound (XV
The reaction leading to III) is by oxidizing compound (IV)
The reaction can be carried out in the same manner as in the reaction leading to (V).

Compound (XVIII) is reacted with compound (VI) to give compound (XIX).
The reaction can be carried out in the same manner as in the reaction (VI).

The reaction leading to the compound (XX) by reacting the compound (XIX) with the metal salt of the compound (IX-b) can be carried out in a suitable solvent. As the metal salt of the compound (IX-b), a lithium salt or the like can be preferably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, dioxane, diethyl ether, and dimethoxyethane, can be used as appropriate. The reaction is carried out at −78 ° C.
Proceeds favorably at room temperature.

In the reaction for oxidizing compound (XX) to give compound (Ib), compound (XVI) is oxidized to compound (XVI)
It can be carried out analogously to the reaction leading to I).

The reaction between compound (XIX) and Grignard compound (XXI) can be carried out in a suitable solvent. As the solvent, tetrahydrofuran, dioxane, diethyl ether and the like can be suitably used.
This reaction suitably proceeds at −78 ° C. to 60 ° C., particularly at −78 ° C. to room temperature.

The compound (XXII) is oxidized to give the compound (XX)
The reaction leading to III) can be carried out in the same manner as the reaction leading to compound (XVII) by oxidizing compound (XVI).

The compound (XXIII) is reacted with a compound (XXIV) wherein R ⁶ is a morpholino group, a 4-lower alkylpiperazinyl group, a 3-pyridylamino group, a 2-pyrimidinyl lower alkylamino group or a di-lower alkylamino group. The reaction for obtaining a compound (I-c) wherein R ⁶ is a morpholino group, a 4-lower alkylpiperazinyl group, a 3-pyridylamino group, a 2-pyrimidinyl lower alkylamino group or a di-lower alkylamino group is carried out in the presence of a base. It can be carried out in a suitable solvent in the absence or in the absence. As the base, organic bases such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium hydrogencarbonate can be suitably used. As the solvent, any of ethanol, N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane, dimethylsulfoxide and the like can be suitably used. This reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 60 ° C.

[0074] On the other hand, the compound (XXIII) to the compound R ⁶ is reacted compounds R ⁶ is a hydroxyl group or a lower alkoxy group and (XXIV) is a hydroxyl group or a lower alkoxy group (XX
The reaction leading to I) can be carried out in the presence of an acid, without solvent or in a suitable solvent. As the acid, inorganic acids such as sulfuric acid and methanesulfonic acid, camphorsulfonic acid,
Organic acids such as toluenesulfonic acid and benzenesulfonic acid can be suitably used. As the solvent, any of diethyl ether, toluene, benzene, N, N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide and the like can be suitably used. The reaction is carried out between 0 and 1
It proceeds suitably at 50 ° C, especially at room temperature to 60 ° C.

[Method C] The reaction of removing the carboxyl-protecting group R ⁵ of the compound (IV) to give the compound (XXV)
Compound (VII) obtained by removing carboxyl protecting group R ⁵
The reaction can be carried out in the same manner as in the reaction for obtaining (VIII).

Compound (XXV) is reacted with compound (IX-a) to give compound (XXVI-a).
The reaction can be carried out in the same manner as in the reaction of II) with compound (IX-a).

Compound (XXVI-a) is oxidized to give compound
The reaction leading to (XXVII-a) can be carried out in the same manner as the reaction leading to the oxidation of compound (IV) to give compound (V).

The reaction of reacting compound (XXVII-a) with compound (VI) to give compound (Ia) which is an active ingredient of the present invention is carried out in the same manner as in the reaction of compound (V) with compound (VI). Can be implemented.

[Method D] Compound (IX-VII) was added to compound (IX-
The reaction of reacting the metal salt of b) to give the compound (XXVIII) can be carried out in the same manner as in the reaction of the compound (XIX) with the metal salt of the compound (IX-b).

Compound (XXVIII) is oxidized to give compound
The reaction leading to (XXVI-b) can be carried out in the same manner as the reaction leading to the compound (XVII) by oxidizing compound (XVI).

Compound (XXVI-b) is oxidized to give compound
After converting to (XXVII-b), the reaction leading to compound (Ib), which is the active ingredient of the present invention, comprises oxidizing compound (XXVI-a) to convert to compound (XXVII-a), The reaction can be carried out in the same manner as in the reaction leading to compound (Ia) as an active ingredient.

[Method E] The reaction of reacting compound (XXIX) with compound (XXIX) to give compound (XXX) is carried out in the presence of a base.
It can be carried out in a suitable solvent. As the base,
Lithium diisopropylamide, lithium 2,2,6,6
-An alkali metal salt of an organic base such as tetramethylpiperidide can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, or the like can be used as appropriate. This reaction suitably proceeds at -100 ° C to -30 ° C, particularly at -100 ° C to -70 ° C.

The compound (XXX) is oxidized to give the compound (XXX)
The reaction leading to I) can be carried out in the same manner as the reaction leading to compound (XVII) by oxidizing compound (XVI).

The compound (XXXI) is reacted with compound (III) to give compound (XXXII).
The reaction can be carried out in the same manner as in the reaction of (II) with compound (III).

Further, compound (XXXII) was added to compound (V
The reaction which leads to the compound (Ib) which is an active ingredient of the present invention by reacting the compound (I) or a salt thereof comprises the compound (V) and the compound (V
The reaction can be carried out in the same manner as in the reaction of I).

The reaction of reacting compound (XXX) with compound (III) to give compound (XXXIII) can be carried out in the same manner as in the reaction of compound (II) with compound (III). In addition, the reaction of oxidizing compound (XXXIII) to give compound (XXXII) can be carried out in the same manner as the reaction of oxidizing compound (XVI) to give compound (XVII).

[Method F] Compound (XIII) and compound (XXX)
The reaction with IV) can be carried out in a solvent in the presence or absence of a deoxidizing agent. N, N-
Diisopropylethylamine, N-methylmorpholine,
Organic bases such as triethylamine and pyridine, and inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate and sodium hydrogencarbonate can be suitably used. As the solvent, any solvent which does not inhibit the reaction, such as N, N-dimethylformamide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane, xylene, N, N-dimethylformamide, can be suitably used. The present reaction suitably proceeds at -10 ° C to room temperature, particularly at 0 ° C to room temperature.

The reaction of compound (XXXV) with compound (VI) or a salt thereof can be carried out in the same manner as in the reaction of compound (V) with compound (VI).

In the reaction for removing the carboxyl-protecting group R ⁵ of the compound (XXXVI) to give the compound (XXXVII), the compound (VIII) is obtained by removing the carboxyl-protecting group R ⁵ of the compound (VII). The reaction can be carried out in the same manner as in the reaction.

Compound (XXXVII) and compound (IX-a)
Can be carried out in the same manner as in the reaction of compound (VIII) with compound (IX-a).

The oxidation reaction of the compound (XXXIX)
The reaction can be carried out in the same manner as in the reaction from (IV) to (V), and m-chloroperbenzoic acid or the like can be suitably used as the oxidizing agent. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, methylene chloride, dichloroethane, and acetic acid, can be used as appropriate. This reaction suitably proceeds at −78 ° C. to 50 ° C., particularly at −10 ° C. to 10 ° C.

The subsequent reaction with compound (III) can be carried out in the same manner as in the reaction of compound (II) with compound (III).

The compound (I) thus obtained can be converted into a pharmaceutically acceptable salt thereof, if desired.

The starting compound (II) can be prepared, for example, from Journal of American Chemical Society,
It can be produced according to the method described on page 350, volume 65, 1943.

[0095]

[Experimental example] Experimental example 1 (PDE V inhibitory action) (Preparation method of PDE V) The supernatant obtained by centrifuging the lung homogenate isolated from a hybrid male dog was fractionated by anion exchange column chromatography. And the following 1. ~
5. The fractions satisfying all of the above conditions were mixed to obtain a partially purified preparation of PDEV. 1. 1. Selectively hydrolyzing cGMP. 2. Its cGMP degradation activity is not affected by EGTA or calmodulin. 3. Not inhibited by PDE III selective inhibitor CI930. Rolipram (Ro), a PDE IV selective inhibitor
lipram). 5. Inhibition by P-40V selective inhibitor E-4021

Here, EGTA is represented by the formula [xv]

Embedded image And inhibits the activity of PDE I by chelating calcium from an enzyme solution.

CI930 is represented by the formula [xvi]

Embedded image Is a PDE III selective inhibitor represented by PDE
It is used to confirm that PDE III is not mixed in the enzyme solution of V.

Rolipram is represented by the formula [xvii]

Embedded image Is a PDE IV selective inhibitor represented by PDE
It is used to confirm that PDEIV is not mixed in the enzyme solution of V.

E-4021 is represented by the formula [xviii]

Embedded image Is a PDEV selective inhibitor represented by

(Measurement of PDEV Activity) The method of Thompson et al. (Advanced in Cyclic Nucleotide Research [Advances in Cyclic]
Nucleotide Research], 10 volumes,
Raven Press, New York, pp. 69-92, 197
9 years) with some modifications. That is, 50 mM T
100 μl of a partially purified preparation of PDEV V diluted with ris-HCl, pH 8.0 to hydrolyze about 10% of the total substrate
Was added to a glass test tube. The test tube was filled with a reaction buffer solution (50 mM Tris-HCl, pH 8.0, 12.
200 μl of 5 mM MgCl 2, 10 mM 2-mercaptoethanol) was added, and the sample was dissolved in dimethyl sulfoxide (the compound obtained in the following Production Example) (10
(0-fold concentration) was added. After pre-incubating this solution at 37 ° C. for 5 minutes, 2.5 μM [3H] cG
200 μl of MP (3.7 kBq / 200 μl) was added,
The reaction was started (final concentration 50 mM Tris-HCl,
pH 8.0, 5 mM MgCl2, 4 mM 2-mercaptoethanol). After reaction at 37 ° C. for 30 minutes, the test tube was transferred into a boiling water bath to stop the reaction. After 90 seconds, the test tube was transferred into an ice water bath, and the temperature of the reaction solution was lowered to room temperature. After preincubation at 37 ° C. for 5 minutes, 100 μl of a 1 mg / ml snake venom aqueous solution was added to the test tube.
The reaction was performed at 30 ° C. for 30 minutes. 500 methanol in the test tube
After the reaction was stopped by adding μl, 1 m of the reaction solution was added to a column to which 200 μl of Dowex resin (trade name: Dowex 1 × 8, manufactured by Sigma) had been added in advance.
1 was provided. Subsequently, the resin was washed by adding 1 ml of methanol. The reaction solution passed through the column and the washing solution were combined, and [3H] guanosine (Guanos) in the solution was combined.
Ine) radioactivity was measured to determine PDEV inhibition activity.

The blank in which only the buffer solution was added without adding the enzyme standard was used as a blank, and the enzyme standard was added but in which only dimethyl sulfoxide was added instead of the sample solution was used as a control. Calculated. The PDEV inhibition activity was evaluated by IC50 (concentration at which the inhibition rate of each sample with respect to the control was 50%; nM). Here, the IC50 value of each sample was calculated by determining the inhibition rate at three or more sample concentrations and performing linear regression (liner regression).

The results are shown in Table 1 below.

[0103]

[Table 1]

[0104]

[Table 2]

[0105]

[Table 3]

[0106]

[Table 4]

[0107]

[Table 5]

[0108]

[Table 6]

Experimental Example 2 (Rabbit isolated cavernous body relaxing action) (Preparation of specimen) Male rabbits 10-20 weeks old (New Zealand W
hite system). After anesthesia, the animals were exsanguinated and killed, and the corpus cavernosum was immediately excised, and the connective tissue was removed to prepare a strip specimen about 5 mm in length. The specimen was suspended in a Magnus tube filled with 10 ml of nutrient solution with a static tension of about 1.5 g, and the tension of the specimen was stabilized for about 60 minutes. High concentration KCl (120mM)
After confirming the shrinkage reaction of the sample by, it was used for the experiment. The nutrient solution during the experiment was aerated with 95% O ₂ , 5% CO ₂ mixed gas.
Maintained at ± 0.5 ° C. Isometric tension was measured via a U gauge and strain amplifier (AP600 series, Nihon Kohden) and recorded on a pen writing recorder (GRAPHTEC MULTICORDER MC6621). Nutrient solution composition (mM): NaCl 118.0, KCl 4.7, CaCl ₂ 1.
5, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, NaHCO ₃ 25.0, glucose 11.
0, EDTA 0.023

(Relaxation Action in Phenylephrine-Contracted Specimen) After the specimen was contracted by phenylephrine (5 μM) to enter the continuous phase, the specimen was subjected to 0.1, 1, 10, 100, 1000 nM and 30 nM.
Cumulative additions were made at minute intervals. Finally, papaverine (100μM)
Was added to confirm the maximum relaxation response of the sample. The magnitude of relaxation at each concentration depends on the relaxation by papaverine (100 μM).
Calculated as 100%. The concentration of the sample that exhibits a 30% relaxation action
It was calculated as EC ₃₀ (nM), and the relaxing action of the specimen was evaluated.

The results are shown in Table 2 below.

[0112]

[Table 7]

[0113]

Production Examples Specific examples (production examples) of compound (I), which is an active ingredient of the present invention, synthesized by the above exemplified methods are shown below, but the invention is not limited thereto.

Production Example 1 (1) 3-chloro-4-methoxybenzylamine was added to a solution of 25.33 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine in 85 ml of N, N-dimethylformamide under ice cooling. A solution of 62 g of N, N-dimethylformamide in 15 ml and triethylamine in 16.7 ml
Add. After stirring at room temperature for 20 minutes, 940 mg of 3-chloro-4-methoxybenzylamine is added, and the mixture is stirred for 15 minutes. Then, 940 mg of the amine is further added and stirred for 15 minutes. The reaction mixture was poured into an ice water-citric acid mixture, extracted with ethyl acetate, washed with a 10% aqueous citric acid solution, water and brine in that order,
Dry over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure,
The residue was washed with n-hexane and 4- (3-chloro-4-
(Methoxybenzylamino) -5-ethoxycarbonyl-
38.34 g of 2-methylthiopyrimidine are obtained. Melting point:
86 ° C.

(2) 5.00 g of the compound obtained in the above (1)
To a 50 ml solution of chloroform in 50 ml of a chloroform solution was added 4.00 g of m-chloroperbenzoic acid under ice cooling.
Stir for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 4- (3-chloro-
A crude product of 4-methoxybenzylamino) -5-ethoxycarbonyl-2-methylsulfinylpyrimidine is obtained. MS (m / z): 447 (MH ^<+> ).

(3) The crude product obtained in the above (2) is dissolved in 40 ml of tetrahydrofuran, and a solution of 1.50 g of L-prolinol and 1.60 g of triethylamine in 10 ml of tetrahydrofuran is added at room temperature. After stirring overnight, the reaction mixture is diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and brine, and then the organic layer is dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform), crystallized from ether-n-hexane, and treated with (S) -4- (3-chloro-4-methoxybenzylamino). 4.72 g of -5-ethoxycarbonyl-2- (2-hydroxymethyl-1-pyrrolidinyl) pyrimidine are obtained. Melting point: 88-90
° C. MS (m / z): 421 (MH ^<+> ).

(4) 3.4 g of the compound obtained in the above (3),
23 ml of a 10% aqueous sodium hydroxide solution and 34 ml of dimethyl sulfoxide are stirred at room temperature for 15 hours. The reaction mixture was poured into a 10% aqueous citric acid solution, and the precipitate was crystallized from tetrahydrofuran-ether to give (S) -4-
2.52 g of (3-chloro-4-methoxybenzylamino) -5-carboxy-2- (2-hydroxymethyl-1-pyrrolidinyl) pyrimidine are obtained. Melting point: 205-208
° C. MS (m / z): 391 (M-H) ^- .

(5) Compound 600m obtained in the above (4)
g, 2-aminomethylpyrimidine 217 mg, 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (323 mg), 1-hydroxybenztriazole monohydrate (227 mg) and N, N-dimethylformamide (12 ml) were stirred at room temperature for 8 hours, and the reaction mixture was treated with hydrogen carbonate. Pour into aqueous sodium solution. Extract with ethyl acetate, wash with brine and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: chloroform: methanol =
50: 1), and purified by (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidylmethyl)
610 mg of carbamoyl] pyrimidine are obtained. Melting point: 1
60-163 ° C.

Production Example 2 (1) To a suspension of 4.15 g of lithium aluminum hydride in 150 ml of tetrahydrofuran was added 2-methylthio-4-.
A solution of 38.32 g of (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine in 100 ml of tetrahydrofuran is added over 1 hour at 5 to 10 ° C under ice cooling. After the addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for 1 hour. 4.15 ml of water was added to the reaction mixture under ice-cooling, and then 4.15 ml of a 3N aqueous sodium hydroxide solution.
Add ml. 4.15 ml of water are added to the mixture three times and stirred at room temperature for 1 hour. After treating the reaction mixture with magnesium sulfate, the precipitated solid is separated by filtration and the solid is washed with tetrahydrofuran. The combined filtrate and washings are concentrated under reduced pressure and triturated with ethyl acetate-isopropyl ether. The obtained crystals are collected by filtration and sufficiently washed with isopropyl ether to give a pale yellow crystalline powder of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5.
Obtaining hydroxymethylpyrimidine. 1st generation; yield: 25.10 g, melting point: 162-16
2nd generation at 3 ° C .; yield: 2.32 g, melting point: 159-160
C. Further, the precipitated solid was washed again with isopropyl ether, and the filtrate was concentrated under reduced pressure to obtain a colorless crystal. The obtained solid was suspended in isopropyl ether, filtered, and the precipitate was sufficiently washed with isopropyl ether and hexane to obtain 4.26 g of colorless crystalline 2-methylthio-4- (3-chloro-4-methoxybenzyl). (Amino) -5-hydroxymethylpyrimidine is obtained. Melting point: 161-162 [deg.] C.

(2) 2-methylthio- obtained in the above (1)
4- (3-chloro-4-methoxybenzylamino) -5
To a suspension of 25.10 g of hydroxymethylpyrimidine in 150 ml of chloroform is added 37.6 g of manganese dioxide powder and the reaction mixture is stirred vigorously at room temperature for 1 day. Further, 12.6 g of manganese dioxide powder (0.5 times the amount of the starting compound)
And stir for 3 nights. The insolubles were quickly removed by filtration through Celite, the filtrate was concentrated under reduced pressure, and the residue was concentrated in ethyl acetate.
Suspend in isopropyl ether. The precipitate was filtered and washed sequentially with isopropyl ether and hexane to give colorless crystalline 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine (22.43 g)
Get. Melting point: 124-125 [deg.] C.

(3) 2-methylthio-4- (3-chloro-
A solution of 2.057 g of 4-methoxybenzylamino) -5-formylpyrimidine in 20 ml of chloroform is treated with 1.468 g of m-chloroperbenzoic acid (80%) at 0 ° C. for 30 minutes. 0.901 L-prolinol was added to the reaction mixture.
g, and then 1.33 ml of triethylamine was added.
And react for 1 hour. The reaction mixture was warmed to room temperature, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, and the precipitate was removed by filtration through a silica plug. The filtrate was concentrated under reduced pressure to give a colorless amorphous (S) -2- (2-
1.9990 g of hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine are obtained. MS (m / z): 377 (M
H ⁺ ).

(4) (S) -2- (2-hydroxymethyl-
To a solution of 91.0 mg of 1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine in 20 ml of tetrahydrofuran was added 1.1 ml (1.10 M) of a methyllithium ether solution at -78 ° C. After reacting for 10 minutes, an aqueous solution of sodium hydrogen carbonate is added.
The reaction mixture was extracted with ethyl acetate to give (S) -2-
(2-Hydroxymethyl-1-pyrrolidinyl) -4- (3
A crude product of -chloro-4-methoxybenzylamino) -5- (1-hydroxyethyl) pyrimidine was obtained. MS (m /
z): 393 (MH ^<+> ).

(5) The crude product obtained in the above (4) is treated at room temperature with 0.5 g of manganese dioxide, and the mixture is stirred overnight. The reaction mixture was heated under reflux for 5 hours, insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (solvent: chloroform: ethyl acetate =
3: 1) and purified as a colorless oil (S)-(2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-acetylpyrimidine 56.
7 mg are obtained. MS (m / z): 391 (MH ^<+> ).

Production Example 3 (1) A solution of 84 mg of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine in about 1 ml of tetrahydrofuran , A 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran was added dropwise while cooling on a dry ice-acetone bath. The reaction mixture was cooled to -78 ° C.
For 10 minutes and then at room temperature for 10 minutes. The reaction mixture is poured into ice-saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product is subjected to preparative thin-layer chromatography.
(Solvent; ethyl acetate: methanol = 20: 1),
(S) -2- (2-hydroxymethyl-1-) as a colorless oil
(Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (1-hydroxy-2-propene-1-
Il) 30 mg of pyrimidine are obtained. MS (m / z): 405
(MH ⁺ ).

(2) (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (1-hydroxy-2-propene-
1-yl) pyrimidine 144 mg of chloroform 2.5 m
To this solution, 432 mg of manganese dioxide is added and stirred vigorously at room temperature for three nights. The insolubles were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 124 mg of a pale yellow oil.
The obtained crude product was purified by silica gel column chromatography (silica gel 20 g, solvent; chloroform: ethyl acetate = 2: 1) to give colorless crystals of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl). -4- (3-chloro-4-methoxybenzylamino) -5- (acryloyl)
Obtain 90 mg of pyrimidine. Melting point: 113-115 [deg.] C.
MS (m / z): 403 (MH ^<+> ).

(3) (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- (acryloyl) pyrimidine 72 m
g of ethanol in 2 ml of solution at room temperature
Is added and the mixture is stirred at room temperature for 40 minutes. The reaction mixture is concentrated under reduced pressure, the residue is poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give (S)-
2- (2-hydroxymethyl-1-pyrrolidinyl) -4-
(3-chloro-4-methoxybenzylamino) -5-[(2
-Morpholinoethyl) carbonyl] pyrimidine (91 mg) is obtained.

The obtained crude product is dissolved in 10 ml of ethyl acetate, and the solution is treated with 5 ml of a saturated solution of hydrochloric acid / methanol and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered, and the obtained solid was sufficiently washed with hexane to give (S)
-2- (2-hydroxymethyl-1-pyrrolidinyl) -4
-(3-chloro-4-methoxybenzylamino) -5
65 mg of [(2-morpholinoethyl) carbonyl] pyrimidine dihydrochloride are obtained. MS (m / z): 490 (MH ^<+> ).

Production Example 4 (1) 4- (3-chloro-4) obtained in the above Production Example 1 (1)
-Methoxybenzylamino) -5-ethoxycarbonyl-2-methylthiopyrimidine (972 mg) in a chloroform (8 ml) solution was m-chloroperbenzoic acid (80%) (598 mg).
Is added under ice-cooling for 30 minutes. The reaction mixture is stirred for 1 hour under ice cooling. The reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate, the chloroform layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a colorless caramel 2. -Methylsulfinyl-
4- (3-chloro-4-methoxybenzylamino) -5
Ethoxycarbonylpyrimidine is obtained quantitatively. MS (m
/ z): 384 (MH ⁺ ).

(2) To a solution of 2-methylsulfinyl-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine obtained in (1) above in 6 ml of tetrahydrofuran was added 2N hydroxide under ice-cooling. 1.32 ml of sodium was added dropwise over 2 minutes under ice cooling, and the reaction mixture was stirred for 30 minutes under ice cooling. Further tetrahydrofuran 8
ml and N, N-dimethylacetamide (6 ml) were added, and the reaction mixture was stirred for 30 minutes under ice cooling. 5ml of water and N, N
-2 ml of dimethylacetamide is added, and the reaction solution is stirred for 1 hour under ice cooling. The reaction mixture is acidified with a 10% aqueous citric acid solution, diluted with water and extracted twice with ethyl acetate.
The extracts are collected, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (silica gel 20 g, solvent; chloroform: ethyl acetate = 5: 1 → chloroform: isopropanol = 30: 1) to give 2-hydroxy-4- () as a slightly yellow crystalline powder. 618 mg of 3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine are obtained. Melting point: 195-197C.

(3) The 2-hydroxy- obtained in the above (2)
4- (3-chloro-4-methoxybenzylamino) -5
A mixture of 500 mg of ethoxycarbonylpyrimidine, 2 ml of diethylaminobenzene and 4 ml of phosphorus oxychloride is stirred at 80 ° C. for 30 minutes and then at 100 ° C. for 5 hours. After cooling, the reaction is poured into ice-water and the mixture is stirred at room temperature for 30 minutes. The obtained product is extracted with ethyl acetate, and the organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 7 g, solvent: chloroform) to give 2-chloro-
4- (3-chloro-4-methoxybenzylamino) -5
375 mg of ethoxycarbonylpyrimidine are obtained. Melting point: 114-115 [deg.] C. MS (m / z): 356 (MH ^<+> ).

(4) 2-chloro-4- obtained in the above (3)
285 mg of (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine, 5,6,7,8-
197 mg of tetrahydroimidazo [1,2-a] pyrazine,
0.22 ml of triethylamine and 3 ml of chloroform
Was stirred at room temperature for 2.5 hours, then at 60 ° C. for 2.5 hours.
Stir for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(10 g silica gel, chloroform: methanol = 5
0: 1) and concentrated under reduced pressure. Trituration with isopropyl ether gave colorless crystalline powder 2-
(5,6,7,8-Tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine 290
mg. Melting point: 179-182 [deg.] C. MS (m / z): 4
43 (MH ⁺ ).

(5) 2- (5,6,7,8) obtained in the above (4)
-Tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino)
290 mg of 5-ethoxycarbonylpyrimidine and 2N
A suspension of 1.64 ml of sodium hydroxide in dimethylsulfoxide-water (5 ml-1 ml) is stirred at room temperature for 1 hour. 5 ml of tetrahydrofuran are added and the mixture is stirred at room temperature for 13 hours. Tetrahydrofuran is distilled off under reduced pressure, and the obtained solution is diluted with water and neutralized with a 10% aqueous citric acid solution. The resulting precipitate was separated, washed with water, methanol, and isopropyl ether to give 2- (5,6,7,8-tetrahydroimidazo [1,2-a] as colorless crystalline powder.
Pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5-carboxypyrimidine 187m
g. Melting point: 223-226 ° C (decomposition). MS (m /
z): 413 (M−H) ⁻ .

(6) 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5-carboxy Pyrimidine 60 mg, 4-methyl-2-aminomethylmorpholine 22.7 mg, 1- (3-dimethylaminopropyl)
-3-Ethylcarbodiimide hydrochloride 30.6 mg, 1-
21.6 mg of hydroxybenzotriazole and N, N-
A mixture of 3 ml of dimethylformamide is stirred at room temperature for 22 hours. Pour water into the reaction mixture and extract with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 70.0 mg of colorless crystals. This was recrystallized from chloroform-hexane to give colorless needle-like crystals of 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4 51.7 mg of -methoxybenzylamino) -5- [N-[(4-methyl-2-morpholinyl) methyl] carbamoyl] pyrimidine are obtained. Melting point: 132-134 ° C. MS (m / z): 527 (MH
⁺ ).

Preparation Examples 5 to 6 The corresponding starting materials were treated in the same manner as in Preparation Example 4 (6) to give the compounds shown in Table 3 below.

[0135]

[Table 8]

Preparation Examples 7 to 21 The corresponding starting materials were treated in the same manner to give the compounds shown in Table 4 below.

[0137]

[Table 9]

[0138]

[Table 10]

Production Example 22 (1) To a solution of 0.78 g of diisopropylamine in 40 ml of tetrahydrofuran, 4.82 ml of a 1.6 M solution of n-butyllithium in hexane was added dropwise over 3 minutes while cooling in a dry ice-acetone bath. The mixture is stirred for 30 minutes on the same bath. A solution of 0.50 g of 2,6-dichloropyrazine in 5 ml of tetrahydrofuran is added dropwise at the same temperature over 15 minutes, and the mixture is stirred for 1 hour. Pour the reaction mixture into dry ice and stir at room temperature for 1 hour. Add 10 reaction mixtures
Dilute with aqueous hydrochloric acid to a pH of about 2 and extract with ethyl acetate. The collected organic layer was extracted with a saturated aqueous solution of sodium bicarbonate, and the aqueous extract was washed with ethyl acetate and washed with 10%
Acidify with aqueous hydrochloric acid and extract with ethyl acetate. The collected organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is triturated with chloroform-hexane (1: 1) to give 234 mg of 2-carboxy-3,5-dichloropyrazine as a slightly brown crystalline powder. Melting point: 139-141 [deg.] C. MS
(m / z): 191 (MH) ^- .

(2) 2-carboxy- obtained in the above (1)
A mixture of 226 mg of 3,5-dichloropyrazine, 118 mg of sodium hydrogen carbonate, 0.5 ml of methyl iodide and 1.8 ml of N, N-dimethylformamide is stirred at room temperature for 14 hours. The mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The collected organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-methoxycarbonyl- as a pale brown crystalline powder.
245 mg of 3,5-dichloropyrazine are obtained. Melting point: 6
0-63 ° C. MS (m / z): 206 (M ^<+> ).

(3) A mixture of 234 mg of 2-methoxycarbonyl-3,5-dichloropyrazine, 204 mg of 3-chloro-4-methoxybenzylamine, 0.17 ml of triethylamine and 3 ml of anhydrous toluene obtained in the above (2) was added at room temperature. Stir for 7 hours. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The extract is washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified and separated by silica gel column chromatography (silica gel 5 g, solvent; hexane: chloroform = 1: 1), and the desired fraction was concentrated under reduced pressure to give 2-methoxycarbonyl-3- as a pale yellow crystalline powder.
102 mg of (3-chloro-4-methoxybenzylamino) -5-chloropyrazine are obtained. Melting point: 149-151
° C. MS (m / z): 342 (MH ^<+> ).

(4) 2-methoxycarbonyl-3- (3-
(Chloro-4-methoxybenzylamino) -5-chloropyrazine 150 mg, 2-hydroxymethylpyrrolidine 8
A mixture of 8.6 mg and 0.12 ml of triethylamine in 5 ml of tetrahydrofuran was stirred at room temperature for 4 hours, and then stirred for 5 hours.
Heat at 0 ° C. for 2 hours. Then 44.3 mg of 2-hydroxymethylpyrrolidine are added and the mixture is stirred at 50 ° C. for 1 hour. After cooling, water is added to the mixture and extracted with ethyl acetate. The extract is washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting yellow oil was purified by silica gel flash column chromatography (solvent;
Purified with chloroform: hexane = 1: 1) to give (S) -2-methoxycarbonyl-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1) as a pale yellow powder. 123 mg of -pyrrolidinyl) pyrazine are obtained. MS (m / z): 407 (MH ^<+> ).

(5) 775 mg of (S) -2-methoxycarbonyl-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine obtained in the above (4). In 8 ml of ethanol
1.43 ml of aqueous N sodium hydroxide solution are added and the mixture is stirred at room temperature for 24 hours. The reaction mixture was acidified with 10% hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.
After washing with isopropyl alcohol, yellow crystals of (S)-
537 mg of 2-carboxy-3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine are obtained. Melting point: 169-1
71 ° C. MS (m / z): 391 (M-H) ^- .

(6) (S) -2-carboxy-3- (3-chloro-4-methoxybenzylamino) obtained in the above (5)
80 mg of -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine, 26.7 m of 2-aminomethylpyrimidine
g, a mixture of 43 mg of 1,2-dichloroethane and 30.3 mg of 1-hydroxybenzotriazole in 3 ml of N, N-dimethylformamide is stirred at room temperature for 18 hours. Pour water into the reaction mixture and extract with ethyl acetate. The extract is washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give (S) -2- [N-
87.6 mg of (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine are obtained. MS (m / z): 484 (MH ^<+> ).

Examples 23 to 24 The corresponding starting materials are treated in a similar manner to Example 22 to give the compounds listed in Table 5 below.

[0146]

[Table 11]

Production Example 25 (S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
-4- (3-chloro-4-methoxybenzylamino) -5
-(Acryloyl) pyrimidine 31 mg, methanol 1 m
A mixture of 1 and 1 drop of concentrated sulfuric acid is heated at reflux for 2 days. After the reaction, the solvent was distilled off, and the residue was separated by silica gel thin-layer chromatography (solvent: chloroform: methanol = 30: 1) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4. 27 mg of-(3-chloro-4-methoxybenzylamino) -5-[(2-methoxyethyl) carbonyl] pyrimidine are obtained as a colorless oil. MS
(m / z): 435 (MH ^<+> ).

Production Example 26 (S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
-4- (3-chloro-4-methoxybenzylamino) -5
82.48 g of-[N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine and benzenesulfonic acid monohydrate 60.
By concentrating a solution of 06 g of methanol in 1000 ml and recrystallizing from a methanol-acetone mixture, the (S)-
2- (2-hydroxymethyl-1-pyrrolidinyl) -4-
(3-chloro-4-methoxybenzylamino) -5- [N
121.8 g of-(2-pyrimidinylmethyl) carbamoyl] pyrimidine-2-benzenesulfonate are obtained as colorless crystals. Melting point: 158.5-161.5 [deg.] C.

Production Example 27 The (S) -4- (3-chloro-4-) obtained in Production Example 1 (4)
(Methoxybenzylamino) -5-carboxy-2- (2-
(Hydroxymethyl-1-pyrrolidinyl) pyrimidine 10
0 mg, 4-amino-1,3,5-trimethylpyrazole 47.9 mg, 1- (3-dimethylaminopropyl) -3
-Ethylcarbodiimide hydrochloride 58.7 mg, 1-hydroxybenztriazole monohydrate 41.3 mg,
After stirring a mixture of 3 ml of N, N-dimethylformamide at room temperature for 8 hours, the reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate. After extraction with ethyl acetate, the organic layer is washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: chloroform: methanol =
5: 1), and purified by (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3, 5-trimethyl-
115 mg of 4-pyrazolyl) carbamoyl] pyrimidine are obtained. MS (m / z): 500 (MH ^<+> ).

Production Example 28 (1) 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (5.0 g), sulfuryl chloride (20 ml)
Heat the solution at 50 ° C. for 1 hour. Concentrate the reaction mixture,
Pour saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate, the organic layer is washed with water, brine, dried over sodium sulfate and concentrated. The residue is purified by silica gel flash column chromatography (solvent; ethyl acetate: hexane = 1: 10) to quantitatively obtain 4.87 g of 2,4-dichloro-5-ethoxycarbonylpyrimidine as a yellow oil. MS (m / z): 220 (M ^<+> ).

(2) A solution of 4.2 g of 2,4-dichloro-5-ethoxycarbonylpyrimidine obtained in the above (1) and 2.30 g of mercaptobenzene in 40 ml of toluene at 0 ° C.
Then, 3.94 g of potassium carbonate is added, and the mixture is stirred at room temperature for 1 hour, then at 50 ° C. for 1 hour, and further at 100 ° C. for 10 minutes. Pour water and extract with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and concentrated. Silica gel flash column chromatography of the residue
(Solvent; ethyl acetate: hexane = 1: 20 to ethyl acetate: hexane = 1: 10) to give 2-colorless crystals.
4.16 g of chloro-4-phenylthio-5-ethoxycarbonylpyrimidine are obtained. MS (m / z): 295 (M
H ⁺ ).

(3) 2-chloro-4- obtained in the above (2)
Phenylthio-5-ethoxycarbonylpyrimidine 4.
To a solution of 05 g in 40 ml of tetrahydrofuran, 1.66 g of L-prolinol and 2.77 g of triethylamine were added.
The mixture is stirred at room temperature for 20 hours. Pour water into the reaction mixture and extract with ethyl acetate. Wash the organic layer with saline,
Dry over sodium sulfate and concentrate. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate: hexane = 1: 2) to give a colorless viscous oil (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-phenylthio. 4.16 g of -5-ethoxycarbonylpyrimidine are obtained. MS (m / z): 360 (M
H ⁺ ).

(4) The (S) -2- (2-) obtained in the above (3)
To a solution of 4.10 g of (hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5-ethoxycarbonylpyrimidine in 50 ml of ethanol is added 8.6 ml of 4N aqueous sodium hydroxide solution, and the mixture is stirred at room temperature for 15 hours.
Until the reaction solution becomes weakly acidic, 10% aqueous citric acid solution 3
0 ml is added and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give colorless crystals of (S) -2- (2-hydroxymethyl-1).
3.65 g of -pyrrolidinyl) -4-phenylthio-5-carboxypyrimidine are obtained. MS (m / z): 330 (M-
H) ^- .

(5) The (S) -2- (2-) obtained in the above (4)
(Hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5-carboxypyrimidine 2.55 g, 2-aminomethylpyrimidine 1.09 g, 1,2-dichloroethane 1.77 g and 1-hydroxybenztriazole 1.2
A mixture of 5 g of N, N-dimethylformamide 40 ml is stirred at room temperature for 16 hours. Pour water and extract with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated to give 4.05 g of pale yellow crystals. This is subjected to silica gel flash column chromatography (solvent; ethyl acetate).
To give colorless crystals of 2- (2-hydroxymethyl-
1-pyrrolidinyl) -4-phenylthio-5- [N- (2
-Pyrimidylmethyl) carbamoyl] pyrimidine 2.39
g. Melting point: 154-156 [deg.] C. IR (Nujol): 1
633cm ^-1. MS (m / z): 423 (MH ^<+> ).

(6) The (S) -2- (2-) obtained in the above (5)
(Hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5- [N- (2-pyrimidylmethyl) carbamoyl]
To a solution of 100 mg of pyrimidine in 3 ml of chloroform was added m-
70.1 mg of chloroperbenzoic acid are added at 0 ° C. and the mixture is stirred at 0 ° C. for 30 minutes. Then, 50.3 mg of 3-chlorobenzylamine and 48.0 mg of triethylamine were added to 0%.
C. and the mixture is stirred at room temperature for 17 hours. Pour water, extract with chloroform, wash the organic layer with brine,
Dry over sodium sulfate, then concentrate to a yellow oil 16
Obtain 9 mg. This was purified by silica gel flash column chromatography (solvent; ethyl acetate) and triturated with ethyl acetate-hexane to give a colorless powder.
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
95.3 mg of 4- (3-chlorobenzylamino) -5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine
Get. Melting point: 153-156C. IR (Nujol): 32
41, 1637 cm ^-1 . MS (m / z): 454 (MH ^<+> ).

(7) The (S) -2- (2-) obtained in the above (5)
(Hydroxymethyl-1-pyrrolidinyl) -4-phenylthio-5- [N- (2-pyrimidylmethyl) carbamoyl]
To a solution of 100 mg of pyrimidine in 3 ml of chloroform was added m-
70.1 mg of chloroperbenzoic acid (70%) are added at 0 ° C.
The mixture is stirred at 0 ° C. for 30 minutes. Then, 48.8 mg of 4-methoxybenzylamine and 48.8 of triethylamine.
0 mg is added at 0 ° C. and the mixture is stirred at room temperature for 20 hours. Pour water, extract with chloroform, wash the organic layer with brine, dry over sodium sulfate, and concentrate to give 143 mg of a yellow oil. This was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (4-methoxybenzylamino) -5- [N- (2-pyrimidylmethyl) carbamoyl]
88.2 mg of pyrimidine are obtained. IR (Neat): 329
6, 1633 cm ^-1 . MS (m / z): 450 (MH ^<+> ).

Production Example 29 (1) (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-) obtained in Production Example 2 (3)
(Methoxybenzylamino) -5-formylpyrimidine 1
1.6 mg of a 1.0 mg solution of tetrahydrofuran in 1.6 mg
M n-butyllithium in hexane solution
After treatment at 3 ° C. for 3 minutes, an aqueous sodium hydrogen carbonate solution is added. The reaction mixture was extracted with ethyl acetate to give an oil
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
-4- (3-chloro-4-methoxybenzylamino) -5
13.7 mg of-(1-hydroxypentyl) pyrimidine are obtained.

(2) (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4- obtained above.
Methoxybenzylamino) -5- (1-hydroxypentyl) pyrimidine is treated with manganese dioxide (25 mg) at room temperature, 100 mg of manganese dioxide is slowly added, and the mixture is stirred overnight. The reaction mixture was heated under reflux for 5 hours, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure and separated by preparative thin-layer chromatography to give (S) -2- (2 5.8 mg of -hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-pentanoylpyrimidine are obtained. M
S (m / z): 433 (MH ^<+> ).

Preparation Examples 30 to 83 The corresponding starting materials were treated in the same manner to give the compounds shown in Table 6 below.

[0160]

[Table 12]

[0161]

[Table 13]

[0162]

[Table 14]

[0163]

[Table 15]

[0164]

[Table 16]

Preparation Examples 84 to 86 The corresponding starting materials are treated in the same manner to give the compounds shown in Table 7 below.

[0166]

[Table 17]

Production Example 87 (S) -2-carboxy-3- obtained in Production Example 22 (5)
(3-chloro-4-methoxybenzylamino) -5- (2
-Hydroxymethyl-1-pyrrolidinyl) pyrazine 80
mg, 2-aminomethyl-4-methylmorpholine 31.
A mixture of 9 mg, 43 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 30.3 mg of 1-hydroxybenzotriazole in 3 ml of N, N-dimethylformamide is stirred at room temperature for 18 hours. Pour water into the reaction mixture and extract with ethyl acetate. The extract is washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent; ethyl acetate) to give (S) -2- [N-
(4-methyl-2-morpholinyl) methylcarbamoyl]
-3- (3-chloro-4-methoxybenzylamino) -5
80.5 mg of-(2-hydroxymethyl-1-pyrrolidinyl) pyrazine are obtained. MS (m / z): 505 (MH ⁺ ), IR
(Nujol): 3295, 1635 cm ^-1 .

Preparation Examples 88 to 91 The corresponding starting materials were treated in the same manner to give the compounds shown in Table 8 below.

[0169]

[Table 18]

Examples 92 to 145 The corresponding starting materials are treated in a similar manner to give the compounds shown in Table 9 below.

[0171]

[Table 19]

[0172]

[Table 20]

[0173]

[Table 21]

[0174]

[Table 22]

[0175]

[Table 23]

[0176]

[Table 24]

Preparation 146 The corresponding starting material is treated in a similar manner to give the compound of the following formula as a foam. MS (m / z): 464 (MH ^<+> ).

Embedded image

Production Example 147 (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N obtained in Production Example 1 (5) To a solution of 307 mg of-(2-pyrimidylmethyl) carbamoyl] pyrimidine in 6 ml of methylene chloride, 300 µl of boron bromide is added dropwise under ice-cooling. The reaction mixture is stirred at 0 ° C. for 4 hours. Methanol and then a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction mixture under ice cooling. The mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran, and the organic layer was washed successively with water and brine,
Dry over sodium sulfate and concentrate in vacuo to give 227 mg of a slightly brown amorphous. This was suspended in chloroform, the resulting insolubles were removed by filtration, the filtrate was subjected to silica gel column chromatography, and then purified by NH-silica gel column chromatography to obtain a colorless foam (S) -2- ( 129 mg of 2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-hydroxybenzylamino) -5- [N- (2-pyrimidylmethyl) carbamoyl] pyrimidine are obtained. MS (m / z): 470
(MH ⁺ ). IR (Nujol): 3279, 1632, 159
3, 1569, 1518, 1463 cm ^-1 .

Production Example 148 (1) 2-Methylthio-4- (3) obtained in Production Example 1 (1)
-Chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine (2.00 g) is suspended in dimethyl sulfoxide (10 ml) and treated with a 10% aqueous sodium hydroxide solution (10 ml) at room temperature. Dimethyl sulfoxide 5m
and the reaction mixture is stirred overnight at room temperature. The resulting clear reaction solution is made acidic by adding citric acid. Excess water
(About 50 ml), and the resulting precipitate was collected by filtration, washed with isopropyl alcohol, and further washed with isopropyl ether, and dried under reduced pressure to give a pale yellow fine powder,
1.864 g of -methylthio-4- (3-chloro-4-methoxybenzylamino) -5-carboxypyrimidine are obtained. Melting point: 238-240 ° C (decomposition).

(2) 150 mg of oxalyl chloride and N, N-dimethylformamide were added to a suspension of 200 mg of 4- (3-chloro-4-methoxybenzylamino) -5-carboxy-2-methylthiopyrimidine in 5 ml of methylene chloride. The mixture was stirred at room temperature for 30 minutes. The reaction mixture is concentrated, 144 mg of dimethylaminopyridine is added to a suspension of the obtained acid chloride compound and 84.0 mg of 5-aminopyrimidine in 5 ml of methylene chloride at room temperature, and the mixture is stirred at room temperature. Pour water, extract with ethyl acetate, wash the organic layer with saturated aqueous sodium bicarbonate, water, brine, dry over sodium sulfate, and concentrate. The residue was triturated with a mixed solvent of ethyl acetate and n-hexane to give pale yellow needle-like crystals of 4- (3-chloro-4-methoxybenzylamino) -5- (5-pyrimidinylaminocarbonyl) -2-. 216 mg of methylthiopyrimidine are obtained. Melting point: 238-240 ° C. IR (Nujol): 325
1,1666 cm ^-1 . MS (m / z): 416 (M ⁺ ).

(3) 150 mg of the compound obtained in the above (2)
107 mg of m-chloroperbenzoic acid was added to 10 ml of a chloroform suspension at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour, and then m-chloroperbenzoic acid 53 mg
At 0 ° C. and stir at 0 ° C. for 30 minutes. 43.7 mg of L-prolinol and 72.9 mg of triethylamine were added at 0 ° C.
And the mixture is stirred at room temperature for 20 hours. Pour water,
After extraction with chloroform, the organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a yellow viscous oil.
01 mg, which was purified by flash column chromatography on NH-silica gel (solvent; ethyl acetate), washed with a mixed solvent of ethyl acetate and hexane to give colorless needle-like crystals of (S) -4- (3-chloroform). -4-methoxybenzylamino) -5- (5-pyrimidinylaminocarbonyl) -2
81 mg of-(2-hydroxymethyl-1-pyrrolidinyl) pyrimidine are obtained. Melting point: 192-195C. IR (Nuj
ol): 3279, 1669 cm- ¹ . MS (m / z): 470
(MH ⁺ ).

Production Examples 149 to 156 In the same manner as in Production Example 148, the following first compounds were prepared from the corresponding starting materials.
The compounds shown in Table 0 are obtained.

[0183]

[Table 25]

Production Example 157 (1) 4- (3-chloro-4) obtained in Production Example 148 (1)
-Methoxybenzylamino) -5-carboxy-2-methylthiopyrimidine 154.0 mg of methylene chloride 5m
The suspension is treated with 119 μl of oxalyl chloride at room temperature, and N, N-dimethylformamide is added. The mixture is stirred for 1 hour and the solvent is removed in vacuo. The residue is treated with ether and refrigerated overnight. Volatiles are removed in vacuo and the residue is treated with excess diazomethane at 0 ° C. and then refrigerated overnight. The reaction is stopped by adding methanol. Silica gel chromatography (solvent; hexane: ethyl acetate =
2: 1) to give 4- (3-chloro-4-methoxybenzylamino) -5- (diazomethylcarbonyl) -2-
21.5 mg of methylthiopyrimidine are obtained as a pale yellow solid. IR (Nujol): 3277, 2115, 160
7, 1567, 1461, 1377, 1357, 114
1 cm ^-1 . MS (m / z): 364 (MH ^<+> ). Melting point: 162-
165 ° C (decomposition).

(2) 16.5 m of the compound obtained in the above (1)
g of methanol (3 ml) was treated with toluene sulfonic acid monohydrate (16.5 mg) at room temperature. The solvent was removed in vacuo and the residue was purified by preparative TLC (solvent; hexane: ethyl acetate = 2: 1) to give 4- (3-chloro-4-
11.0 mg of (methoxybenzylamino) -5- (methoxymethylcarbonyl) -2-methylthiopyrimidine are obtained as a colorless oil.

(3) 11.0 m of the compound obtained in the above (2)
g of chloroform in 1.0 ml are treated with 7.4 mg of m-chloroperbenzoic acid at 0 ° C. The mixture is treated at room temperature with 8.3 μl of triethylamine and 36 mg of L-prolinol and the reaction mixture is stirred overnight. The reaction mixture is diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over sodium sulfate. The residue was purified by preparative TLC (solvent; chloroform: ethyl acetate =
1: 1) to give (S) -4- (3-chloro-4-methoxybenzylamino) -5- (methoxymethylcarbonyl) -2- (2-hydroxymethyl-1-pyrrolidinyl) as a colorless oil. ) 8.5 mg of pyrimidine are obtained. MS (m / z): 4
21 (MH ^<+> ).

[0187]

The compound (I) as an active ingredient of the present invention and a pharmaceutically acceptable salt thereof have an excellent PDEV inhibitory activity, and are used in pharmaceutical compositions, particularly for the prevention and treatment of penile erectile dysfunction. Useful as an agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 31/662 A61K 31/662 A61P 1/00 A61P 1/00 3/10 3/10 9/12 9 / 12 11/00 11/00 15/10 15/10 43/00 111 43/00 111 C07D 401/04 C07D 401/04 // C07D 239/42 239/42 Z 401/14 401/14 403/04 403 / 04 403/14 403/14 413/04 413/04 413/14 413/14 417/14 417/14 471/04 104 471/04 104Z 105 105Z 116 116 487/04 140 487/04 140 513/04 343 513 / 04 343 (72) Inventor Kohei Yoshikawa 2--22-4 Kitaharadai, Kawaguchi-shi, Saitama F-term (reference) 4C050 AA01 BB05 CC08 EE03 FF01 GG01 HH04 4C063 AA01 AA03 BB02 BB09 CC29 CC54 CC62 DD03 DD15 DD29 AEE04 A05 BB04 BB05 BB10 CC01 DD02 DD03 EE02 HH01 JJ01 KK01 LL01 LL04 PP14 4 C072 AA01 BB02 CC02 CC16 EE13 FF07 GG08 HH07 UU01 4C086 AA01 AA02 BC42 BC73 BC74 CB05 CB09 DA34 GA07 GA12 MA01 MA04 NA14 ZA42 ZA59 ZA66 ZA81 ZC02 ZC20 ZC35

Claims (24)

[Claims] 1. A compound of the general formula (I) (Wherein, ring A is an optionally substituted nitrogen-containing heterocyclic group, R ¹ is an optionally substituted lower alkyl group, formula: —NH—Q—R ³ (wherein, R ³ is substituted A nitrogen-containing heterocyclic group which may be
Group or the formula Q is represented by representing) a lower alkylene group or a single bond: -NH-R ⁴ (wherein the groups represented by R ⁴ represents a cycloalkyl group which may be substituted), R ² is One of the optionally substituted aryl groups, Y and Z, has the formula: ＣＨCH- and the other has the formula: ＮN-), or a pharmacologically acceptable aromatic nitrogen-containing six-membered ring compound thereof. A pharmaceutical composition comprising a salt which can be used as an active ingredient. 2. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A has the formula: A monocyclic or bicyclic nitrogen-containing heterocyclic group represented by the above-mentioned "optionally substituted nitrogen-containing heterocyclic group"
Substituent is a group selected from a lower alkyl group, a hydroxyl-substituted lower alkyl group, an oxo group and an amino group, R ¹
Is a lower alkyl group which may be substituted with a group selected from a lower alkoxy group, a morpholinyl group, a pyrimidinyl group-substituted lower alkylamino group, a pyridyl group, a pyridylamino group and a lower alkyl group-substituted piperazinyl group, formula: -NH-Q- A group represented by R ³ or a group represented by the formula: —NH—R ⁴ , wherein the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula: : Wherein the substituent of the `` nitrogen-containing heterocyclic group which may be substituted '' is a lower alkyl group, a hydroxyl-substituted lower alkyl group, a cyano group-substituted lower alkyl group, an oxo group, an amino group, a di-lower alkyl group. Amino group, lower alkanoyl group,
A lower alkoxy group-substituted group selected from a lower alkanoyl group and a lower alkoxy group, R <sup>4</sup> is a cycloalkyl group substituted with a group selected from a hydroxyl group, a lower alkoxy group and a pyrimidinyloxy group, and R <sup>2</sup> is a lower alkoxy group The pharmaceutical composition according to claim 1, which is a phenyl group substituted by a group selected from a halogen atom, a cyano group and a nitro group. 3. An optionally substituted group represented by ring A
The nitrogen-containing heterocyclic group in the “nitrogen-containing heterocyclic group” has the formula:A monocyclic or bicyclic nitrogen-containing heterocyclic group represented by
And the above-mentioned "optionally substituted nitrogen-containing heterocyclic group"
Is a hydroxyl-substituted lower alkyl group or a formyl group
A group selected from<sup>1</sup>Is substituted with a lower alkoxy group
An optionally substituted lower alkyl group of the formula: —NH—Q—R<sup>Three</sup> Or a group represented by the formula: -NH-R<sup>Four</sup> A group represented by<sup>Three</sup>Is replaced with
Nitrogen-containing heterocyclic group "
But the formula:And the above-mentioned `` nitrogen-containing heterocyclic ring optionally substituted ''
Group is a lower alkyl group or a cyano group-substituted lower group
A group selected from alkyl groups,^FourIs hydroxyl group and low
Substituted with a group selected from lower alkoxy groups
A kill group, ^TwoIs lower alkoxy group and halogen atom
A phenyl group substituted with a group selected from the group consisting of
The formula: = N-, and Z is the formula: = CH-.
The pharmaceutical composition described above. 4. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is 5 to 5.
A 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, wherein the substituent of the aforementioned “optionally substituted nitrogen-containing heterocyclic group” is (1) lower alkyl group, (2) hydroxyl-substituted lower alkyl group, (3) formyl group,
(4) an oxo group, (5) an amino group, (6) a hydroxyl group, (7) a lower alkoxycarbonyl group, and (8) (i) a benzylamino group substituted with a halogen atom and a lower alkoxy group;
(ii) a group selected from a pyrimidinyl group substituted with a hydroxyl-substituted cycloalkylcarbamoyl group, wherein R ¹ is a lower alkoxy group, a hydroxyl group, a morpholinyl group, a lower alkylsulfonyl group, a di-lower alkylphosphino group, a di-lower alkylamino group, a pyrimidinyl-substituted lower alkylamino group, a pyridyl group, a pyridylamino group and a lower alkyl group substituted with a group selected from substituted piperazinyl group is optionally may be a lower alkyl group, the formula: a group represented by -NH-Q-R ³ Or a group represented by the formula: —NH—R ⁴ , wherein the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a 5- to 6-membered monocyclic group A group selected from a nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, wherein the above-mentioned "optionally substituted nitrogen-containing heterocyclic group" is substituted; Group, a lower alkyl group, a hydroxyl-substituted lower alkyl group, an oxo group, an amino group, a di-lower alkylamino group, a group selected from lower alkanoyl group and a cyano group-substituted lower alkyl group, R ⁴ is a hydroxyl group, a lower alkoxy group And a cycloalkyl group substituted with a group selected from pyrimidinyloxy groups, wherein R ² is a phenyl group substituted with a group selected from a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxyl group and a lower alkyl group. The pharmaceutical composition according to claim 1. 5. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A is represented by the following formula: A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or
Formula: 5 to 6-membered monocyclic nitrogen-containing heterocyclic group represented by
A bicyclic nitrogen-containing heterocyclic group in which a 6-membered ring is fused,
The nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ has the formula: Or a non-aromatic nitrogen-containing heterocyclic group represented by the formula: The pharmaceutical composition according to claim 4, which is an aromatic nitrogen-containing heterocyclic group represented by the formula: 6. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A is 5 to 5.
A 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, wherein the substituent of the aforementioned “optionally substituted nitrogen-containing heterocyclic group” is A lower alkyl group, a hydroxyl-substituted lower alkyl group, a formyl group and an oxo group, wherein R ¹ may be substituted with a group selected from a lower alkoxy group and a morpholinyl group; group or the formula represented by NH-Q-R ^3: a group represented by -NH-R ^4, the "optionally substituted nitrogen-containing heterocyclic group" represented by R ³ is a lower alkyl group A 5- or 6-membered monocyclic nitrogen-containing heterocyclic group which may be substituted, R ⁴ is a cycloalkyl group substituted with a group selected from a hydroxyl group and a lower alkoxy group, and R ² is a lower alkoxy group; Group, a halogen atom and a cyano group. The pharmaceutical composition of claim 1, wherein the phenyl group. 7. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A has the formula: A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: or a compound represented by the formula: Is a bicyclic nitrogen-containing heterocyclic group in which a 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is condensed with the 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by And the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula: Or a non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula or a compound represented by the formula: The pharmaceutical composition according to claim 6, which is an aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: 8. The ring A is of the formula: Wherein R ¹ is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a morpholinyl group-substituted lower alkyl group, a group represented by the formula: —NH—Q—R ³ or a formula: —NH—R ⁴ Wherein R ³ is a group represented by the formula: Wherein R ⁴ is a group represented by the formula: Wherein R ² is a group represented by the formula: The pharmaceutical composition according to claim 1, which is a group represented by the formula: 9. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A is 5 to 5.
A 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, wherein the substituent of the aforementioned "optionally substituted nitrogen-containing heterocyclic group" is A lower alkyl group, a hydroxyl-substituted lower alkyl group, a formyl group and an oxo group, wherein R ¹ is a lower alkyl group substituted with a lower alkoxy group, a group represented by the formula: —NH—Q—R ³ or the formula: a group represented by -NH-R ^4, represented by R ³ 'substituted optionally nitrogen-containing heterocyclic group which may "is to have it 5-6 membered also substituted by a lower alkyl group 2. A monocyclic nitrogen-containing heterocyclic group, wherein R ⁴ is a cycloalkyl group substituted with a hydroxyl group, and R ² is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom. A pharmaceutical composition according to claim 1. 10. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A,
Formula: A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: or a compound represented by the formula: Wherein the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula: A non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: or a compound represented by the formula: The pharmaceutical composition according to claim 9, which is an aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: 11. Ring A is of the formula: R ¹ is a lower alkyl group substituted with a lower alkoxy group, a group represented by the formula: —NH—QR ³ or a group represented by the formula: —NH—R ⁴ , ³ is the formula: Wherein R ⁴ is a group represented by the formula: Wherein R ² is a group represented by the formula: The pharmaceutical composition according to claim 1, which is a group represented by the formula: 12. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by ring A is 5
A 6 to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic nitrogen-containing heterocyclic group, and a substituent of the above-mentioned "optionally substituted nitrogen-containing heterocyclic group" Is a hydroxyl-substituted lower alkyl group, R ¹ is a group represented by the formula: —NH—Q—R ³ , and the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a lower alkyl group A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group which may be substituted with a group, wherein R ² is a phenyl group substituted with a group selected from a lower alkoxy group and a halogen atom. Pharmaceutical composition. 13. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” for ring A,
Formula: A 5- to 6-membered non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: or a compound represented by the formula: Wherein the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ³ is a group represented by the formula: A non-aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: or a compound represented by the formula: The pharmaceutical composition according to claim 12, which is an aromatic monocyclic nitrogen-containing heterocyclic group represented by the formula: 14. Ring A is of the formula: Wherein R ¹ is a group represented by the formula: —NH—Q—R ³ , and R ³ is a group represented by the formula: Wherein R ² is a group represented by the formula: The pharmaceutical composition according to claim 1, which is a group represented by the formula: 15. Y is the formula: = N- and Z is the formula: = C
The pharmaceutical composition according to any one of claims 1 to 14, which is H-. 16. (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (6,7-dihydro-5H
-Pyrrolo [3,4-b] pyridin-6-yl) -4- (3-
Cyano-4-methoxybenzylamino) -5- [N- (2
-Pyrimidinylmethyl) carbamoyl] pyrimidine; 2-
(5,6,7,8-Tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-methoxy Cyclohexyl) carbamoyl] pyrimidine; 2- (6,7-dihydro-5H-pyrrolo [3,4-b] pyridin-6-yl)
-4- (3-cyano-4-methoxybenzylamino) -5
-[N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- (6,7-dihydro-5H
-Pyrrolo [3,4-b] pyridin-6-yl) -4- (3-
Cyano-4-methoxybenzylamino) -5- [N- (2
-Morpholinoethyl) carbamoyl] pyrimidine; (S)-
2- (2-hydroxymethyl-1-pyrrolidinyl) -4-
(3-chloro-4-methoxybenzylamino) -5- [N
-(2-morpholinoethyl) carbamoyl] pyrimidine;
2-[(2S) -2-hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino)
-5- [N-[[(2R) -4-methyl-2-morpholinyl]
Methyl] carbamoyl] pyrimidine; 2-[(2S) -2-
Hydroxymethyl-1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino) -5- [N-[[(2S)
-4-methyl-2-morpholinyl] methyl] carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1
-Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (4-methyl-3-oxo-
1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- (4-
Formyl-1-piperazinyl) -4- (3-chloro-4-
Methoxybenzylamino) -5- [N- (trans-4-
Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (5,6,7,8-tetrahydroimidazo [1,2-a]
Pyrazin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- [cis-2,5-bis (hydroxy Methyl) -1-pyrrolidinyl] -4- (3-chloro-4-methoxybenzylamino)
-5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydroimidazo
[1,2-a] pyrazin-7-yl) -4- (3-chloro-
4- (methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,
7,8-tetrahydroimidazo [1,2-a] pyrazine-7
-Yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl]
Pyrimidine; 2- (5,6,7,8-tetrahydro-1,7
-Naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1 -Pyrrolidinyl) -4- (3-chloro-
4-methoxybenzylamino) -5-acetylpyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (4 -Pyridazinylmethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1
-Pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl)- 4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyridylmethyl) carbamoyl] pyrimidine; (S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- ( 3-chloro-4-
(Methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4
-Methoxybenzylamino) -5-[(2-morpholinoethyl) carbonyl] pyrimidine; 2- (5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-7-yl) -4
-(3-chloro-4-methoxybenzylamino) -5
[N-[(4-methyl-2-morpholinyl) methyl] carbamoyl] pyrimidine; (S) -2- [N- (2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-
Pyrrolidinyl) pyrazine; 2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (5,6,7,8-tetrahydroimidazo [1,2- a) pyrazin-7-yl) pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
-4- (3-chloro-4-methoxybenzylamino) -5
-[(2-methoxyethyl) carbonyl] pyrimidine, (S)
-2- (2-hydroxymethyl-1-pyrrolidinyl) -4
-(3-chloro-4-methoxybenzylamino) -5
A pharmaceutical composition comprising [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine or a pharmacologically acceptable salt thereof as an active ingredient. (17) (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) 4- (3-chloro-4-methoxybenzylamino) -5- [N- (4-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (4-methyl-3
-Oxo-1-piperazinyl) -4- (3-chloro-4-
Methoxybenzylamino) -5- [N- (trans-4-
Hydroxycyclohexyl) carbamoyl] pyrimidine;
2- (4-formyl-1-piperazinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (trans-4-hydroxycyclohexyl) carbamoyl] pyrimidine; 2- (5,6, 7,8-tetrahydroimidazo
[1,2-a] pyrazin-7-yl) -4- (3-chloro-
4- (methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,
7,8-tetrahydroimidazo [1,2-a] pyrazine-7
-Yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl]
Pyrimidine; 2- (5,6,7,8-tetrahydro-1,7
-Naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1 -Pyrrolidinyl) -4- (3-chloro-
4-methoxybenzylamino) -5- [N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2-
[N- (2-pyrimidinylmethyl) carbamoyl] -3-
(3-chloro-4-methoxybenzylamino) -5- [2
-Hydroxymethyl-1-pyrrolidinyl] pyrazine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl)
-4- (3-chloro-4-methoxybenzylamino) -5
-[(2-methoxyethyl) carbonyl] pyrimidine, (S)
-2- (2-hydroxymethyl-1-pyrrolidinyl) -4
-(3-chloro-4-methoxybenzylamino) -5
A pharmaceutical composition comprising [N- (1,3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine or a pharmacologically acceptable salt thereof as an active ingredient. (18) (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) 4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydroimidazo [1,2-a] Pyrazin-7-yl) -4
-(3-chloro-4-methoxybenzylamino) -5
[N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine; 2- (5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine; (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [ N- (5-pyrimidinylmethyl) carbamoyl] pyrimidine; (S) -2- [N- (2-pyrimidinylmethyl) carbamoyl] -3- (3-chloro-
4-methoxybenzylamino) -5- [2-hydroxymethyl-1-pyrrolidinyl] pyrazine; (S) -2- [N-
(2-morpholinoethyl) carbamoyl] -3- (3-chloro-4-methoxybenzylamino) -5- (2-hydroxymethyl-1-pyrrolidinyl) pyrazine, (S) -2- (2
-Hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,
Pharmaceutical composition comprising 3,5-trimethyl-4-pyrazolyl) carbamoyl] pyrimidine or a pharmaceutically acceptable salt thereof as an active ingredient. (S) -2- (2-hydroxymethyl-
Pharmaceutical composition comprising 1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (2-pyrimidinylmethyl) carbamoyl] pyrimidine or a pharmacologically acceptable salt thereof as an active ingredient Composition. 20. 2- (5,6,7,8-tetrahydro-
1,7-naphthyridin-7-yl) -4- (3-chloro-
A pharmaceutical composition comprising 4-methoxybenzylamino) -5- [N- (2-morpholinoethyl) carbamoyl] pyrimidine or a pharmacologically acceptable salt thereof as an active ingredient. 21. (S) -2- (2-hydroxymethyl-
1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5- [N- (1,3,5-trimethyl-4
-Pyrazolyl) carbamoyl] pyrimidine, or a pharmaceutically acceptable salt thereof, as a pharmaceutical composition. 22. The pharmaceutical composition according to claim 1, which is used for prevention and / or treatment of penile erectile dysfunction. 23. The pharmaceutical composition according to claim 1, which is used for prevention and treatment of pulmonary hypertension. 24. The pharmaceutical composition according to any one of claims 1 to 21, which is used for prevention and treatment of diabetic gastroparesis.