JP2004083587A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide medicinal compositions containing a new compound having excellent PDE V inhibitory action and useful for prevention/treatment of erectile dysfunction. <P>SOLUTION: The medicinal composition contains a pyridopyrimidine or a naphthyridine derivative shown by general formula (I) or their pharmacologically acceptable salt as an effective ingredient, wherein R<SP>1</SP>represents an optionally substituted nitrogen containing heterocyclic group or the like, R<SP>2</SP>represents H or a lower alkyl group, R<SP>3</SP>represents H, an optionally substituted lower alkyl group or the like, R<SP>4</SP>represents H, a lower alkyl group, COOH or the like, R<SP>5</SP>represents H, an optionally substituted aryl group or the like, X and Y represent one CH and the other N or both N. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention relates to a pharmaceutical composition.

In general, cGMP, which is an intracellular second messenger, is degraded and inactivated by phosphodiesterase widely distributed in tissues of a living body. When the PDE activity is inhibited, the concentration of intracellular cGMP increases, and as a result, It is known that 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 exhibited.

In addition, compounds having such cGMP-specific PDE inhibitory activity (ie, PDEV inhibitory activity) can be used for various diseases caused by dysfunction of cGMP signaling, such as hypertension, angina pectoris, myocardial infarction, chronic It is known to be useful for treating acute heart failure, pulmonary hypertension (Patent Literature 1, etc.), prostatic hypertrophy (Patent Literature 2, etc.), and female dysfunction (Non-Patent Literature 1), diabetic stomach For the treatment of paresis (Non-patent document 2), achalasia (Non-patent document 3), diarrhea (Non-patent document 4), constipation (Non-patent document 5), asthma (Non-patent document 6), premature ejaculation (Patent document 3) Possible uses have been reported.

Further, 1- [4-ethoxy-3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidine-5 having a PDEV inhibitory action. Yl) phenylsulfonyl] -4-methylpiperazine (generic name; Sildenafil) has also been reported to be useful for the treatment of diseases such as penile erectile dysfunction (Non-Patent Document 7, Non-Patent Document 8, and Non-Patent Document 8). Patent Document 9).

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 (Non-Patent Document 10, Non-Patent Document 11 and Non-Patent Document 12). .

In dog experiments, it has been reported that sildenafil correlates with the PDE VI inhibitory effect on the effect of retinal tissue light response (Non-Patent Document 13), whereas retinal PDE VI is important for visual function. It has also been reported that it plays an important role (Non-Patent Documents 14 and 15).

WO 96/05176 pamphlet Australian Patent Application No. 9955977 U.S. Pat. No. 6,403,597 Vemulapalli et al., Life Sciences, Vol. 67, pp. 23-29 (2000) (Life Sciences) Watkins et al., Journal of Clinical Investigation, Vol. 106, pp. 373-384 (2000) (J. Clin. Invest.) Bortolotti et al., Gastroenterology, Vol. 118, pp. 253-257 (2000) (Gastroenterology) Mule et al., British Journal of Pharmacology, 127, 514-520 (1999) (Br. J. Pharmacol.) Bakre et al., Journal of Cellular Biochemistry, Vol. 77, pp. 159-167 (2000) (J. Cell. Biochem.) Turner et al., British Journal of Pharmacology, Vol. 111, pp. 1198-1204 (1994) (Br. J. Pharmacol.) Boolell et al., The Journal of Urology, Supplement, Vol. 155, No. 5, 495A, p. 739 (1996) (The Journal of Urology, Supplement). Terrett et al., Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 15, p. 1819 (1996) (Bioorganic & Medicinal Chemistry Letters) Ballard et al., British Journal of Pharmacology, Proceeding Supplement, Vol. 118, 153P (1996) (British Journal of Pharmacology, Proceeding Supplement) Irwin et al., The New England Journal of Medicine, 338, 20, 1397-1404 (1998) (The New England Journal of Medicine). Morales et al., International Journal of Impotence Research, Vol. 10, No. 2, pp. 69-73 (1998) (International Journal of Impotence Research) Goldenberg, Clinical Therapeutics, Vol. 20, No. 6, pp. 1033-1048 (1998) (Clinical Therapeutics) Morales et al., International Journal of Impotence Research, Vol. 10, No. 2, pp. 69-73 (1998) (International Journal of Impotence Research) Morales et al., International Journal of Impotence Research, Vol. 10, No. 2, pp. 69-73 (1998) (International Journal of Impotence Research) Estrade et al., European Journal of Pharmacology, 352, 157-163 (1998) (European Journal of Pharmacology)]

The present invention provides a pharmaceutical composition comprising, as an active ingredient, a novel pyridopyrimidine or naphthyridine derivative which has an excellent phosphodiesterase V (PDE V) inhibitory activity and is useful as a prophylactic / therapeutic agent for penile erectile dysfunction with few side effects. To provide.

(式中、Ｒ¹は置換されていてもよい含窒素複素環式基、置換されていてもよいアミノ基または置換されていてもよい低級アルコキシ基を表し；
Ｒ²は水素原子または低級アルキル基を表し；
Ｒ³は水素原子、置換されていてもよい低級アルキル基または置換されていてもよいヘテロアリール基を表し；
Ｒ⁴は水素原子、低級アルキル基またはエステル化若しくはアミド化されていてもよいカルボキシル基を表し；
Ｒ⁵は置換されていてもよいアリール基、置換されていてもよいヘテロアリール基およびジ低級アルキルアミノ基から選ばれる基で置換されていてもよい低級アルキル基を表し；
ＸおよびＹは、一方が式：＝ＣＨ−で示される基で他方が窒素原子であるか、両方が窒素原子を表す)
で示されるピリドピリミジンまたはナフチリジン誘導体またはその薬理的に許容し得る塩を有効成分としてなる医薬組成物に関する。 The present invention provides a compound of the general formula (I):

(Wherein, R ¹ represents an optionally substituted nitrogen-containing heterocyclic group, an optionally substituted amino group or an optionally substituted lower alkoxy group;
R ² represents a hydrogen atom or a lower alkyl group;
R ³ represents a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted heteroaryl group;
R ⁴ represents a hydrogen atom, a lower alkyl group or a carboxyl group which may be esterified or amidated;
R ⁵ represents a lower alkyl group which may be substituted with a group selected from an optionally substituted aryl group, an optionally substituted heteroaryl group and a di-lower alkylamino group;
X and Y each represent a group represented by the formula: ＣＨCH— and the other is a nitrogen atom, or both represent a nitrogen atom.
And a pharmacologically acceptable salt thereof as an active ingredient.

In the compound (I) which is an active ingredient of the present invention, the nitrogen-containing heterocyclic group of the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ may be a 5- to 10-membered monocyclic or Bicyclic nitrogen-containing heterocyclic groups, more specifically, 5- to 6-membered monocyclic nitrogen-containing heterocyclic groups and 8- to 10-membered bicyclic nitrogen-containing heterocyclic groups, Specifically, a pyrrolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, and the like. 8- to 10-membered bicyclic nitrogen-containing heterocyclic groups such as a 6-membered monocyclic nitrogen-containing heterocyclic group, an indolyl group, an isoindolyl group, an indolizinyl group, a quinolyl group, an isoquinolyl group, and a purinyl group. Can be

Examples of the substituent of the "optionally substituted nitrogen-containing heterocyclic group" for R ¹ include a lower alkyl group which may be substituted with a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group. .

The substituent in the “optionally substituted amino group” for R ¹ includes a lower alkyl group optionally substituted with a heteroaryl group, a lower alkyl group optionally substituted with an aryl group, and a lower alkoxy group And the heteroaryl group is a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group such as a pyridyl group or a pyrimidinyl group. The aryl group is a 5- to 10-membered group such as a phenyl group or a naphthyl group. Monocyclic or bicyclic aromatic hydrocarbon groups are exemplified.

Examples of the substituent in the “optionally substituted lower alkoxy group” for R ¹ include (1) an aryl group optionally substituted with a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group, or (2) Examples include a lower alkyl group which may be substituted with a heteroaryl group which may be substituted with a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group. Here, the aryl group and the heteroaryl group mean the same as those described above.

Examples of the substituent in the “optionally substituted lower alkyl group” represented by R ³ include a nitrogen-containing heterocyclic group, and more specifically, in the above R ¹ , Examples include the groups exemplified above.

The heteroaryl group in the “optionally substituted heteroaryl group” for R ³ means the same 5- to 10-membered monocyclic or bicyclic nitrogen-containing aromatic heterocyclic group as described above, and its substituent Examples thereof include a group selected from a lower alkyl group, a hydroxyl group, a halogen atom and a lower alkoxy group.

Examples of the aryl group of the “optionally substituted aryl group” for R ⁵ include the same 5- to 10-membered monocyclic or bicyclic aromatic hydrocarbon groups as described above, and specifically, a phenyl group And a naphthyl group.

Examples of the heteroaryl group of the “optionally substituted heteroaryl group” for R ⁵ include the same 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic groups as described above. And pyrimidyl groups.

Examples of the substituent of the “optionally substituted aryl group” and the “optionally substituted heteroaryl group” represented by R ⁵ include a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkylenedioxy group and the like. Is mentioned.

Examples of the carboxyl group esterified in the “carboxyl group which may be esterified or amidated” represented by R ⁴ include a carboxyl group esterified by a lower alkyl group, and a carboxyl group amidated. Is a lower alkyl group substituted amino group which may be substituted with a hydroxyl group or a 5- or 6-membered monocyclic nitrogen-containing heterocyclic group which may be substituted, or a 5- or 6-membered group which may be substituted. A carboxyl group amidated by a monocyclic nitrogen-containing heterocyclic group is exemplified. Examples of the amidated carboxyl group include, for example, a pyrrolyl group optionally substituted with a lower alkyl group, an oxazolyl group, a pyrazolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, A lower alkyl-substituted amino group optionally substituted by a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group selected from a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, an imidazolidinyl group and a thiazolyl group Or optionally substituted with a lower alkyl group, a pyrrolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group , Triage Group, include amidated carboxyl group by a monocyclic nitrogen-containing heterocyclic group 5-6 membered selected from imidazolidinyl group and thiazolyl group.
Examples of the substituent in the “optionally substituted 5- to 6-membered monocyclic nitrogen-containing heterocyclic group” include a lower alkyl group.

を 通 じ て Throughout this specification, a lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 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. The lower alkylenedioxy group means a straight-chain or branched-chain alkylenedioxy group having 1 to 6 carbon atoms such as methylenedioxy, ethylenedioxin and trimethylenedioxy. 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 are those having a substituent in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ in the general formula (1). A lower alkyl group which may be substituted with a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group, wherein the substituent in the “optionally substituted amino group” may be substituted with a heteroaryl group; An alkyl group, a group selected from a lower alkyl group and a lower alkoxy group which may be substituted with an aryl group, wherein the substituent in the “optionally substituted lower alkoxy group” is (1) a hydroxyl group, a halogen atom and An aryl group which may be substituted with a group selected from a lower alkoxy group or (2) a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group; A lower alkyl group which may be substituted with an optionally substituted heteroaryl group, wherein the substituent in the “optionally substituted lower alkyl group” represented by R ³ is a nitrogen-containing heterocyclic group; A substituent in the “optionally substituted heteroaryl group” is a group selected from a lower alkyl group, a hydroxyl group, a halogen atom and a lower alkoxy group, and the “optionally substituted aryl group” represented by R ⁵ And the substituent in "optionally substituted heteroaryl group" is a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group, and compounds wherein X and Y are both nitrogen atoms.

Among the compound (I) which is an active ingredient of the present invention, another preferred compound is a `` optionally substituted aryl group, which may be substituted, represented by R ⁵ in the general formula (I) A group wherein the aryl group which may be substituted in the lower alkyl group which may be substituted with a group selected from a heteroaryl group or a di-lower alkylamino group is selected from a lower alkoxy group, a lower alkylenedioxy group and a halogen atom And the heteroaryl group which may be substituted is a pyridyl group or a pyrimidyl group which may be substituted with a lower alkoxy group and / or a halogen atom.

In another preferred embodiment, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ is a pyrrolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolyl group, a pyrrolidinyl group, 5- to 6-membered monocyclic nitrogen-containing heterocyclic group selected from imidazolyl group, piperidyl group, piperazinyl group, morpholinyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and triazinyl group, or indolyl group, isoindolyl group , indolizinyl group, quinolyl group, a bicyclic nitrogen-containing heterocyclic group 8-10 membered selected from isoquinolyl group and purinyl group, represented by R ⁴ "esterified or amidated or unprotected carboxyl Group, wherein the amidated carboxyl group may be substituted with a lower alkyl group Oxazolyl group, pyrazolyl group, pyrrolyl group, pyrrolidinyl group, imidazolyl group, piperidyl group, piperazinyl group, morpholinyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, imidazolidinyl group and thiazolyl group A pyrrolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolyl group which may be substituted with a lower alkyl group which may be substituted with a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group, which may be substituted with an amino group or a lower alkyl group; A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group selected from pyrrolidinyl, imidazolyl, piperidyl, piperazinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolidinyl and thiazolyl groups By cyclic group Compound is a bromide of carboxyl groups.

で示される５〜６員の単環式含窒素複素環式基または、式：

で示される８〜１０員の二環式含窒素複素環式基であり、
Ｒ⁴で表される「エステル化若しくはアミド化されていてもよいカルボキシル基」が、式：

で示される基で置換されていてもよい低級アルキル基置換アミノ基、低級アルキル基で置換されていてもよい、式：

で示される基で置換されていてもよいアミノ基または低級アルキル基で置換されていてもよい、式：

で示される基から選ばれる基によりアミド化されたカルボキシル基である化合物が挙げられる。 More preferably, the nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ is a group represented by the formula:

Or a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group represented by the formula:

An 8- to 10-membered bicyclic nitrogen-containing heterocyclic group represented by
The “carboxyl group which may be esterified or amidated” represented by R ⁴ has the formula:

A lower alkyl group which may be substituted with a group represented by the following, an amino group which may be substituted with a lower alkyl group;

An amino group or a lower alkyl group which may be substituted with a group represented by the following formula:

And a carboxyl group amidated by a group selected from the groups represented by

であり、
Ｒ⁴で表される「エステル化若しくはアミド化されていてもよいカルボキシル基」が、式：

で示される基で置換されていてもよい低級アルキル基置換アミノ基、式：

で示される基で置換されていてもよいアミノ基または式：

で示される基から選ばれる基によりアミド化されたカルボキシル基である化合物が挙げられる。 More specifically, the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ has the formula:

And
The “carboxyl group which may be esterified or amidated” represented by R ⁴ has the formula:

A lower alkyl group-substituted amino group optionally substituted with a group represented by the formula:

An amino group optionally substituted by a group represented by the formula:

And a carboxyl group amidated by a group selected from the groups represented by

から選ばれる基であり、
Ｒ²が水素原子であり、
Ｒ³が水素原子であり、
Ｒ⁴が、水酸基若しくは式：

で示される基で置換されていてもよい低級アルキル基置換アミノ基または式：

で示される基で置換されていてもよいアミノ基から選ばれる基によりアミド化されたカルボキシル基であり、
Ｒ⁵が低級アルコキシ基および／またはハロゲン原子により置換されていてもよいフェニル基で置換された低級アルキル基である化合物が挙げられる。 Among the compound which is the active ingredient of the present invention (I), as more preferred compounds, in general formula (I), R ¹ has the formula:

Is a group selected from
R ² is a hydrogen atom,
R ³ is a hydrogen atom,
R ⁴ is a hydroxyl group or a formula:

A lower alkyl group-substituted amino group optionally substituted by a group represented by the formula:

A carboxyl group amidated by a group selected from an amino group which may be substituted with a group represented by
Compounds in which R ⁵ is a lower alkyl group substituted with a lower alkoxy group and / or a phenyl group optionally substituted with a halogen atom.

から選ばれる基であり、
Ｒ²が水素原子であり、
Ｒ³が水素原子であり、
Ｒ⁴が、式：

で示される基で置換されていてもよいアミノ基から選ばれる基によりアミド化されたカルボキシル基であり、
Ｒ⁵が低級アルコキシ基および／またはハロゲン原子により置換されていてもよいフェニル基である化合物が挙げられる。 Particularly preferred compounds, in general formula (I), R ¹ has the formula:

Is a group selected from
R ² is a hydrogen atom,
R ³ is a hydrogen atom,
R ⁴ has the formula:

A carboxyl group amidated by a group selected from an amino group which may be substituted with a group represented by
Compounds in which R ⁵ is a lower alkoxy group and / or a phenyl group optionally substituted with a halogen atom.

Among the compounds (I) which are the active ingredients of the present invention, examples of the compound which is preferable in terms of pharmacological effect include a compound selected from the following group or a pharmaceutically acceptable salt thereof.
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- [2- (4-morpholinyl) ethyl] -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7 -Oxo-pyrido [2,3-d] pyrimidine,
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6- [N- {4- (1,3,5-trimethyl) pyrazolyl} carbamoyl] -8- (3-chloro-4-methoxybenzyl ) -7,8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3- d] Pyrimidine.

Among the compounds (I), which are the active ingredients of the present invention, compounds more preferable in terms of medicinal effect include (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6- [N- {4- (1, 3,5-Trimethyl) pyrazolylcarbamoyl] -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine or a pharmaceutically acceptable salt thereof And the salts that can be used.

When R ¹ , R ² , R ³ , R ⁴ , R ⁵ and / or R ⁷ have an asymmetric atom, the compound (I) or a pharmaceutically acceptable salt thereof which is an active ingredient of the present invention is applicable to the compound (I). Although it may exist as optical isomers based on asymmetric atoms, the present invention includes both of these optical isomers and mixtures thereof.

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, oxalate, citrate, Organic acid salts such as methanesulfonate, benzenesulfonate, tosylate and maleate are exemplified.
The compound (I) or a salt thereof of the present invention includes any of its inner 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, fine granules, and pills. , Capsules, powders, injections, inhalants, buccal preparations, sublingual preparations, syrups, dry syrups, jellies, suppositories, ointments, elixirs, liniments, lotions, drinks, nasal drops, It can be used as a conventional pharmaceutical preparation such as a transdermal preparation and a rapidly disintegrating preparation in the oral cavity. These pharmaceutical preparations are prepared by formulating them together with pharmaceutically acceptable excipients, binders, wetting agents, disintegrants, bulking agents and other additives in a conventional manner.
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. About 0.001 to 100 mg / kg per day, especially about 0.1 to 10 mg / kg, and for oral preparation, usually about 0.1 to 200 mg / kg, especially about 0.1 to 80 mg / kg per day. It is preferred that

The compound (I) or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, has an excellent selective PDEV inhibitory activity. Various diseases caused by dysfunction (e.g., pulmonary hypertension, diabetic gastroparesis, hypertension, angina, myocardial infarction, chronic and acute heart failure, female sexual dysfunction, prostatic hypertrophy, asthma, diarrhea, constipation, achalasia , Premature ejaculation, etc.).

化合物 Compound (I) which is an active ingredient of the present invention can be produced by the following [Method A] to [Method G].

(式中、Ｒ⁴¹は水素原子または低級アルキル基を表し、他の記号は前記と同一意味を有する)
で示される化合物は、一般式(II)：

(式中、Ｘ¹はハロゲン原子を表し、Ｒ⁶は置換されていてもよい含窒素複素環式基、置換されていてもよいアミノ基、置換されていてもよい低級アルコキシ基、ハロゲン原子または式：−ＳＲ⁹(Ｒ⁹は置換されていてもよい低級アルキル基または置換されていてもよいアリール基を表し)、Ｒ⁸はカルボキシル基の保護基を表し、他の記号は前記と同一意味を有する)
で示される化合物に式(１)：
　　　　　Ｒ⁵−ＮＨ₂　　　(１)
(式中、記号は前記と同一意味を有する)
で示される化合物を反応させて一般式(III)：

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、 [Method A]
Among the compounds (I) which are the active ingredients of the present invention, compounds wherein R ⁴ is a hydrogen atom or a lower alkyl group, that is, a compound represented by the general formula (I-1):

(In the formula, R ⁴¹ represents a hydrogen atom or a lower alkyl group, and other symbols have the same meanings as described above.)
The compound represented by the general formula (II):

(In the formula, X ¹ represents a halogen atom, and R ⁶ represents an optionally substituted nitrogen-containing heterocyclic group, an optionally substituted amino group, an optionally substituted lower alkoxy group, a halogen atom or Formula: -SR ⁹ (R ⁹ represents an optionally substituted lower alkyl group or an optionally substituted aryl group), R ⁸ represents a carboxyl-protecting group, and other symbols have the same meanings as described above. Has)
A compound represented by the formula (1):
R ⁵ -NH ₂ (1)
(Wherein the symbols have the same meanings as described above)
Is reacted with a compound represented by the general formula (III):

(Wherein the symbols have the same meanings as described above)
To produce a compound represented by

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、さらに酸化して、一般式(Ｖ)：

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、 The obtained compound (III) is reduced to give a compound of the general formula (IV):

(Wherein the symbols have the same meanings as described above)
And further oxidized to give a compound of the general formula (V):

(Wherein the symbols have the same meanings as described above)
To produce a compound represented by

(式中、記号は前記と同一意味を有する)
で示される化合物とし、 Then, if necessary, the general formula (2):
R ³¹ -H (2)
(Wherein, R ³¹ represents an optionally substituted lower alkyl group or an optionally substituted heteroaryl group)
By reacting a metal salt of a compound represented by the general formula (VI):

(Wherein the symbols have the same meanings as described above)
And a compound represented by

(式中、Ｒ⁵¹は低級アルキル基、Ｒ⁸¹はカルボキシル基の保護基を表し、他の記号は前記と同一意味を有する)
で示される化合物を作用させ、一般式(VII)：

(式中、記号は前記と同一意味を有する)
で示される化合物とした後、閉環させ、 The compound (VI) further has a general formula (3):

(In the formula, R ⁵¹ represents a lower alkyl group, R ⁸¹ represents a protecting group for a carboxyl group, and other symbols have the same meanings as described above.)
Is reacted with a compound represented by the general formula (VII):

(Wherein the symbols have the same meanings as described above)
And then ring-closing,

(式中、Ｒ⁷はハロゲン原子または式：
　　　　　−ＳＲ⁹
で示される基を表し、Ｒ⁹は置換されていてもよい低級アルキル基または置換されていてもよいアリール基を表し、他の記号は前記と同一意味を有する)
である場合には、更に、 The obtained compound has the general formula (VIII-1):

(Wherein R ⁷ is a halogen atom or a formula:
−SR ⁹
Wherein R ⁹ represents an optionally substituted lower alkyl group or an optionally substituted aryl group, and other symbols have the same meanings as described above.)
If, then

(a) When R ⁷ is a halogen atom, the general formula (4):
R ¹ -H (4)
(Wherein the symbols have the same meanings as described above)
Reacting the compound represented by

(式中、記号は前記と同一意味を有する)
で示される化合物である場合は、得られた化合物を酸化して、一般式(IX)：

(式中、記号は前記と同一意味を有する)
で示される化合物とし、更に化合物(４)を作用させることにより、製することができる。 (b) R ⁷ is a group —SR ⁹ , that is, a compound represented by the general formula (VIII-2):

(Wherein the symbols have the same meanings as described above)
In the case of the compound represented by the formula, the obtained compound is oxidized to obtain a compound represented by the general formula (IX):

(Wherein the symbols have the same meanings as described above)
Can be produced by further reacting compound (4) with the compound represented by

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、得られた化合物を還元して、一般式(IV')：

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、 [Method B]
Compound (I-1) is prepared by reacting compound (II) with ammonia to obtain a compound of the general formula (III ′):

(Wherein the symbols have the same meanings as described above)
And the obtained compound is reduced to give a compound of the general formula (IV ′):

(Wherein the symbols have the same meanings as described above)
To produce a compound represented by

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、必要に応じ、該化合物(Ｖ')に化合物(２)を作用させ、ついで得られた化合物に化合物(３)を作用させ、一般式(VII')：

(式中、記号は前記と同一意味を有する)
で示される化合物とした後、閉環させて、一般式(VIII−３)：

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、得られた化合物に一般式(５)：
　　　　　Ｒ⁵−Ｘ²　　　(５)
(式中、Ｘ²はハロゲン原子を示し、他の記号は前記と同一意味を有する)
で示される化合物を作用させ、Ｒ⁶がハロゲン原子である場合は、化合物(４)を作用させることにより、また、Ｒ⁶が基−ＳＲ⁹である場合は、更に、得られた化合物を酸化して化合物(IX)に導き、これに化合物(４)を作用させることにより製することができる。 The compound (IV ') is further oxidized to give a compound of the general formula (V'):

(Wherein the symbols have the same meanings as described above)
And, if necessary, reacting the compound (2) with the compound (V '), and then reacting the compound (3) with the obtained compound to obtain a compound of the general formula (VII'):

(Wherein the symbols have the same meanings as described above)
After ring closure, the compound represented by the general formula (VIII-3):

(Wherein the symbols have the same meanings as described above)
And a compound represented by the general formula (5):
R ⁵ -X ² (5)
(Wherein, X ² represents a halogen atom, and other symbols have the same meanings as described above)
And reacting the compound (4) when R ⁶ is a halogen atom, and further oxidizing the obtained compound when R ⁶ is a group —SR ⁹ Then, compound (IX) is obtained, and compound (4) is allowed to act on compound (IX) to produce the compound (IX).

(式中、Ｒ⁴²はエステル化またはアミド化されていてもよいカルボキシル基を表し、他の記号は同一意味を有する)
は、化合物(VI)に、マロン酸ジ低級アルキルまたはマロン酸を作用させた後、閉環させ、適宜、常法により加水分解し、再度エステル化またはアミド化することにより、一般式(VIII−４)：

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、Ｒ⁶がハロゲン原子である場合は、化合物(４)を作用させることにより、また、Ｒ⁶が基−ＳＲ⁹である場合は、得られる化合物を酸化した後、化合物(４)を作用させることにより、製することができる。また、得られた化合物(Ｉ−２)におけるＲ⁴²は、適宜、常法により加水分解し、再度エステル化またはアミド化してもよい。 [Method C]
In the compound (I) which is an active ingredient of the present invention, R ⁴ is a carboxyl group which may be esterified or amidated, and a general formula (I-2):

(Wherein, R ⁴² represents a carboxyl group which may be esterified or amidated, and other symbols have the same meaning)
Is reacted with a di-lower alkyl malonate or malonic acid on the compound (VI), and then the ring is closed. ):

(Wherein the symbols have the same meanings as described above)
Is produced by reacting the compound (4) when R ⁶ is a halogen atom, or after oxidizing the obtained compound when R ⁶ is a group —SR ⁹ , The compound can be produced by reacting compound (4). Further, R ⁴² in the obtained compound (I-2) as appropriate, by a conventional method to hydrolyze may be re-esterified or amidated.

で示される化合物を作用させた後、酸化して、式(Ｘ)：

(式中、記号は前記と同一意味を有する)
で示される化合物を製し、次いで、式(７)：
　　　　　Ｒ³³−Ｈ　　　(７)
(式中、Ｒ³³はＲ³のエチル基上の置換基を表し、他の記号は前記と同一意味を有する)
で示される化合物を作用させ、式(XI)：

(式中、記号は前記と同一意味を有する)
で示される化合物を製した後、次いで、式(８)：
　　　　　Ｌ−ＣＨＲ⁴ＣＯＯＲ⁸²　　　(８)
(式中、Ｌは脱離基を表し、Ｒ⁸²はカルボキシル基の保護基を表し、他の記号は前記と同一意味を有する)
で示される化合物を作用させることにより、製することができる。 [Method D]
Further, among the compounds (I) which are the active ingredients of the present invention, the compound wherein R ⁴ is an optionally substituted ethyl group is represented by the formula (6):

After reacting the compound represented by the formula, the compound is oxidized to give a compound of the formula (X):

(Wherein the symbols have the same meanings as described above)
Then, a compound represented by the following formula:
R ³³ -H (7)
(Wherein, R ³³ represents a substituent on the ethyl group of R ³ , and other symbols have the same meanings as described above)
Is reacted with a compound represented by the formula (XI):

(Wherein the symbols have the same meanings as described above)
After preparing the compound represented by the formula, then, the compound represented by the formula (8):
L-CHR ⁴ COOR ⁸² (8)
(Wherein, L represents a leaving group, R ⁸² represents a protecting group for a carboxyl group, and other symbols have the same meanings as described above.)
Can be produced by reacting the compound represented by

[Method E]
The metal compound of the compound (2) is allowed to act on the compound represented by the general formula (VII) or (VII ′) wherein R ³ is a hydrogen atom, followed by ring closure and oxidation, whereby R ³ is substituted. May be converted to an optionally substituted lower alkyl group or an optionally substituted heteroaryl group. In the general formula (I-1), R ³ may be an optionally substituted lower alkyl group or an optionally substituted heteroaryl group. Compounds that are aryl groups can be prepared.

[Method F]
In the general formula (I-1), when R ² and / or R ³ is a hydrogen atom, the metal compound of the compound (2) is allowed to act and then oxidized to thereby form R ² and / or R ³ Can be converted to a group other than a hydrogen atom.

(式中、Ｒ⁷¹はハロゲン原子または式：
　　　　　−ＳＲ⁹
で表される基を表し、Ｒ⁹は前記と同一意味を有し、他の記号は前記と同一意味を有する)
である場合には、更に、
(ａ)Ｒ⁷¹がハロゲン原子である場合は、前記化合物(４)を作用させ、
(ｂ)また、Ｒ⁷¹が基：−ＳＲ⁹、即ち、一般式(VI−２)：

(式中、記号は前記と同一意味を有する)
で示される化合物である場合は、得られた化合物を酸化して、一般式(XII)：

(式中、記号は前記と同一意味を有する)
で示される化合物とし、更に化合物(４)を作用させ、一般式(XIII)：

(式中、記号は前記と同一意味を有する)
で示される化合物とした後、前記化合物(３)を作用させ、一般式(XIV)：

(式中、記号は前記と同一意味を有する)
で示される化合物とした後、閉環させることにより製することができる。 [Method G]
In addition, the compound of the general formula (I-1) is prepared in the same manner as in the above-mentioned Method A, and the obtained compound is represented by the general formula (VI-1):

(Wherein, R ⁷¹ is a halogen atom or a formula:
−SR ⁹
Wherein R ⁹ has the same meaning as described above, and other symbols have the same meanings as described above.)
If, then
(a) when R ⁷¹ is a halogen atom, reacting the compound (4);
(b) R ⁷¹ is a group: —SR ⁹ , that is, a compound represented by the general formula (VI-2):

(Wherein the symbols have the same meanings as described above)
When the compound is represented by the formula, the obtained compound is oxidized to give a compound represented by the general formula (XII):

(Wherein the symbols have the same meanings as described above)
A compound represented by general formula (XIII):

(Wherein the symbols have the same meanings as described above)
Then, the compound (3) is reacted with the compound represented by the general formula (XIV):

(Wherein the symbols have the same meanings as described above)
And then ring-closing the compound.

[Method A] to [Method G] can be carried out as follows.
[Method A]
The reaction between compound (II) and compound (1) 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, any solvent that does not inhibit the reaction, such as dimethyl sulfoxide, tetrahydrofuran, toluene, ethyl acetate, chloroform, dimethoxyethane, xylene, and N, N-dimethylformamide, can be suitably used. The present reaction suitably proceeds at -10 ° C to the boiling point of the solvent used, particularly at 0 ° C to room temperature.

反 応 The reaction for reducing compound (III) to give compound (IV) can be carried out in the presence of a reducing agent in a suitable solvent. As the reducing agent, alkali metal aluminum hydride such as lithium aluminum hydride, alkali metal borohydride such as lithium borohydride, or the like can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, dioxane, diethyl ether, and 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.

反 応 The reaction of oxidizing compound (IV) to give compound (V) 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 suitably proceeds at 0 ° C to 100 ° C, particularly at room temperature to 70 ° C.

反 応 The reaction of reacting the compound (V) with the metal salt of the compound (2) to give the compound (VI) can be carried out in a suitable solvent. As the metal salt of the compound (2), a lithium salt or the like can be suitably 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. This reaction suitably proceeds at -78 ° C to room temperature.

反 応 The reaction of reacting compound (VI) with compound (3) to give compound (VII) is carried out in a suitable solvent in the presence of a base. Examples of the base include sodium hydride, potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium amide, lithium amide, lithium diisopropylamide and the like. As a solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, methanol, ethanol, dimethoxyethane, N, N-dimethylformamide, dimethylsulfoxide, diethyl ether, dimethoxyethane, dioxane, and toluene can be used. This reaction is suitably carried out at -78 ° C to the boiling point of the solvent used, especially at -10 ° C to 60 ° C.

環 The ring closing reaction of compound (VII) is performed in an appropriate solvent in the presence of a base catalyst. Examples of the base catalyst include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and the like. As the solvent, a solvent that does not inhibit the reaction, such as methanol, ethanol, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide, and the like can be used. This reaction is suitably carried out at 0 ° C to the boiling point of the solvent used, especially at room temperature to 100 ° C.

反 応 The reaction of oxidizing compound (VIII-2) to give compound (IX) can be carried out in a suitable solvent in the presence of an oxidizing agent. Examples of the oxidizing agent include peracids such as m-chloroperbenzoic acid and peracetic acid, manganese dioxide, sodium periodate, hydrogen peroxide, nitrous oxide, halogen, hydroperoxide, iodobenzene acetate, and hypochlorous acid t. Inorganic oxidants such as -butyl, sulfuryl chloride and potassium peroxymonosulfate can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, methylene chloride, dichloromethane, and acetic acid, can be appropriately used. This reaction suitably proceeds at −78 ° C. to 50 ° C., particularly at −10 ° C. to 10 ° C.

The reaction of reacting compound (VIII-1) or compound (IX) with compound (4) to obtain compound (I-1) 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 salt of compound (4), 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. The present reaction suitably proceeds at 0 ° C to 150 ° C, particularly at room temperature to 60 ° C.

[Method B]
The method of producing compound (III ′) by reacting compound (II) with ammonia is carried out in the same manner as in the reaction of compound (II) with compound (1) in the above-mentioned Method A.

The reaction for reducing the compound (III ') to obtain the compound (IV') can be carried out in the same manner as the reaction for reducing the compound (III) in the above-mentioned Method A to obtain the compound (IV).
The reaction of oxidizing compound (IV ') to obtain compound (V') can be carried out in the same manner as the reaction of oxidizing compound (IV) to obtain compound (V).
The step of reacting the compound (2) with the compound (V ') and the step of further reacting the compound (3) to obtain the compound (VII') are also performed by the reaction between the compound (V) and the compound (2) in the above-mentioned Method A. And the reaction between compound (VI) and compound (3). In addition, the reaction for converting the compound (VII ') to a compound (VIII-3) can be carried out in the same manner as the reaction for converting the compound (VII) to a compound (VIII-1).

工程 The step of reacting compound (VIII-3) with compound (5) can be carried out in a suitable solvent in the presence of a deoxidizing agent. Examples of the deoxidizing agent include potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like. As the solvent, a solvent which does not inhibit the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, toluene, tetrahydrofuran, dioxane and the like can be used. The present reaction suitably proceeds at -10 ° C to the boiling point of the solvent used, particularly at room temperature to 60 ° C.

Of the above reaction products, when R ⁶ is —SR ⁹ , the oxidation treatment can be carried out in the same manner as in the above-mentioned Method A, in which compound (VIII-2) is oxidized to obtain compound (IX). Further reacting the compound (4) with the product of the compound (VIII-3) and the compound (5) or the oxidized product (IX) to obtain the compound (I-1), And the compound (4) is reacted with the compound (VIII-1) or compound (IX) to obtain the compound (I-1).

[Method C]
The reaction of reacting compound (VI) with malonic acid di-lower alkyl ester or malonic acid can be carried out in a suitable solvent in the presence of a base. The reaction is further promoted by the addition of a catalytic amount of acid. Examples of the base include organic bases such as piperidine, pyridine, diethylamine, and triethylamine, and inorganic bases such as sodium methoxide. Examples of the catalytic amount of acid to be added include hydrochloric acid, acetic acid, benzoic acid, and titanium tetrachloride. As the solvent, a solvent that does not inhibit the reaction, such as methanol, ethanol, benzene, toluene, acetonitrile, propionitrile, tetrahydrofuran, carbon tetrachloride, or the like can be used. This reaction suitably proceeds at −50 ° C. to 200 ° C., particularly 0 ° C. to the boiling point of the solvent used. Subsequently, the reaction leading to compound (VIII-4) by ring closure suitably proceeds as it is at 50 ° C. to the boiling point of the solvent used.

The oxidation of the above product is carried out in the same manner as in the above-mentioned method A, in which the compound (VIII-2) is oxidized to give the compound (IX), and the reaction product of the above compound (VI) with malonic acid or the like. Alternatively, a method of reacting compound (4) with an oxidation product thereof to obtain compound (I-2) comprises reacting compound (4) with compound (VIII-1) or compound (IX) in the above-mentioned Method A to give compound (4). This is performed in the same manner as in the method for obtaining (I-1).

[Method D]
The reaction between compound (V) and compound (6) 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. Then, the reaction of oxidizing the product to compound (X) 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 a corresponding carbonyl compound. 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 suitably proceeds at 0 ° C to 100 ° C, particularly at room temperature to 70 ° C.

反 応 The reaction between compound (X) and compound (7) can be carried out in a suitable solvent in the presence or absence of a base. 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. The present reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 60 ° C.

反 応 The reaction between compound (XI) and compound (8) can be carried out in a suitable solvent in the presence of a base. Examples of the leaving group L of the compound (8) include a trialkylsilyl group, a trialkyl and a triarylphosphonyl group. Examples of the base include sodium hydride, sodium methoxide, sodium ethoxide, lithium hydroxide, triethylamine, potassium hexamethylsilazide, lithium diisopropylamide, lithium dicyclohexylamide and the like. As the solvent, a solvent that does not inhibit the reaction, such as tetrahydrofuran, dimethyl sulfoxide, toluene, methanol, N, N-dimethylformamide, benzene, dimethoxyethane, and tetrahydroethylenediamine can be used. This reaction suitably proceeds at -100 ° C to the boiling point of the solvent used, particularly at -78 ° C to 30 ° C.

[Method E]
The ring closure reaction of the compound (VII) or (VII ′) in which R ³ is a hydrogen atom by reacting the metal compound of the compound (2) can be carried out in a suitable solvent. Examples of the metal compound of the compound (2) include a compound prepared from a metal salt of the compound (2) and copper cyanide. As the solvent, a solvent that does not inhibit the reaction, such as ether, tetrahydrofuran, dioxane, toluene, benzene, and ethanol, can be used as appropriate. This reaction suitably proceeds at -100 ° C to 50 ° C, preferably at -80 ° C to room temperature.
The oxidation reaction of the resulting compound can be carried out in a suitable solvent in the presence of an oxidizing agent. As the oxidizing agent, manganese dioxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, chloranil, selenium dioxide, oxygen (air) and the like can be suitably used. As the solvent, a solvent that does not inhibit the reaction, such as chloroform, carbon tetrachloride, acetonitrile, N, N-dimethylformamide, p-cinone, xylene, toluene, benzene, dioxane, tetrahydrofuran, nitrobenzene, pyridine, acetic acid, etc., is appropriately used. Can be done. This reaction suitably proceeds at -20 ° C to the boiling point of the solvent used, preferably at room temperature to 100 ° C.

[Method F]
The reaction of the compound (I-1) (wherein R ² and / or R ³ is a hydrogen atom) with the metal compound of the compound (2) and the oxidation of the resulting compound are carried out by the above-mentioned Method E. Can be carried out in the same manner as in the reaction of compound (2) with a metal compound and the oxidation reaction of the obtained compound.

[Method G]
The step of allowing compound (4) to act on compound (VI-1) can be carried out in the same manner as the step of allowing compound (4) to act on compound (VIII-1) in the above-mentioned Method A.
The step of oxidizing the compound (VI-2) can be performed in the same manner as the step of oxidizing the compound (VIII-2) in the above-mentioned Method A.
The step of causing compound (4) to act on compound (XII) can be carried out in the same manner as the step of allowing compound (IX) to act on compound (4) in the above-mentioned Method A.
The step of allowing compound (3) to act on compound (XIII) can be carried out in the same manner as in the above-mentioned Method A, wherein the step of causing compound (3) to act on compound (VI).
The step of closing the compound (XIV) can be performed in the same manner as the step of closing the compound (VII).

Hereinafter, the present invention will be described in detail with reference to experimental examples and production examples, but these do not limit the present invention.
Experimental Example 1 (PDE V inhibitory action)
(Preparation method of PDE V)
The supernatant obtained by centrifuging the lung homogenate isolated from the hybrid male dog was fractionated by anion exchange column chromatography. ~ 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 the PDE III selective inhibitor CI930. 4. Not inhibited by Rolipram, a PDE IV selective inhibitor. Inhibition by P-40V selective inhibitor E-4021

で示されるカルシウムキレート剤であり、酵素液からカルシウムキレートすることでＰＤＥ Ｉの活性を阻害する。
　ＣＩ９３０とは、式［ｘｖｉ］

で示されるＰＤＥ ＩＩＩ選択的阻害剤である。ＰＤＥ Ｖの酵素液の中にＰＤＥ ＩＩＩが混入していないことを確認するために使用する。
　ロリプラムとは、式［ｘｖｉｉ］

で示されるＰＤＥ ＩＶ選択的阻害剤である。ＰＤＥ Ｖの酵素液の中にＰＤＥ ＩＶが混入していないことを確認するために使用する。
　Ｅ−４０２１とは、式［ｘｖｉｉｉ］

で示されるＰＤＥ Ｖ選択的阻害剤である。 Here, EGTA is represented by the formula [xv]

And inhibits the activity of PDE I by chelating calcium from an enzyme solution.
CI930 is represented by the formula [xvi]

Is a PDE III selective inhibitor represented by It is used to confirm that PDE III is not mixed in the enzyme solution of PDE V.
Rolipram is represented by the formula [xvii]

Is a PDE IV selective inhibitor represented by It is used to confirm that PDE IV is not mixed in the enzyme solution of PDE V.
E-4021 is represented by the formula [xviii]

Is a PDE V selective inhibitor represented by

(Measurement of PDE V activity)
The method of Thompson et al. (Advance in Cyclic Nucleotide Research), Vol. 10, Raven Press, New York, pp. 69-92, 1979, was partially modified. That is, 100 μl of a partially purified PDEV sample diluted with 50 mM Tris-HCl, pH 8.0 to hydrolyze about 10% of the total substrate was added to a glass test tube. After adding 200 μl of a buffer solution for reaction (50 mM Tris-HCl, pH 8.0, 12.5 mM MgCl ₂ , 10 mM 2-mercaptoethanol) to the test tube, a test compound dissolved in dimethyl sulfoxide (obtained in the production example described later) Compound (100-fold concentration) was added in an amount of 5 μl. After pre-incubating this solution at 37 ° C. for 5 minutes, 200 μl of 2.5 μM [ ³ H] cGMP (3.7 kBq / 200 μl) was added to start the reaction (final concentration 50 mM Tris-HCl, pH 8.0, 5 mM MgCl 2). ₂ , 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 play incubation at 37 ° C. for 5 minutes, 100 μl of a 1 mg / ml snake venom aqueous solution was added to the test tube and reacted at 37 ° C. for 30 minutes. After the reaction was stopped by adding 500 μl of methanol to the test tube, 1 ml of the reaction solution was supplied to a column to which 200 μl of Dowex resin (trade name: Dowex, 1 × 8, manufactured by Sigma) was previously added. 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 the radioactivity of [ ³ H] guanosine (Guanosine) in the solution was measured to determine the PDEV inhibition activity.

The inhibition ratio of each sample with respect to the control was calculated by using a blank in which only the buffer solution was added without adding the enzyme standard and a control in which the enzyme standard was added but only dimethyl sulfoxide was added instead of the sample solution as a control. The PDEV inhibition activity was evaluated by IC ₅₀ (concentration at which the inhibition rate of each sample with respect to the control was 50%; nM). Here, the calculation of the IC ₅₀ value of each sample was performed by determining the inhibition rates at three or more sample concentrations and performing linear regression.
The results are as shown in Table 1 below.

Experimental Example 2 (relaxing action of isolated rabbit cavernous body)
(Preparation of specimen)
A 10-20 week old male rabbit (New Zealand White line) was used. 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. After confirming the contraction reaction of the sample at a high concentration of KCl (120 mM), it was used in the experiment. The nutrient solution during the experiment was maintained at 37 ± 0.5 ° C. with a gas mixture of 95% O ₂ and 5CCO ₂ aerated. Isometric tension was measured via a U-cage and strain amplifier (AP600 series, Nihon Kohden) and recorded on a pen writing recorder (GRAPHTEC MULTICORDER MC6621).
Nutrient solution composition (mM): NaCl 118.1, KCl 4.7, CaCl ₂ 1.5, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, NaHCO ₃ 25.0, gulucose 11.0, EDTA 0.023

(Relaxation effect in phenylephrine contraction specimen)
After the specimen was contracted with phenylephrine (5 μM) to enter the continuous phase, the specimens were cumulatively added at 0.1, 10, 100, and 1000 nM at 30-minute intervals. Finally, papaverine (100 μM) was added to confirm the maximum relaxation of the specimen. The magnitude of relaxation at each concentration was calculated assuming that relaxation by papaverine (100 μM) was 100%. The concentration of the sample showing a relaxing action of 30% was calculated as EC ₃₀ (nM), and the relaxing action of the sample was evaluated.
The results are shown in Table 2 below.

[Production example]
Specific examples (production examples) of the compound (I) which is an active ingredient of the present invention synthesized by each of the above exemplified methods are shown below.
Production Example 1
Of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine Synthesis

(1) A solution of 25.33 g of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine in 85 ml of N, N-dimethylformamide was added with 19.62 g of N, N- A solution of 15 ml of dimethylformamide and 16.7 ml of triethylamine are added. 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 is poured into an ice water-citric acid mixture, extracted with ethyl acetate, washed successively with a 10% aqueous citric acid solution, water and brine, and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is washed with n-hexane to obtain 38.34 g of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine. Melting point: 86 [deg.] C.

(2) To a suspension of 4.15 g of lithium aluminum hydride in 150 ml of tetrahydrofuran, a solution of 38.32 g of 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-ethoxycarbonylpyrimidine in 100 ml of tetrahydrofuran was ice-cooled. Add over 1 hour at below 5-10 ° C. 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 are added to the reaction mixture under ice cooling, and then 4.15 ml of a 3N aqueous sodium hydroxide solution. 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 obtain 2-methylthio-4- (3-chloro-4-methoxybenzylamino) -5-hydroxymethylpyrimidine as a pale yellow crystalline powder.
First crop; yield: 25.10 g, melting point: 162-163 ° C.
2nd generation; yield: 2.32 g, melting point: 159-160 ° C
Further, the precipitated solid is washed again with isopropyl ether, and the filtrate is 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.

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

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

(5) A solution of diethyl phosphonoacetic acid methyl ester (0.084 g) in anhydrous tetrahydrofuran (2.0 ml) was treated with sodium hydride (60% oil suspension, 9.9 mg) at 0 ° C. for 30 minutes. Hydrogen gas evolves quickly to obtain a clear solution. To this solution was added (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine (aldehyde, 0.100 g) in tetrahydrofuran. Add and stir the mixture at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate are added, the ethyl acetate layer is separated, and washed with water and saturated saline. Purification by preparative TLC (solvent; hexane: ethyl acetate = 1: 1), trituration with ethyl acetate and diisopropyl ether to give a light yellow solid (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) 4- (3-Chloro-4-methoxybenzylamino) -5- (methoxycarbonylvinyl) pyrimidine (15.3 mg) is obtained. Melting point: 163-164C. IR (nujol): 3380, 1707, 1597, 1556, 1500, 1463, 1193, 1174 cm ^-1 . MS (m / z): 433 (MH ^<+> , base peak), 401.

(6) A mixture of the compound (45.0 mg) obtained in (5) above, a 1N aqueous sodium hydroxide solution (0.31 ml) and methanol (2 ml) is stirred at room temperature overnight and refluxed for 5 hours. Cool the reaction mixture and wash with diethyl ether. The aqueous layer is acidified with citric acid, sodium chloride (solid) is added to the aqueous layer, the organic layer is separated, dried over sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by preparative TLC (solvent; chloroform: methanol = 5: 1), concentrated, and triturated with diisopropyl ether and ethyl acetate to give (S) -2- (2-hydroxyl) as a colorless solid. Methyl-1-pyrrolidinyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (8.8 mg) is obtained. Melting point: 142-143 [deg.] C. MS (m / z): 401 (MH ^<+> , base peak).

Production Example 2
Synthesis of 2- (2-pyridylmethoxy) -5- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine

(1) A suspension of sodium hydride (60% oil suspension, 0.556 g) in anhydrous tetrahydrofuran (60 ml) is treated with dimethylphosphonoacetic acid methyl ester (2.25 ml) at 0 ° C. Tetrahydrofuran (20 ml) is added to the precipitated colorless salt, and the mixture is stirred at 0 ° C. for 30 minutes. 2-Methylthio-4- (3-chloro-4-methoxybenzylamino) -5-formylpyrimidine (3.00 g) obtained in (2) of Production Example 1 above was added at once, and tetrahydrofuran (10 ml) was added. To dissolve the precipitated salt. The colorless reaction mixture turns yellow upon addition of the aldehyde compound. Ethyl acetate and water are added to the reaction mixture, the organic layer is separated, washed with saturated saline and dried over sodium sulfate. The obtained residue was purified by silica gel chromatography (solvent; hexane: ethyl acetate = 3: 1, then chloroform alone) to give 2-methylthio-4- (3-chloro-4-methoxybenzylamino)-as a pale yellow solid. 5- (Methoxycarbonylvinyl) pyrimidine (2.827 g) is obtained. Melting point: 144-144.5C.

(2) The compound (2.827 g) obtained in the above (1) is treated with methanol (50 ml) containing sodium hydride (35 mg) under reflux for 1.5 hours. The reaction mixture was cooled, the precipitate was collected by filtration, and the obtained crystal was washed with methanol and then with diisopropyl ether to give 2-methylthio-8- (3-chloro-4-methoxybenzylamino) as a colorless fine powder. ) -7,8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine (2.490 g) is obtained. Melting point: 189-190C. MS (m / z): 530 (MH ^<+> , base peak). IR (nujol): 1735, 1694, 1583, 1553, 1503, 1439, 1260, 1143, 1028 cm ^-1 .
(3) A mixture of the compound (0.500 g) obtained in the above (2), m-chloroperbenzoic acid (0.311 g) and chloroform (7 ml) is reacted at room temperature for 5 minutes. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate. The precipitate is washed and dissolved in chloroform. Wash the chloroform solution with saturated aqueous sodium bicarbonate, dry over sodium sulfate, filter, and concentrate in vacuo. The residue was triturated with ethyl acetate to give brown solid 2-methylsulfonyl-8- (3-chloro-4-methoxybenzylamino) -7,8-dihydro-7-oxo-pyrido [2,3-d ] Pyrimidine (0.520 g) is obtained. Melting point: 212-214 [deg.] C. IR (nujol): 1673, 1557, 1504, 1455, 1362, 1292, 1257, 1142, 1071, 800 cm ^-1 . MS (m / z): 364 (MH ⁺ , base peak), 332 (MH ⁺ -32).

(4) A solution of 2-pyridinemethanol (54 mg) in tetrahydrofuran (3 ml) was treated with sodium hydride (19.8 mg) at room temperature for 1 hour. To the obtained sodium salt suspension, the compound (150 mg) obtained in the above (3) is added all at once. The mixture is stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added, the organic layer is separated, washed with water and saturated saline, and dried over sodium sulfate. Purification by silica gel chromatography gave a colorless oil which was recrystallized from ethyl acetate: diisopropyl ether to give the desired 2- (2-pyridylmethoxy) -8- (3-chloro-4-methoxybenzylamino)- 7,8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine (78.8 mg) is obtained. Melting point: 130-131 ° C. IR (nujol): 1665, 1584, 1505, 1265, 1040, 803 cm ^-1 . MS (m / z): 409 (MH ^<+> , base peak).

Production Example 3
Synthesis of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -8-N-methyl-7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine

(1) 28% aqueous ammonia (30 ml) was added to a solution of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine (10.0 g) in tetrahydrofuran (150 ml) to obtain an emulsion. To this is added methanol (about 20 ml) to make a clear solution, which is stirred overnight at room temperature. The reaction mixture is concentrated in vacuo and extracted with ethyl acetate. The organic layer is washed sequentially with water (twice) and brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless solid. This was recrystallized from ethyl acetate (high temperature, about 100 ml) to give colorless prism crystals of 2-methylthio-5-ethoxycarbonyl-4-aminopyrimidine (7.00 g). Melting point: 131-132 ° C. MS (m / z): 214 (MH ^<+> ). IR (nujol): 3412, 3269, 3133, 1693, 1630, 1567, 1367, 1311, 1206, 1096 cm- ¹ .

(2) To a suspension of lithium aluminum hydride (664 mg) in tetrahydrofuran (35 ml) was added dropwise a solution of the compound (3.55 g) obtained in the above (1) in tetrahydrofuran (35 ml) over an ice bath over 30 minutes. The whole reaction is stirred for a further 30 minutes. Water (0.66 ml) and then a 3N aqueous sodium hydroxide solution (0.66 ml) are added to the reaction solution to obtain a gel-like gray suspension. After stirring for a while, treat again with water (3 × 0.66 ml = 2 ml) and stir for 2 hours. The mixture is filtered over a bed of magnesium sulfate, the precipitate is washed well with tetrahydrofuran, and the collected filtrate is concentrated in vacuo to give a colorless solid. This solid was suspended in a mixed solvent of ethyl acetate-diisopropyl ether, and the resulting crystals were separated by filtration and sufficiently washed with diisopropyl ether and hexane to give 2-methylthio-5-hydroxymethyl-4-colorless crystalline powder. Aminopyrimidine (2.56 g) is obtained. Melting point: 129 [deg.] C. MS (m / z): 172 (MH +), 154 (-H 2 O). IR (nujol): 3438, 3289, 3134, 1637, 1547, 1524, 1480, 1466, 1356, 1267 cm- ¹ .

(3) To a suspension of the compound obtained in (2) (2.52 g) in chloroform (70 ml) was added manganese dioxide powder (7.56 g) in an amount three times the amount of the starting material, and the mixture was vigorously stirred at room temperature overnight. Stir. The insolubles are removed by filtration and the filtrate is concentrated in vacuo to give a colorless solid. It is very poorly soluble in organic solvents. The obtained solid was recrystallized from a mixed solution of chloroform and methanol, triturated with a mixed solvent of chloroform-diisopropyl ether-hexane, washed with diisopropyl ether and hexane, and dried to give 2-methylthio-5-formyl as a colorless powder. -4-Aminopyrimidine (1.75 g) is obtained. Melting point: 186-187 [deg.] C. MS (m / z): 170 (MH ^<+> ). IR (nujol): 3406, 3289, 3177, 1667, 1631, 1616, 1585, 1529, 1387, 1180, 781 cm ^-1 .

(4) To a suspension of sodium hydride (60% oil suspension, 130 mg) in anhydrous tetrahydrofuran (15 ml) was added trimethylphosphonoacetic acid (526 μl) on an ice bath. Insoluble salts precipitate during the addition. The reaction mixture is stirred at the same temperature for 30 minutes. The powder of the compound (500 mg) obtained in (3) above is added to the suspension at once on an ice bath. The ice bath is removed and the heterogeneous mixture is stirred vigorously to obtain a clear solution after a few minutes. Ethyl acetate and water are added at room temperature, the organic layer is separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a colorless solid. This was suspended in a mixed solution of ethyl acetate and diisopropyl ether, filtered and then washed with diisopropyl ether and hexane to give a slightly yellow crystalline powder of 2-methylthio-5- (methoxycarbonylvinyl) -4-aminopyrimidine (619 mg). ). Melting point: 192-196 ° C. MS (m / z): 226 (MH ^<+> ). IR (nujol): 3446, 3302, 1706, 1644, 1624, 1573, 1381, 1329, 1167 cm ^-1 .

(5) Sodium hydride (60%, 130 mg) was added to a suspension of the compound (610 mg) obtained in the above (4) in methanol (12 ml), and the mixture was refluxed for 1 hour. The reaction solution was neutralized by adding a 2N aqueous hydrochloric acid solution, the mixture was diluted with water, and the precipitated solid was collected, washed with water, ether and hexane, and then washed with 2-methylthio-7,8-dihydro-7-oxo- The pyrido [2,3-d] pyrimidine (481 mg) is obtained in powder form. Melting point: 270-271 ° C. MS (m / z): 194 (MH ^<+> ). IR (nujol): 1672, 1608, 1597, 1525, 1460, 1383, 1167 cm- ¹ .

(6) To a suspension of the compound (103 mg) obtained in (5) above in anhydrous dimethylformamide (3 ml), add iodomethyl (37 μl) with a microsyringe on an ice bath, and then add potassium carbonate powder (81 mg) all at once. . The reaction mixture is stirred at 0 ° C. for 30 minutes and then at room temperature for 30 minutes. Water is added to the reaction mixture, the mixture is extracted with ethyl acetate, and the organic layer is washed successively with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless solid. The obtained crude product was suspended in a mixed solvent of ethyl acetate and diisopropyl ether, and the solid was collected by filtration and washed with a mixed solution of diisopropyl ether and hexane to give 2-methylthio-8-N-methyl-7 as a colorless powder. , 8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine (82 mg) is obtained. Melting point: 192-193C. MS (m / z): 208 (MH ^<+> ). IR (nujol): 1677, 1569, 1459, 1369, 1173 cm- ¹ .

(7) To a solution of the compound (70 mg) obtained in (6) above in chloroform (1.5 ml) is added m-chloroperbenzoic acid (70%, 92 mg) at a time on an ice bath, and the mixture is stirred for 20 minutes. . A mixture of L-prolinol (38 mg) and triethylamine (103 mg) in chloroform (0.5 ml) was reacted with the reaction mixture and stirred at room temperature for 3 hours. Water was added, more potassium carbonate was added, the organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give a mixture of a yellow oil and a white solid (crude, 106 mg). The residue was suspended in a mixture of ethyl acetate and diisopropyl ether, a slightly yellow solid was filtered off, washed thoroughly with a mixture of diisopropyl ether and hexane, and treated with (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) Obtain -8-N-methyl-7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (65 mg). Melting point: 143-144 [deg.] C. MS (m / z): 261 (MH ^<+> ). IR (nujol): 3336, 3275, 1647, 1611, 1574, 1517, 1463, 1413, 1341, 1049 cm ^-1 .

(１)２−メチルチオ−５−ホルミル−４−(３−クロロ−４−メトキシベンジルアミノ)ピリミジン(０.７０００ｇ)、マロン酸ジメチル(７ｍｌ)、ピペリジン(２１４μｌ)および酢酸(２４８μｌ)の混合物を室温で１週間攪拌し、ついで１２０℃で４時間攪拌する。反応混合物を冷却し、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過する。濾液を真空濃縮し、残渣をジイソプロピルエーテルと酢酸エチルでトリチュレーションして、黄色粉末状の２−メチルチオ−８−(３−クロロ−４−メトキシベンジル)−６−(メトキシカルボニル)−７,８−ジヒドロ−７−オキソ−ピリド[２,３−ｄ]ピリミジン(０.６８１９ｇ)を得る。融点：１９１〜１９３℃。ＩＲ(nujol)：１７４９、１６９８、１６７２、１６１３、１５７８、１５２９、１５０３、１４１３、１３６４、１３３１、１２８９、１２５９、１１７９、８００ｃｍ^-1。ＭＳ(m/z)：４０６(ＭＨ⁺、base peak)。 Production Example 4
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6- (methoxycarbonyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2 Synthesis of [, 3-d] pyrimidine

(1) A mixture of 2-methylthio-5-formyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (0.7000 g), dimethyl malonate (7 ml), piperidine (214 μl) and acetic acid (248 μl) Stir at room temperature for 1 week and then at 120 ° C. for 4 hours. The reaction mixture is cooled, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was triturated with diisopropyl ether and ethyl acetate to give 2-methylthio-8- (3-chloro-4-methoxybenzyl) -6- (methoxycarbonyl) -7, a yellow powder. 8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine (0.6819 g) is obtained. Melting point: 191-193C. IR (nujol): 1749, 1698, 1672, 1613, 1578, 1529, 1503, 1413, 1364, 1331, 1289, 1259, 1179, 800 cm- ¹ . MS (m / z): 406 (MH ^<+> , base peak).

(2) A chloroform (8 ml) solution of the compound (0.846 g) obtained in the above (1) is treated with m-chloroperbenzoic acid (70%, 0.513 g) at room temperature for 30 minutes with stirring. Triethylamine (0.435 ml) and L-prolinol (0.232 g) are added to the mixture, and the mixture is stirred for 3 nights. The reaction mixture is diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried with sodium sulfate. Purification by silica gel column chromatography (solvent; chloroform: ethyl acetate = 6: 1 → ethyl acetate alone) gave a yellow powder, which was triturated with a mixture of ethyl acetate and diisopropyl ether to give a yellow powder ( S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -6-methoxycarbonyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3- d] Pyrimidine (21.5 mg) is obtained. Melting point: 175-176 ° C.

(１)２−メチルチオ−５−ホルミル−４−(３−クロロ−４−メトキシベンジルアミノ)ピリミジン(０.２０００ｇ)、２−ホスフォノプロピオン酸トリエチルエステル(０.４４１ｇ)、水素化ナトリウム(６０％油状懸濁物、７４.１ｍｇ)および無水テトラヒドロフラン(５ｍｌ)の混合物を室温下１時間攪拌する。溶媒を真空除去し、残渣をさらに精製することなく次の工程に用いる。
　上記で得られた残渣のクロロホルム(５ｍｌ)溶液をｍ−クロロ過安息香酸(７０％、１６８ｍｇ)で室温下１５分間処理する。混合物にＬ−プロリノール(６９ｍｇ)とトリエチルアミン(１７２μｌ)を加え、室温下一晩攪拌する。シリカゲルクロマトグラフィー(溶媒；クロロホルム：酢酸エチル＝１：１)で精製して、無色油状の２−メチルスルフィニル−５−(２−エトキシカルボニル−１−プロペニル)−６−(３−クロロ−４−メトキシベンジルアミノ)ピリジン(約０.２０ｇ)を得る。
　この２−メチルスルフィニル−５−(２−エトキシカルボニル−１−プロペニル)−６−(３−クロロ−４−メトキシベンジルアミノ)ピリジン(０.２０ｇ)、Ｌ−プロリノール(６９ｍｇ)、トリエチルアミン(１７２μｌ)およびクロロホルム(５ｍｌ)を６時間還流する。シリカゲルクロマトグラフィーで精製して(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−５−(２−エトキシカルボニル−１−プロペニル)−６−(３−クロロ−４−メトキシベンジルアミノ)ピリミジン(約２００ｍｇ)を得る。 Production Example 5
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3- Synthesis of d] pyrimidine

(1) 2-methylthio-5-formyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (0.2000 g), triethyl 2-phosphonopropionate (0.441 g), sodium hydride (60 % Oil suspension, 74.1 mg) and anhydrous tetrahydrofuran (5 ml) were stirred at room temperature for 1 hour. The solvent is removed in vacuo and the residue is used for the next step without further purification.
A solution of the residue obtained above in chloroform (5 ml) is treated with m-chloroperbenzoic acid (70%, 168 mg) at room temperature for 15 minutes. L-Prolinol (69 mg) and triethylamine (172 μl) are added to the mixture, and the mixture is stirred overnight at room temperature. Purification by silica gel chromatography (solvent; chloroform: ethyl acetate = 1: 1) gave colorless oily 2-methylsulfinyl-5- (2-ethoxycarbonyl-1-propenyl) -6- (3-chloro-4-). Methoxybenzylamino) pyridine (about 0.20 g) is obtained.
This 2-methylsulfinyl-5- (2-ethoxycarbonyl-1-propenyl) -6- (3-chloro-4-methoxybenzylamino) pyridine (0.20 g), L-prolinol (69 mg), triethylamine (172 μl) ) And chloroform (5 ml) are refluxed for 6 hours. Purify by silica gel chromatography to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (2-ethoxycarbonyl-1-propenyl) -6- (3-chloro-4-methoxybenzylamino) Pyrimidine (about 200 mg) is obtained.

(2) A mixture of the compound obtained in the above (1) (about 200 mg), sodium hydride (60% oil suspension, 17.4 mg) and methanol (2 ml) is refluxed for 6 hours. Unreacted starting material is recovered by silica gel column chromatography. The recovered starting material dissolved in chloroform is mixed with silica gel and the volatiles are removed in vacuo. The residue is left for 24 hours. The product is recovered by washing with a mixed solution of chloroform: methanol (10: 1).
The recovered starting material is treated in the same manner as described above except for silica gel (Merck; 60 g).
Separation by preparative TLC (chloroform: methanol = 20: 1) and repetition of preparative TLC twice gave a lactam compound-rich fraction, from which a colorless solid (partially crystallized) (30.7 mg) )) Of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2, 3-d] pyrimidine is obtained. IR (film): 3383, 1653, 1589, 1520, 1502, 1458, 1446, 1257, 1063.5, 799, 751 cm ^-1 . MS (m / z): 415 (MH ^<+> , base peak).

(１)ヨウ化銅(１３３ｍｇ)のジエチルエーテル(１.４ｍｌ)懸濁液に１.１Ｍ メチルリチウムジエチルエーテル溶液(１.２７ｍｌ)を−１５℃〜−２０℃にて２０分かけて滴下する。このとき反応液の色は黄色に変わり黄色の懸濁液を得、これはメチルリチウムの添加に伴って無色透明溶液に変化する。得られた溶液を１５分間攪拌し、テトラヒドロフラン(２ｍｌ)を加え、２−メチルチオ−７−オキソ−８−(３−クロロ−４−メトキシベンジル)−７,８−ヒドロピリド[２,３−ｄ]ピリミジン(５０.０ｍｇ)のテトラヒドロフラン(４ｍｌ)溶液を加える。反応混合物を攪拌しながら−２０℃からゆっくりと室温まで４時間かけて昇温する。
　反応混合物を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルを加える。生じた沈殿物を濾過し、濾過ケーキを酢酸エチルで洗浄する。濾液と洗浄液を集め飽和食塩水で洗浄する。シリカゲルカラムクロマトグラフィー(溶媒；クロロホルム：酢酸エチル＝３：１)で精製し、トリチュレーションして明黄色粉末状の２−メチルチオ−４−メチル−８−(３−クロロ−４−メトキシベンジル)−３,４,７,８−テトラヒドロ−７−オキソ−ピリド[２,３−ｄ]ピリミジン(２６.０ｍｇ)を得る。融点：１８４〜１８６℃。ＩＲ(nujol)：３１７２、１６３５、１５７２、１４６６、１２９５、１２５３、１１６２、１０６６、８０９ｃｍ^-1。ＭＳ(m/z)：３６４(ＭＨ⁺、base peak)。 Production Example 6
(S) -2- (2-hydroxy-1-pyrrolidinyl) -4-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d ] Synthesis of pyrimidine

(1) To a suspension of copper iodide (133 mg) in diethyl ether (1.4 ml) was added dropwise a 1.1 M methyllithium diethyl ether solution (1.27 ml) at -15 ° C to -20 ° C over 20 minutes. . At this time, the color of the reaction solution changes to yellow to obtain a yellow suspension, which changes to a colorless and transparent solution with the addition of methyllithium. The resulting solution was stirred for 15 minutes, tetrahydrofuran (2 ml) was added, and 2-methylthio-7-oxo-8- (3-chloro-4-methoxybenzyl) -7,8-hydropyrido [2,3-d]. A solution of pyrimidine (50.0 mg) in tetrahydrofuran (4 ml) is added. The reaction mixture is slowly warmed from -20 ° C to room temperature over 4 hours with stirring.
Pour the reaction mixture into saturated aqueous sodium bicarbonate and add ethyl acetate. The precipitate formed is filtered and the filter cake is washed with ethyl acetate. The filtrate and washing solution are collected and washed with saturated saline. Purification by silica gel column chromatography (solvent; chloroform: ethyl acetate = 3: 1), trituration and light yellow powder of 2-methylthio-4-methyl-8- (3-chloro-4-methoxybenzyl) -3,4,7,8-Tetrahydro-7-oxo-pyrido [2,3-d] pyrimidine (26.0 mg) is obtained. Melting point: 184-186 [deg.] C. IR (nujol): 3172, 1635, 1572, 1466, 1295, 1253, 1162, 1066, 809 cm ^-1 . MS (m / z): 364 (MH ^<+> , base peak).

(2) A mixture of the compound (70.0 mg) obtained in the above (1), manganese dioxide (0.35 g) and chloroform (5 ml) is stirred at room temperature for 3 days. Then, manganese dioxide (0.35 g) was added, and the mixture was further stirred overnight. The insoluble matter was removed by filtration, and the residue was purified by silica gel column chromatography to give a colorless solid, 2-methylthio-4-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-. Pyrido [2,3-d] pyrimidine (31.9 mg) is obtained.

(3) To a solution of the compound obtained in the above (2) (31.9 mg) in chloroform (3 ml) was added m-chloroperbenzoic acid (19.0 mg), the mixture was reacted at room temperature for 15 minutes, and L was added to the reaction mixture. -Prolinol (8.6 mg) and triethylamine (21.4 μl) were added and reacted at room temperature for 3 days. The reaction solution was subjected to silica gel column chromatography equilibrated with hexane: ethyl acetate (1: 1), and eluted with hexane: ethyl acetate (2: 1) to obtain a colorless oil, which was obtained by diisopropyl ether-ethyl acetate. The mixture was crystallized to give a colorless crystalline powder of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro- 7-oxo-pyrido [2,3-d] pyrimidine (28.7 mg) is obtained. Melting point: 152-153 [deg.] C. IR (nujol): 3355, 1653, 1640, 1600, 1571, 1527, 1503, 1343, 1262, 1047, 826, 799 cm- ¹ . MS (m / z): 415 (MH ^<+> , base peak).

(１)トリメチルホスフォノ酢酸(９４０μｌ)を水素化ナトリウム(６０％、２３２ｍｇ)のテトラヒドロフラン(４５ｍｌ)懸濁液に０℃で加える。混合物を０℃で１時間攪拌する(この間、無色塩が沈殿する)。混合液に２−メチルチオ−５−ホルミル−４−(３−クロロ−４−メトキシベンジルアミノ)ピリミジン(１.５０ｇ)を一度に加え、混合物を０℃で１時間攪拌する。酢酸エチルと水を加え、有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥する。硫酸ナトリウムを濾過して除き、濾液を真空濃縮し、残渣をシリカゲルカラムクロマトグラフィー(シリカゲル５０ｇ、溶媒；クロロホルム：酢酸エチル＝３：１)で精製して無色結晶の２−メチルチオ−５−(メトキシカルボニルビニル)−４−(３−クロロ−４−メトキシベンジルアミノ)ピリミジン(１.７４ｇ)を得る。融点：１４１〜１４２.５℃。ＭＳ(FAB)：３８０(ＭＨ⁺)。ＩＲ(nujol)：１７１４、１６２９ｃｍ^-1。 Production Example 7
(S) -2- (2-hydroxy-1-pyrrolidinyl) -5-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d ] Synthesis of pyrimidine

(1) Trimethylphosphonoacetic acid (940 µl) is added to a suspension of sodium hydride (60%, 232 mg) in tetrahydrofuran (45 ml) at 0 ° C. The mixture is stirred at 0 ° C. for 1 hour (during which time a colorless salt precipitates). To the mixture is added 2-methylthio-5-formyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (1.50 g) in one portion and the mixture is stirred at 0 ° C. for 1 hour. Ethyl acetate and water are added and the organic layer is washed with brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (silica gel 50 g, solvent; chloroform: ethyl acetate = 3: 1) to give colorless crystals of 2-methylthio-5- (methoxy). There is obtained (carbonyl vinyl) -4- (3-chloro-4-methoxybenzylamino) pyrimidine (1.74 g). Melting point: 141-142.5 ° C. MS (FAB): 380 (MH ^<+> ). IR (nujol): 1714, 1629 cm ^-1 .

(2) A 1.1 M solution of methyllithium in diethyl ether (5.98 ml) was added to a suspension of copper cyanide (294 mg) in diethyl ether (2 ml) at -78 ° C. The mixture is stirred at 0 ° C. for 1.5 hours (converts to a pale yellow solution). Then, a solution of the compound (250 mg) obtained in the above (1) in tetrahydrofuran (10 ml) is added dropwise to the reaction mixture at -78 ° C. The mixture is warmed to 0 ° C. and stirred at 0 ° C. for another hour. A mixture of a saturated aqueous ammonium chloride solution and aqueous ammonia (1: 1) is added, and the mixture is extracted with ethyl acetate, washed with brine, and dried over sodium sulfate.
The sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (silica gel 25 g, solvent: hexane: ethyl acetate = 2: 1) to give 2-methylthio-5-methyl as pale brown crystals. -8- (3-Chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro-7-oxo-pyrido [2,3-d] pyrimidine (107 mg) is obtained. Melting point: 118-120.5 ° C. MS (APCI): 396 (MH + + CH 3 OH).

(3) A mixture of the compound (85 mg) obtained in the above (2), m-chloroperbenzoic acid (63 mg) and chloroform (3 ml) is stirred at 0 ° C. for 1 hour. L-Prolinol (28 mg) and triethylamine (48 mg) are added, and the mixture is stirred at room temperature for 3 hours. Further, L-prolinol (24 mg) was added, and the mixture was further stirred at room temperature for 1.5 hours and then at 60 ° C. for 9 hours. An additional portion of prolinol (72 mg) is added and the mixture is stirred at 60 ° C. for 1.5 days.
Water is added to the reaction mixture, and the organic layer is washed with brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was dried in vacuo, and the residue was purified by column chromatography (20 g of silica gel, solvent: ethyl acetate) to give a colorless amorphous (S) -2- (2-hydroxymethyl-1-pyrrolidinyl). ) -5-Methyl-8- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro-7-oxo-pyrido [2,3-d] pyrimidine (73 mg) is obtained. MS (APCI): 417 (MH ^<+> ). IR (nujol): 1693, 1601, 1551, 1503 cm ^-1 .

(4) The compound obtained in the above (3) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in dioxane at room temperature for 3 days and then at 60 ° C. for 10 hours, to give (S ) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -5-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] Get pyrimidine. Melting point: 150-153 [deg.] C.

(１)２−メチルチオ−６−メトキシカルボニル−８−(３−クロロ−４−メトキシベンジル)−７,８−ジヒドロ−７−オキソ−ピリド[２,３−ｄ]ピリミジン(８６０ｍｇ)、ｍ−クロロ過安息香酸(５７５ｍｇ)およびクロロホルム(１６ｍｌ)の混合物を０℃で１時間攪拌する。Ｌ−プロリノール(２３６ｍｇ)とトリエチルアミン(４３０ｍｇ)を加え、０℃でさらに１時間攪拌する。炭酸水素ナトリウム水溶液を加え、有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥する。硫酸ナトリウムをを濾過して除き、濾液を真空濃縮し、残渣をカラムクロマトグラフィー(シリカゲル５０ｇ、溶媒；ヘキサン：酢酸エチル＝１：２→酢酸エチル)で精製して無色結晶の(Ｓ)−２−(２−ヒドロキシメチル−１−ピロリジニル)−６−メトキシカルボニル−５−(３−クロロ−４−メトキシベンジル)−７,８−ジヒドロ−７−オキソ−ピリド[２,３−ｄ]ピリミジン(６６７ｍｇ)を得る。融点：１７４.５℃〜１７６℃。ＭＳ(FAB)：４５９(ＭＨ⁺)。ＩＲ(nujol)：１６９５、１６１４、１５１０ｃｍ^-1。 Production Example 8
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -2-methyl-6-methoxycarbonyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido Synthesis of [2,3-d] pyrimidine

(1) 2-methylthio-6-methoxycarbonyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (860 mg), m- A mixture of chloroperbenzoic acid (575 mg) and chloroform (16 ml) is stirred at 0 ° C. for 1 hour. L-Prolinol (236 mg) and triethylamine (430 mg) were added, and the mixture was further stirred at 0 ° C for 1 hour. An aqueous solution of sodium hydrogen carbonate is added, and the organic layer is washed with brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel 50 g, solvent; hexane: ethyl acetate = 1: 2 → ethyl acetate) to give colorless crystals of (S) -2. -(2-hydroxymethyl-1-pyrrolidinyl) -6-methoxycarbonyl-5- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine ( 667 mg). Melting point: 174.5-176 [deg.] C. MS (FAB): 459 (MH ^<+> ). IR (nujol): 1695, 1614, 1510 cm ^-1 .

(2) A 1.1 M solution of methyllithium in diethyl ether (2.73 ml) was added dropwise to a suspension of copper cyanide (134 mg) in diethyl ether (1 ml) at -78 ° C. The reaction mixture is stirred at 0 ° C. for 1 hour. Next, a solution of the compound obtained in the above (1) (115 mg) in tetrahydrofuran (5 ml) was added dropwise at -78 ° C, and the mixture was gradually warmed to 0 ° C and stirred at 0 ° C for 1 hour. A mixed solution (1: 1) of a saturated ammonium chloride aqueous solution and aqueous ammonia and chloroform are added, and the mixture is stirred at room temperature for 1 hour.
Separate the organic layer, wash with brine and dry over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was dried in vacuo, and the residue was purified by column chromatography (NH ₂ type, 20 g, solvent; hexane: ethyl acetate = 2: 1) to give colorless amorphous (S) -2- ( 2-hydroxymethyl-1-pyrrolidinyl) -5-methyl-6-methoxycarbonyl-8- (3-chloro-4-methoxybenzyl) -5,6,7,8-tetrahydro-7-oxo-pyrido [2, 3-D] pyrimidine (84 mg) is obtained. MS (APCI): 475 (MH ^<+> ). IR (nujol): 1741, 1693, 1603 cm ^-1 .

(3) A mixture of the compound (10 mg) obtained in the above (2), 2,2-dichloro-5,6-dicyano-p-benzoquinone (5 mg) and dioxane (2 ml) is stirred at room temperature for 8 hours. After addition of 2,3-dichloro-5,6-dicyano-p-benzoquinone (1 mg), the mixture is further stirred at room temperature for 15 hours. After further addition of 2,2-dichloro-5,6-dicyano-p-benzoquinone (6 mg), the mixture is stirred at room temperature for 1 day and further at 60 ° C. for 1 day. After evaporating the solvent, the residue was purified by column chromatography (NH type, 20 g, solvent: ethyl acetate) to obtain a colorless solid (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5-methyl- 6-methoxycarbonyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (3 mg) is obtained. MS (APCI): 473 (MH ^<+> ). IR (nujol): 1733, 1653 cm ^-1 .

Production Example 9
Synthesis of (S) -1- (3-chloro-4-methoxybenzyl) -7- (2-hydroxymethyl-1-pyrrolidinyl) -1,2-dihydro-2-oxo-1,6-naphthyridine

(1) Lithium aluminum hydride (8 mg) was added little by little to a solution of 3-ethoxycarbonyl-4- (3-chloro-4-methoxybenzylamino) -6-chloropyridine (38 mg) in tetrahydrofuran (3 ml) at 0 ° C. The mixture is stirred at 0 ° C. for 30 minutes. Acetone and then water are added to the mixture, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (solvent; ethyl acetate) to give colorless crystals of 3-hydroxymethyl-4- (3-chloro-4-methoxybenzylamino). -6-Chloropyridine (31 mg) is obtained.

(2) A mixture of the compound (25 mg) obtained in the above (1), manganese dioxide (50 mg) and chloroform (5 ml) is stirred at room temperature for 8 hours. The insolubles were removed by filtration, and the filtrate was concentrated in vacuo to give colorless crystals of 3-formyl-4- (3-chloro-4-methoxybenzylamino) -6-chloropyridine (26 mg). Melting point: 146.5-148 [deg.] C. MS (APCI): 311 (MH ^<+> ). IR (nujol): 1677, 1597, 1566, 1505 cm ^-1 .

(3) Sodium hydride (60%, 67 mg) was added to a solution of trimethylphosphonoacetic acid (30 mg) in tetrahydrofuran (1.5 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The compound (92 mg) obtained in the above (2) is added little by little to the obtained suspension at 0 ° C., and the mixture is stirred at 0 ° C. for 2 hours. Ethyl acetate and water are added, and the organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was triturated with cold diethyl ether to give colorless crystals of 3- (methoxycarbonylvinyl) -4- (3-chloro-4-methoxybenzylamino). -6-Chloropyridine (38 mg) is obtained. Melting point: 170-171 ° C. MS (APCI): 367 (MH ^<+> ). IR (nujol): 1702, 1628, 1593 cm ^-1 .

(4) The compound (80 mg) obtained in the above (3) is suspended in a solution of sodium hydride (60%, 44 mg) in methanol (5 ml) at room temperature, and the mixture is refluxed for 30 minutes. After cooling, the precipitate was collected by filtration, washed with cold methanol, and washed with 1- (3-chloro-4-methoxybenzyl) -7-chloro-1,2-dihydro-2-oxo-1,6-naphthyridine ( 61 mg). Melting point: 208-209.5 <0> C. MS (m / z): 335 (MH ^<+> ). IR (nujol): 1665, 1573 cm ^-1 .

(5) A mixture of the compound (60 mg) obtained in the above (4), L-prolinol (90 mg) and N-methylpyrrolidone (3 ml) is stirred at 150 ° C. for 19 hours. After cooling, ethyl acetate and water are added, and the organic layer is washed with water (3 times) and brine, and dried over sodium sulfate. After the sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (solvent; ethyl acetate) to give pale yellow crystals of (S) -1- (3-chloro-4-methoxybenzyl) -7. -(2-Hydroxymethyl-1-pyrrolidinyl) -1,2-dihydro-2-oxo-1,6-naphthyridine (37 mg) is obtained. Melting point: 148-151 [deg.] C.

(6) Alternatively, 3-formyl-4- (3-chloro-4-methoxybenzylamino) -6-chloropyridine (48 mg), L-prolinol (78 mg) and NMP ( (2 ml) is stirred at 100 ° C. for 1 day. Ethyl acetate and water are added, and the organic layer is washed with water (3 times) and brine, and dried over sodium sulfate. The sodium sulfate was filtered off, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (solvent; chloroform: methanol = 10: 1) to give pale yellow amorphous 3-formyl-4- (3-chloro-4-). Methoxybenzyl) -6- (S)-(2-hydroxymethyl-1-pyrrolidinyl) pyridine (34 mg) is obtained. MS (APCI): 376 (MH ^<+> ). IR (nujol): 1641, 1608, 1565, 1503 cm ^-1 .
The obtained compound is subjected to the same treatment as in the above steps (3) and (4) to give the title compound.

Production Example 10
Synthesis of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-1,8-naphthyridine

(1) 2-chloro-5-carboxy-6- (3-chloro-4-methoxybenzylamino) pyridine (1.21 g), oxalyl chloride (0.39 ml), dimethylformamide (1 drop) and methylene chloride (30 ml) ) Is stirred at room temperature for 1.5 hours. Ethanol (10 ml) is added to the mixture at 0 ° C. and the mixture is stirred at room temperature for 30 minutes. After evaporating the solvent, the residue was purified by column chromatography (silica gel 40 g, solvent; chloroform: hexane = 1: 1) to give 2-chloro-5-ethoxycarbonyl-6- (3-chloro-4-methoxybenzyl). Amino) pyridine (547 mg) is obtained. Melting point: 112.5-114 ° C.

(2) Lithium aluminum hydride (49 mg) is added little by little to a mixture of the compound (231 mg) obtained in the above (1) and tetrahydrofuran (23 ml) at 0 ° C, and the mixture is stirred at 0 ° C for 2 hours. Water (0.05 ml) and a 10% aqueous sodium hydroxide solution (0.075 ml) are added at 0 ° C., and the mixture is stirred at room temperature for 1 hour. The insolubles are filtered off over sodium sulfate and the filtrate is concentrated in vacuo. The residue was purified by column chromatography (20 g of silica gel, solvent; hexane: ethyl acetate = 3: 1) to give 2-chloro-5-hydroxymethyl-6- (3-chloro-4-methoxybenzylamino) as a colorless oil. Pyridine (229 mg) is obtained. MS (m / z): 313 (MH ^<+> ). IR (nujol): 1607, 1573, 1504 cm ^-1 .

(3) A mixture of the compound (196 mg) obtained in the above (2), manganese dioxide (400 mg) and chloroform (20 ml) is stirred at room temperature for 1 day. The insolubles were removed by filtration, and the filtrate was concentrated in vacuo to give 2-chloro-5-formyl-6- (3-chloro-4-methoxybenzylamino) pyridine (180 mg) as dark yellow crystals. Melting point: 134.5-138.5C. MS (APCI): 311 (MH ^<+> ). IR (nujol): 1663, 1589, 1578, 1501 cm ^-1 .

(4) A mixture of sodium hydride (60%, 16 mg) and 2-phosphonopropionic acid trimethyl ester (73 mg) in tetrahydrofuran (3 ml) is stirred at 0 ° C. for 30 minutes. The compound obtained in the above (3) (100 mg) is added, and the mixture is stirred at 0 ° C. for 1 hour. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution are added, and the organic layer is washed with brine and dried over sodium sulfate. The sodium sulfate is filtered off and the filtrate is concentrated in vacuo to give a viscous yellow oil. This oil is dissolved at 0 ° C. in a mixture of sodium hydride (64 mg) in methanol (7 ml) and the mixture is refluxed for 45 minutes. The solvent was removed in vacuo and the residue was purified by preparative TLC (hexane: ethyl acetate = 1: 1) to give colorless crystals of 2-chloro-8- (3-chloro-4-methoxybenzylamino) -7,8. -Dihydro-7-oxo-1,8-naphthyridine (76 mg) is obtained. Melting point: 151-154.5 [deg.] C. MS (APCI): 331 (MH ^<+> ).

(5) A mixture of the compound (69 mg) obtained in the above (4), L-prolinol (104 mg) and NMP (3 ml) is stirred at 120 ° C. for 17 hours. Ethyl acetate and water are added, and the organic layer is washed with water (3 times) and brine, and dried over sodium sulfate. The sodium sulfate was filtered off, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (one sheet, solvent: ethyl acetate) to give a pale yellow solid of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl). ) -8- (3-Chloro-4-methoxybenzylamino) -7,8-dihydro-7-oxo-1,8-naphthyridine (25 mg) is obtained. Melting point: 131-134 ° C. MS (APCI): 400 (MH ^<+> ). IR (nujol): 1645, 1605, 1578 cm ^-1 .

Production Example 11
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (1-methyl-2-imidazolyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7- Synthesis of oxo-pyrido [2,3-d] pyrimidine

(1) A mixture of 2-methylthio-5-hydroxymethyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (9.8 g), manganese dioxide (19.6 g) and chloroform (98 ml) was added at room temperature for 20 minutes. Stir for hours. The manganese dioxide is filtered off and the filtrate is concentrated in vacuo. The residue was triturated with diisopropyl ether to give colorless crystalline 2-methylthio-5-formyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (9.09 g). Melting point: 121.5-124 ° C. MS (APCI): 324 (MH ^<+> ). IR (nujol): 1674, 1588, 1577, 1508 cm ^-1 .

(2) A 1.6 M hexane solution of n-butyllithium (1.73 ml) was added dropwise to a solution of 1-methylimidazole (243 mg) in tetrahydrofuran (6 ml) at -78 ° C, and the mixture was stirred at -78 ° C for 2 hours. . A solution of the compound (300 mg) obtained in (1) above in tetrahydrofuran (6 ml) is added dropwise to the mixture at -78 ° C, and the mixture is stirred at -78 ° C for 30 minutes. Saturated aqueous sodium bicarbonate solution is added and the mixture is warmed to room temperature.
The mixture is extracted with chloroform, washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated in vacuo, and the residue was triturated with diethyl ether to give 2-methylthio-5- (1-methyl-2-imidazolylhydroxymethyl) -6- (3-chloroform as colorless crystals. -4-methoxybenzylamino)) pyrimidine (348 mg) is obtained. Melting point: 179-180.5C. MS (APCI): 406 (MH ^<+> ). IR (nujol): 1593, 1578 cm ^-1 .

(3) A mixture of the compound (340 mg) obtained in the above (2), manganese dioxide (680 mg) and chloroform (15 ml) is stirred at room temperature for 3 days. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo to give 2-methylthio-5- (1-methyl-2-imidazolylcarbonyl-6- (3-chloro-4-methoxybenzylamino) pyrimidine (338 mg) as pale yellow crystals. MS (APCI): 404 (MH ^<+> ) IR (nujol): 1605, 1571 cm < ^-1 >.

(4) Sodium hydride (60%, 19 mg) is added little by little to a solution of trimethylphosphonoacetic acid (85 mg) in toluene (3 ml) at room temperature. The mixture is stirred at room temperature for 1 hour. The compound (150 mg) obtained in the above (3) is added, and the mixture is stirred at room temperature for 1 hour and further at 100 ° C. for 7 hours. A mixture of trimethylphosphonoacetic acid (85 mg) and sodium hydride (60%, 19 mg) in toluene (3 ml) was added, and the mixture was further stirred at 100 ° C. for 13 hours.
Ethyl acetate and water are added to the reaction mixture, and the organic layer is washed with brine and dried over sodium sulfate. After the sodium sulfate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (4 plates, solvent: ethyl acetate) to give 2-methylthio-5- (1-methyl-2-imidazolyl) -8- ( 3-Chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (27 mg) is obtained. Colorless crystals. Melting point: 218-220C.

(5) A mixture of the compound (38 mg) obtained in the above (4), m-chloroperbenzoic acid (26 mg) and chloroform (3 ml) is stirred at 0 ° C. for 1 hour. Prolinol (45 mg) is added and stirred at room temperature for 1 hour. To this reaction mixture is added a saturated aqueous sodium bicarbonate solution. The organic layer is washed with brine and dried over sodium sulfate. The sodium sulfate is filtered off and the filtrate is concentrated in vacuo. The residue was purified by preparative TLC (solvent; ethyl acetate: methanol = 4: 1) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (1-methyl-2-colorless powder. Imidazolyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (41 mg) is obtained. MS (APCI): 481 (MH ^<+> ). IR (nujol): 1655, 1582, 1533 cm ^-1 .

Production Example 12
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (2-pyridyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [ Synthesis of 2,3-d] pyrimidine

(1) A 1.6 M solution of n-butyllithium in hexane (3.54 ml) is added to diethyl ether (10 ml) at -78 ° C. 2-Bromopyridine (0.556 ml) is added dropwise to the mixture at -78 ° C over 7 minutes. The mixture is stirred at -78 C for 20 minutes.
A mixture of (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5-formyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (314 mg) in tetrahydrofuran (10 ml) was mixed at -78 ° C. And the mixture is stirred at −78 ° C. for a further 30 minutes. Aqueous sodium bicarbonate solution is added, the mixture is warmed to room temperature and extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give brown (A) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (2-pyridylhydroxymethyl) -6- (3-chloroform -4-Methoxybenzyl) pyrimidine was obtained, which was stirred with manganese dioxide (0.90 g) and chloroform (15 ml) at room temperature for 15 hours. The manganese dioxide is filtered off and the filtrate is concentrated in vacuo. The residue was purified by column chromatography (40 g of silica gel, solvent; ethyl acetate: chloroform = 1: 1 → ethyl acetate alone) and preparative TLC (solvent: ethyl acetate) to give pale yellow amorphous (S) -2- (2 -Hydroxymethyl-1-pyrrolidinyl) -5- (2-pyridylcarbonyl) -6- (3-chloro-4-methoxybenzylamino) pyrimidine (216 mg) is obtained. MS (APCI): 454 (MH ^<+> ). IR (neat): 1591, 1566, 1524 cm ^-1 .

(2) A mixture of sodium hydride (60%, 36 mg) and trimethylphosphonoacetic acid (70 mg) in toluene (10 ml) was stirred at room temperature for 1 hour. The compound obtained in the above (1) (116 mg) is added, and the mixture is stirred at 100 ° C. for 6 hours. Ethyl acetate and water are added and the organic layer is washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (solvent; ethyl acetate x 2) to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (21 mg) of (2-pyridyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine is obtained. Melting point: 183.5-186.5C. MS (APCI): 478 (MH ^<+> ). IR (nujol): 1644, 1572, 1533 cm ^-1 .

Production Example 13
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (1-methyl-2-imidazolyl) -6-methoxycarbonyl-8- (3-chloro-4-methoxybenzyl) -7,8 Of -Dihydro-7-oxo-pyrido [2,3-d] pyrimidine

(1) A solution of titanium tetrachloride (331 mg) in chloroform (993 mg) was added dropwise to an aqueous solution of tetrahydrofuran under cooling with ice and salt under an argon atmosphere. The mixture is stirred at the same temperature for 30 minutes. Dimethyl malonate (69 mg) is added and 2-methylthio-5- (1-methyl-2-imidazolylcarbonyl) -6- (3-chloro-4-methoxybenzylamino) pyrimidine (141 mg) is added. A solution of pyridine (220 mg) in tetrahydrofuran (1 ml) is added dropwise to the ice-brine cooled mixture, and the mixture is stirred at the same temperature for 30 minutes. Tetrahydrofuran (3 ml) is added and the mixture is stirred at room temperature for 5 hours. Ethyl acetate and sodium hydrogen carbonate are added at 0 ° C., and insolubles are removed by filtration through celite. Separate the organic layer, wash with brine and dry over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated in vacuo, and the residue was triturated with methanol to give 2-methylthio-5- (1-methyl-2-imidazolyl) -6-methoxycarbonyl-8- (3 -Chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (109 mg) is obtained. MS (APCI): 486 (MH ^<+> ).

(2) A mixture of the compound obtained in the above (1) (103 mg) and m-chloroperbenzoic acid (63 mg) in chloroform (3 ml) is stirred at room temperature for 30 minutes. Prolinol (107 mg) and triethylamine (108 mg) are added and the mixture is stirred at room temperature for 15 hours. An aqueous sodium hydrogen carbonate solution is added, the organic layer is separated, washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off, the filtrate was dried in vacuo, and the residue was subjected to column chromatography (silica gel 15 g, solvent; ethyl acetate → ethyl acetate: methanol = 5: 1) and preparative TLC (solvent; ethyl acetate: methanol = 10: (S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -5- (1-methyl-2-imidazolyl) -6-methoxycarbonyl-8- (3-chloroform) -4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine (120 mg) is obtained. Melting point: 142-145 [deg.] C. MS (APCI): 539 (MH ^<+> ). IR (nujol): 1734, 1657, 1597, 1588, 1549, 1503 cm ^-1 .

Production Example 14
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- [2- (4-morpholinyl) ethyl] -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7 Of -oxo-pyrido [2,3-d] pyrimidine

(1) Add a piece of iodine to a suspension of magnesium (11.0 g) in tetrahydrofuran (350 ml) and stir the mixture until the red color fades. A one-tenth volume solution of vinyl bromide (25 ml) in tetrahydrofuran (100 ml) is added. Heat until the reaction starts and slowly reflux the mixture. A solution of vinyl bromide in tetrahydrofuran is added dropwise at a rate at which gentle reflux continues. After the addition is complete, the mixture is refluxed for a further 30 minutes. The insolubles are removed by decantation to obtain a 1N solution of vinylmagnesium bromide in tetrahydrofuran.
(S) -2- (2-Hydroxymethyl-1-pyrrolidinyl) -5-formyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (4.1 g) in tetrahydrofuran (30 ml) was treated with vinylmagnesium bromide. Of tetrahydrofuran (43.5 ml) at 0 ° C. and the mixture is stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution is added to the mixture, and the mixture is extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate.
The sodium sulfate was filtered off, the filtrate was dried in vacuo, and the residue was purified by column chromatography (silica gel 100 g, ethyl acetate → ethyl acetate: methanol = 20: 1, silica gel 50 g, chloroform: methanol = 50: 1). Colorless amorphous (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (1-hydroxymethyl-2-propen-1-yl) -4- (3-chloro-4-methoxybenzylamino) ) Pyrimidine (2.70 g) is obtained. MS (APCI): 405 (MH ^<+> ). IR (nujol): 1606, 1575 cm ^-1 .

(2) A mixture of the compound obtained in the above (1) (2.70 g), manganese dioxide (8.1 g) and chloroform (120 ml) is stirred at room temperature for 15 hours. The insolubles are filtered off and the filtrate is concentrated in vacuo. The residue was purified by column chromatography (silica gel 90 g, chloroform: ethyl acetate = 2: 1), and triturated with cold diethyl ether to give (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) as pale yellow crystals. ) -5-Vinylcarbonyl-4- (3-chloro-4-methoxybenzylamino) pyrimidine (1.92 g) is obtained. Melting point: 118-121.5 [deg.] C. MS (m / z): 403 (MH ^<+> ). IR (nujol): 1639, 1603, 1521 cm ^-1 .

(3) A mixture of the compound (300 mg) obtained in the above (2), morpholine (324 mg) and ethanol (10 ml) is stirred at room temperature for 1 hour. After evaporating the solvent, the residue is diluted with ethyl acetate, washed with water (3 times) and brine, and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give a colorless amorphous (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- (2- (4-morphonyl) ethylcarbonyl) -4- ( 3-chloro-4-methoxybenzylamino) pyrimidine (358 mg) is obtained. MS (APCI): 490 (MH ^<+> ). IR (neat: 1625, 1593, 1525 cm ^-1) .

(4) A 1.6 M solution of n-butyllithium in hexane (1.76 ml) is added to a mixture of dicyclohexylamine (510 mg) in tetrahydrofuran (3 ml) at -78 ° C, and the mixture is stirred at -78 ° C. Methyl trimethylsilyl acetate (462 μl) is added and the whole reaction is stirred at −78 ° C. for 10 minutes. A solution of the compound obtained in the above (3) (138 mg) in tetrahydrofuran is added dropwise to the mixture at -78 ° C, and the mixture is stirred at 0 ° C for 5 hours and then at room temperature for 15 hours. Water and ethyl acetate are added, the organic layer is separated, washed with brine and dried over sodium sulfate.
The sodium sulfate was filtered off, the filtrate was dried in vacuo, and the residue was purified by column chromatography (25 g of NH type, solvent: ethyl acetate) and then purified by preparative TLC (aluminum oxide, solvent: ethyl acetate x 3) to give a colorless amorphous substance. Of ((S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- [2- (4-morpholinyl) ethyl] -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro Obtain -7-oxo-pyrido [2,3-d] pyrimidine (11 mg), MS (APCI): 514 (MH ⁺ ), IR (nujol): 1583 cm ^-1 .

Production Examples 15 to 42
The corresponding starting materials are obtained using any of the methods described above to give the compounds listed in Table 3 below.

Reference Example 1
(1) A mixture of 7.80 g of 3-ethoxycarbonyl-4-hydroxy-6-oxopyridine and 48 ml of phosphoryl chloride is stirred at 100 ° C. for 8 hours. Excess phosphoryl chloride is removed under reduced pressure, and the residue is poured into ice water. The mixture is made basic with sodium carbonate, extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The mixture was filtered to remove sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 100 g, solvent; hexane: ethyl acetate = 10: 1) to give 2,4-dichloro-5-colorless crystals. 8.50 g of ethoxycarbonylpyridine are obtained. Melting point: 32-32.5 [deg.] C. MS (m / z): 220 (MH ^<+> ).

(2) A mixture of 1.02 g of the compound obtained in the above (1), 1.02 g of 3-chloro-4-methoxybenzylamine, 823 mg of triethylamine and 20 ml of acetonitrile is stirred at room temperature for 1.5 days and refluxed for 3 hours. . After evaporating the solvent, the residue is diluted with a mixed solvent of ethyl acetate-aqueous sodium hydrogen carbonate, and the organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and brine, and dried over sodium sulfate. After removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 25 g, solvent; hexane: ethyl acetate = 4: 1), and triturated with cold diethyl ether to give a colorless color 1.17 g of crystalline 3-ethoxycarbonyl-6-chloro-4- (3-chloro-4-methoxybenzylamino) pyridine are obtained. Melting point: 115.5-117.5 ° C. MS (m / z): 355 (MH ^<+> ).

Reference Example 2
(1) 23.2 ml of n-butyllithium is added dropwise to a mixture of 3.76 g of diisopropylamine and 25 ml of tetrahydrofuran at -78 ° C. The mixture is stirred at 0 ° C. for 10 minutes. Then, a solution of 2,6-dichloropyridine (5.0 g) in tetrahydrofuran (25 ml) is added dropwise at -78 ° C over 20 minutes. The mixture is stirred at -78 ° C for 3 hours, poured into powdered dry ice and the resulting mixture is left at room temperature overnight.
After evaporating the solvent, the residue was dissolved in a mixed solvent of ethyl acetate-10% aqueous sodium hydroxide solution, the aqueous layer was separated, acidified with concentrated hydrochloric acid, and the colorless precipitate was collected by filtration and washed with cold water. 4.50 g of 2,6-dichloronicotinic acid are obtained. Melting point: 148-150C. MS (ESI): 190 (MH) < ^- >.

(2) A mixture of 500 mg of the compound obtained in the above (1), 638 mg of 3-chloro-4-methoxybenzylamine, 817 mg of potassium carbonate, 313 mg of copper bromide, and 10 ml of 1-methyl-2-pyrrolidinone was heated at 120 ° C. to a degree of 2.5. Stir for hours. After cooling to room temperature, ethyl acetate and 1N aqueous hydrochloric acid are added to the mixture. The organic layer is separated, washed with water (twice) and brine, and dried over sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 30 g, solvent; chloroform → chloroform: methanol = 70: 1) to obtain colorless crystals of 2- (3-chloro-ethanol). 471 mg of 4-methoxybenzylamino) -6-chloronicotinic acid are obtained. Melting point: 184-185.5C. MS (m / z): 325 (M-H) ^- .

The compound (I), which is an active ingredient of the present invention, and a pharmacologically acceptable salt thereof have excellent PDEV inhibitory activity, and are useful as agents for preventing and treating penile erectile dysfunction.

Claims (19)

General formula (I):

(Wherein, R ¹ represents an optionally substituted nitrogen-containing heterocyclic group, an optionally substituted amino group or an optionally substituted lower alkoxy group;
R ² represents a hydrogen atom or a lower alkyl group;
R ³ represents a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted heteroaryl group;
R ⁴ represents a hydrogen atom, a lower alkyl group or a carboxyl group which may be esterified or amidated;
R ⁵ represents a lower alkyl group which may be substituted with a group selected from an optionally substituted aryl group, an optionally substituted heteroaryl group and a di-lower alkylamino group;
X and Y each represent a group represented by the formula: ＣＨCH— and the other is a nitrogen atom, or both represent a nitrogen atom.
A pharmaceutical composition comprising, as an active ingredient, a pyridopyrimidine or naphthyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof. A substituent in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ is a lower alkyl group which may be substituted with a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group; The substituent in the `` amino group which may be substituted '' is a lower alkyl group which may be substituted with a heteroaryl group, a group selected from a lower alkyl group and a lower alkoxy group which may be substituted with an aryl group, The substituent in the “optionally substituted lower alkoxy group” is (1) an aryl group optionally substituted with a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group, or (2) a hydroxyl group, a halogen atom and a lower alkoxy group. A lower alkyl group which may be substituted with a heteroaryl group which may be substituted with a group selected from an alkoxy group,
The substituent in the “optionally substituted lower alkyl group” represented by R ³ is a nitrogen-containing heterocyclic group, and the substituent in the “optionally substituted heteroaryl group” is a lower alkyl group, A group selected from a hydroxyl group, a halogen atom and a lower alkoxy group,
The substituent in the “optionally substituted aryl group” and the “optionally substituted heteroaryl group” represented by R ⁵ is a group selected from a hydroxyl group, a halogen atom and a lower alkoxy group;
2. The pharmaceutical composition according to claim 1, wherein X and Y are both nitrogen atoms. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ is a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered bicyclic heterocyclic group. A cyclic nitrogen-containing heterocyclic group,
The carboxyl group esterified in the “carboxyl group which may be esterified or amidated” represented by R ⁴ is a carboxyl group esterified by a lower alkyl group, and the amidated carboxyl group is A lower alkyl group optionally substituted by a hydroxyl group or an optionally substituted 5- to 6-membered monocyclic nitrogen-containing heterocyclic group or an optionally substituted 5- to 6-membered monocyclic group A carboxyl group amidated by a nitrogen-containing heterocyclic group,
The aryl group in the “optionally substituted aryl group, the optionally substituted heteroaryl group and the lower alkyl group optionally substituted with a group selected from di-lower alkylamino groups” represented by R ⁵ is The pharmaceutical composition according to claim 2, wherein the compound is a phenyl group and the heteroaryl group is a pyridyl group or a pyrimidyl group. Substituted in the “optionally substituted aryl group, optionally substituted heteroaryl group and lower alkyl group optionally substituted with a group selected from di-lower alkylamino groups” represented by R ⁵ The aryl group which may be substituted is a phenyl group which may be substituted by a group selected from a lower alkoxy group, a lower alkylenedioxy group and a halogen atom, and the optionally substituted heteroaryl group comprises a lower alkoxy group and / or 4. The pharmaceutical composition according to claim 3, which is a pyridyl group or a pyrimidyl group optionally substituted with a halogen atom. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ is a pyrrolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, a piperidyl group, A 5- to 6-membered monocyclic nitrogen-containing heterocyclic group selected from piperazinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, or indolyl, isoindolyl, indolizinyl, quinolyl An 8- to 10-membered bicyclic nitrogen-containing heterocyclic group selected from an isoquinolyl group and a purinyl group,
In the “carboxyl group which may be esterified or amidated” represented by R ⁴ , the amidated carboxyl group may be substituted with a lower alkyl group, such as a pyrrolyl group, an oxazolyl group, a pyrazolyl group, and a pyrrolinyl group. Group, pyrrolidinyl group, imidazolyl group, piperidyl group, piperazinyl group, morpholinyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, 5- to 6-membered monocyclic nitrogen-containing group selected from imidazolidinyl group and thiazolyl group A lower alkyl group which may be substituted with a heterocyclic group, which may be substituted with an amino group or a lower alkyl group, a pyrrolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, a piperidyl group, Piperazinyl group, morpholinyl group, 5. A carboxyl group amidated with a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group selected from a lysyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, an imidazolidinyl group and a thiazolyl group. The pharmaceutical composition according to any one of the preceding claims. The nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ is a group represented by the formula:

Or a 5- to 6-membered monocyclic nitrogen-containing heterocyclic group represented by the formula:

An 8- to 10-membered bicyclic nitrogen-containing heterocyclic group represented by
The “carboxyl group which may be esterified or amidated” represented by R ⁴ has the formula:

A lower alkyl group which may be substituted with a group represented by the following, an amino group which may be substituted with a lower alkyl group;

An amino group or a lower alkyl group which may be substituted with a group represented by the following formula:

The pharmaceutical composition according to claim 5, which is a carboxyl group amidated by a group selected from the groups represented by the formula: The “optionally substituted nitrogen-containing heterocyclic group” represented by R ¹ has the formula:

And
The “carboxyl group which may be esterified or amidated” represented by R ⁴ has the formula:

A lower alkyl group-substituted amino group optionally substituted with a group represented by the formula:

An amino group optionally substituted by a group represented by the formula:

The pharmaceutical composition according to claim 6, which is a carboxyl group amidated by a group selected from the groups represented by the formula: R ¹ has the formula:

Is a group selected from
R ² is a hydrogen atom,
R ³ is a hydrogen atom,
R ⁴ is a hydroxyl group or a formula:

A lower alkyl group-substituted amino group optionally substituted by a group represented by the formula:

A carboxyl group amidated by a group selected from an amino group which may be substituted with a group represented by
R ⁵ is a lower alkyl group substituted with an optionally substituted phenyl group by lower alkoxy and / or halogen atom, according to claim 7 pharmaceutical composition according. R ¹ has the formula:

Is a group selected from
R ² is a hydrogen atom,
R ³ is a hydrogen atom,
R ⁴ has the formula:

A carboxyl group amidated by a group selected from an amino group which may be substituted with a group represented by
And R ⁵ is substituted by a lower alkoxy group and / or halogen atoms is also a phenyl group, claim 8 pharmaceutical composition. (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5- [2- (4-morpholinyl) ethyl] -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7 -Oxo-pyrido [2,3-d] pyrimidine,
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6- [N- {4- (1,3,5-trimethyl) pyrazolyl} carbamoyl] -8- (3-chloro-4-methoxybenzyl ) -7,8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3-d] pyrimidine;
(S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -5-methyl-8- (3-chloro-4-methoxybenzyl) -7,8-dihydro-7-oxo-pyrido [2,3- [d] A pharmaceutical composition comprising, as an active ingredient, pyrimidine or a pharmaceutically acceptable salt thereof. (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -6- [N- {4- (1,3,5-trimethyl) pyrazolyl} carbamoyl] -8- (3-chloro-4-methoxybenzyl ) -7,8-Dihydro-7-oxo-pyrido [2,3-d] pyrimidine;
Or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of penile erectile dysfunction. 医 薬 The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of pulmonary hypertension. The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of diabetic gastroparesis. The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of female sexual dysfunction. The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of chronic and acute heart failure. The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of prostatic hypertrophy. 医 薬 The pharmaceutical composition according to any one of claims 1 to 11, which is used for prevention and treatment of premature ejaculation. A PDEV inhibitor comprising the active ingredient according to any one of claims 1 to 11.