WO2008062770A1

WO2008062770A1 - Quinolone derivative or pharmaceutically acceptable salt thereof

Info

Publication number: WO2008062770A1
Application number: PCT/JP2007/072419
Authority: WO
Inventors: Yuji Koga; Takashi Kamikubo; Takao Okuda; Michihito Kageyama; Hiroyuki Moritomo
Original assignee: Astellas Pharma Inc.
Priority date: 2006-11-22
Filing date: 2007-11-20
Publication date: 2008-05-29
Also published as: TW200829568A; JP2010037198A

Abstract

[PROBLEMS] To provide a pharmaceutical agent having a P2Y12 inhibitory activity, particularly a compound useful as a platelet aggregation inhibitor. [MEANS FOR SOLVING PROBLEMS] An extensive study was made on an P2Y12 inhibitor, and it was found that a quinolone derivative having a substituted carbamoyl group at position-3 wherein the substituent on the carbamoyl group is -(polymethylene in which a carbon atom adjacent to the carbamoyl group is substituted)-CO2R (wherein R represents -H or a lower alkyl) has an excellent platelet aggregation inhibitory activity and has improved in vivo kinetics. The compound is excellent in P2Y12 inhibitory activity and platelet aggregation inhibitory activity, and is therefore useful as a platelet aggregation inhibitor.

Description

Specification

Quinolone derivative or pharmaceutically acceptable salt thereof

Technical field

[0001] The present invention relates to a novel quinophone derivative or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly a platelet aggregation inhibitor, a P2Y12 inhibitor.

Background art

[0002] Since its discovery in 1842 by Donne, platelets have long been treated as a component in blood necessary for hemostasis. Today, platelets not only play a leading role in the mechanism of hemostasis, but also become a clinically recognized arteriosclerosis, cardiovascular disease including thrombotic disease, cancer transition, inflammation, post-transplant rejection, and immune response. It has been clarified to show multifunctionality such as involvement of

[0003] In general, for thrombotic diseases and ischemic diseases, there is a drug! /, A treatment for resuming blood circulation by a physical method. However, after the recent revascularization, platelet activation, adhesion, and aggregation may occur due to the breakdown of vascular tissue including endothelial cells or the breakdown of fibrinolysis / coagulation balance by the drug itself. Increasing phenomenon has been discovered and has become a clinical problem. For example, after recanalization is achieved by thrombolytic therapy using t-PA, fibrinolytic and coagulative activities are activated, and the coagulation / fibrinolytic balance of the whole body is disrupted. I came. Clinically, it causes re-occlusion and is a major therapeutic problem (Non-Patent Document 1).

[0004] On the other hand, PTCA therapy and stent placement have rapidly spread to treat diseases based on coronary stenosis such as angina pectoris and myocardial infarction and aortic stenosis, and have achieved certain results. However, these therapies damage vascular tissue, including endothelial cells, causing acute coronary occlusion and restenosis that occurs in the chronic phase! Platelets play an important role in various thrombotic effects (such as reocclusion) after such revascularization therapy. Therefore, the power at which the effectiveness of antiplatelet agents is expected. Conventional antiplatelet agents have not yet been proven to be sufficiently effective.

[0005] Examples of the preventive or therapeutic agent for these cardiovascular diseases include aspirin, cilostazol, Platelet aggregation inhibitors such as 2, 1,, ku and lu have been used. Recently, GPIIb / IIIa antagonists that inhibit the final stage of platelet aggregation and have strong platelet aggregation activity have been developed, but their use is limited to intravenous infusion during the acute phase of thrombosis! / RU

[0006] With regard to ticlovidin and clopidogrel, which have been used as antiplatelet agents in recent years, it has been clearly demonstrated that the active metabolite exhibits an inhibitory action on platelet aggregation by inhibiting P2Y12, which is an ADP receptor. It became. Subsequently, as compounds having P2Y12 inhibitory action, triazolo [4,5-D] pyrimidine derivatives (Patent Document 1), piperazine and / or homopiperazine derivatives (Patent Document 2, Patent Document 3), virazolidindione derivatives (Patent Document 4), isoquinolinone derivatives (Patent Document 5) and the like have been reported!

On the other hand, Patent Documents 6 and 7 are known as quinolone derivatives.

In Patent Document 6, a compound represented by the formula (A) having an antibacterial action is known, but it is not known that these derivatives have a platelet aggregation inhibitory action. Further, the structure of the compound of the present invention is different from that of the compound of the present invention in that the portion corresponding to the 3-position of the compound of the present invention is a carboxylic acid, an ester or a strong rubamoyl.

(In the formula, R ¹ represents —OR ⁹ , an amino group, or a lower alkylamino group, R ⁹ represents a hydrogen atom or a force loxy protecting group. For other symbols, refer to the publication)

[0008] Patent Document 7 reports that the compound represented by the formula (B) has a P2Y12 inhibitory action. However, there is no specific disclosure of the compound of the present invention.

(See the official gazette for symbols in the formula)

In Patent Document 8, it is reported that the compound represented by the formula (C) has a P2Y12 inhibitory action. However, -C (0) NR ^u R ¹² does not contain -C (O) NH-CH RVCCH) -CO R which is a characteristic structure of the compound of the present invention.

2 n 2

[Chemical 3]

(See the official gazette for symbols in the formula)

In Patent Document 9 filed by the present applicant and published after the priority date of the present application, it is reported that the compound represented by the formula (D) has a P2Y12 inhibitory action. However, there is a substituted canolovamoyl group in, and it is not.

[Chemical 4]

(See the official gazette for symbols in the formula)

Non-patent document 1: “Journal of tne American College of Cardiology”, 1988, Vol. 2, .616-623 Patent document 1: International Publication No. WO 00/34283 Pamphlet

Patent Document 2: International Publication No. WO 02/098856 Pamphlet

Patent Document 3: International Publication No. WO 03/022214 Pamphlet Patent Document 4: International Publication No. WO 2005/000281 Pamphlet

Patent Document 5: International Publication No. WO 2005/035520 Pamphlet

Patent Document 6: International Publication No. WO 98/23592 Pamphlet

Patent Document 7: International Publication No. WO 2005/009971 Pamphlet

Patent Document 8: International Publication WO 2006/077851 Pamphlet

Patent Document 9: International Publication No. WO 2007/105751 Pamphlet

Disclosure of the invention

Problems to be solved by the invention

[0012] An object of the present invention is to provide a compound having a P2Y12 inhibitory action, particularly a compound useful as a platelet aggregation inhibitor.

Means for solving the problem

[0013] The present inventors have already found that the quinolone derivative (B) shown in Patent Document 7 has an excellent platelet aggregation inhibitory action and P2Y12 inhibitory action. The inventors of the present invention have further conducted intensive research to find a platelet aggregation inhibitor having a high balance between pharmacological effects and safety, which have high pharmacological effects. As a result, it has a force rubamoyl group substituted at the 3-position, and the substituent on the carbamoyl group is-(polymethylene in which the carbon atom adjacent to the force rubamoyl group is substituted) -CO R (where R is- The present invention was completed by finding that a quinolone derivative which is H or lower alkyl) has an excellent platelet aggregation inhibitory action and improved pharmacokinetics.

That is, the present invention relates to a quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical 5]

(The symbols in the formula have the following meanings. R: -H or lower alkyl.

R ¹ : lower alkyl, halogeno lower alkyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclic group. However, the aryl and heterocyclic groups in R ¹ may each be substituted.

R ² : -H, halogen or -OH.

R ³ : cycloalkyl or cycloalkylmethyl.

R ⁴ : —CH (R 3), cycloalkyl or monocyclic saturated heterocyclic group. However, the monocyclic saturated heterocyclic group in R ⁴ may be substituted.

R ⁵ : the same or different, lower alkyl or lower alkylene-OH.

X: -CH = or -N

Y: No, Rogen.

n: l, 2 or 3. The same applies below. )

[0014] The present application also relates to a medicine comprising the quinolone derivative represented by the general formula (I) or a salt thereof as an active ingredient, particularly a P2Y12 receptor inhibitor and / or a platelet aggregation inhibitor.

Furthermore, the present application provides a formula for the manufacture of P2Y12 inhibitors and / or platelet aggregation inhibitors.

Use of the compound represented by (1) or a pharmaceutically acceptable salt thereof, and administration of an effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a patient. The present invention also relates to a method for treating cardiovascular diseases closely related to thrombus formation by platelet aggregation.

That is, (1) a pharmaceutical composition comprising the compound of the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;

(2) The pharmaceutical composition according to (1), which is a platelet aggregation inhibitor;

(3) The pharmaceutical composition according to (1), which is a P2Y12 inhibitor; and

(4) The present invention also relates to the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof for producing a platelet aggregation inhibitor or a P2Y12 inhibitor.

The invention's effect

[0015] Since the compound of the present invention has an excellent P2Y12 inhibitory action, it is useful as a pharmaceutical, particularly as a platelet aggregation inhibitor. Therefore, the compound of the present invention forms thrombus by platelet aggregation. Related to cardiovascular diseases such as unstable angina pectoris, acute myocardial infarction and its secondary prevention, post-hepatic artery bypass surgery, re-occlusion and restenosis after PTCA or stent placement, hepatic artery thrombus Ischemic diseases such as accelerated dissolution and re-occlusion prevention; Transient ischemic stroke (TIA) cerebral infarction, subarachnoid hemorrhage (vasospasm), etc .; peripheral arterial disease such as chronic arterial occlusion It is useful as a prophylactic and / or therapeutic agent for such as, and as an adjunct during cardiac surgery or vascular surgery.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the definition in the present specification, “lower alkyl”, “lower alkylene”, and “lower alkylene” are linear or branched, preferably having 1 to 6 carbon atoms (hereinafter, C)) hydrocarbon chain.

1-6

[0017] As the "lower alkyl", preferably C alkyl (methyl, ethyl, n-propyl, isop

1-6

Ropinole, n-butinole, isobutinole, sec-butinole, tert-butinole, n_pentinole, n_hexenole group, etc.). More preferred is C alkyl, and particularly preferred are methyl, ethyl and n-propyl.

1-4

Mouth pill, isopropyl.

[0018] The "lower alkylene" is preferably C alkylene (methylene, ethylene, trimethylene,

1-6

Tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene group, etc.). More preferred is C alkylene, and even more preferred are methylene and ethylene.

1-3

“Halogen” refers to fluoro, black mouth, bromo and iodine.

“Halogeno lower alkyl” refers to C alkyl substituted with one or more halogens (full

1-6

Fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, hexafluoropropyl group, etc.). Preferred is lower alkyl substituted with 1 to 5 halogens, and more preferred is trifluoromethyl.

“Cycloalkyl” is a C 1 saturated hydrocarbon ring group which may have a bridge.

3-10

Preferably it is C cycloalkyl, more preferably cyclopropyl, cyclobutyl,

3-6

Clopentyl and cyclohexyl are preferred, and cyclobutyl and cyclopentanol are more preferred. “Cycloalkenyl” is C cycloalkenyl, which may have a bridge. Concrete

3-15

Specific examples include cyclopentyl, cyclopentaenyl, cyclohexenyl, cyclohexadienyl and the like. More preferred is c cycloalkenyl, even more preferred is

5-10

Cyclopentur, cyclohexenyl.

[0022] The "aryl" is a monocyclic to tricyclic aromatic hydrocarbon ring group of C, more preferably

6-14

Is phenyl or naphthyl, more preferably phenyl.

[0023] "Heterocyclic group" means i) a monocyclic ring containing 1 to 4 heteroatoms selected from 0, S and N

A 3- to 8-membered (preferably 5- to 7-membered) heterocycle, ii) selected from the group consisting of the monocyclic heterocycle and a monocyclic heterocycle, benzene ring, C cycloalkane and C cycloalkene 1 Or 2

5-8 5-8

Bicyclic 8- to 14-membered (preferably 9- to 11-membered) heterocycles containing 1 to 5 heteroatoms selected from 0, S and N And tricyclic; ; Means a cyclic group consisting of 20 to 20-membered (preferably 12 to 15-membered) heterocyclic ring. The ring atom S or N may be oxidized to form an oxide or dioxide.

The “heterocyclic group” is preferably aziridinyl, azetidyl, pyrrolidinyl, piperidinyl, piperazuryl, homopiperadulyl, oxylanyl, oxetanyl, tetrahydrofuranyl, tetrahydrobiranyl, dioxanyl, monorepholinyl, homomorpholinyl, tetrahydro viraniyl. , Pyro !; nore, imidazo !; nore, 卜!; Azo !; nore, tera razo !; nore, pi !; zinore, pi! ; Migele, pyrajur, furyl, chenyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indolizinyl, benzimidazolyl, quinoxalinyl, quinolyl, isoquinolyl, quinazolyl, cinnoninole, phthalazinole, benzofuranoleno, Dioxolyl, benzothiazolyl, canolenozolinole, quinutalidinyl, more preferably azetidyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydroviranyl, dioxanyl, morpholinyl, pyridinole, pyrimidoleyl, pyrajyl, 1,3-benzodioxolyl, even more preferably oxetanyl, piperidinyl, Okisaniru, thienyl, a pin Rijinore.

[0024] "Monocyclic saturated hetero ring group" means i) a saturated monocyclic 3 to 8 member (preferably 4 to 6) containing 1 to 4 heteroatoms selected from 0, S and N Member) means a heterocyclic group. Ring atom S or N may be oxidized to form a dioxide. Preferred are aziridinyl, azetidyl, pyrrolidinyl, piperidinyl, piperazil, homopiperaduryl, oxsilanyl, oxetanyl, tetrahydrofuranyl, tetrahydrobilanyl, dioxanyl, morpholinol, homomorpholinyl, tetrahydrothiopyranyl, more preferably , Azetidyl, pyrrolidinyl, piperidinyl, piperazil, oxetanyl, tetrahydrofuranyl, tetrahydrobiranyl, dioxanyl, morpholinyl, and even more preferably oxetanyl, piperidinyl, dioxanyl.

[0025] "Monocyclic heteroaryl" means i) a monocyclic 5- to 6-membered heterocyclic group having an aromatic attribute containing 1 to 4 heteroatoms selected from 0, S and N . The ring atom S or N may be oxidized to form a dioxide. Preferably, pyrrolyl, imidazolyl, triazolinole, tetrazolinole, pi !; ginole, pi! ; Migere, pyrajure, fu !; nore, cheninole, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, more preferably pyridyl, pyrimigel, pyrajur, furyl, chenil, particularly preferably chenil, It is a pyramid.

The term “which may be substituted” means “unsubstituted” or “having 1 to 5 substituents which are the same or different”. In the case of having a plurality of substituents, these substituents may be the same or different from each other! /.

[0027] Substituents in "aryl" and "heterocyclic group" which may be substituted for R ¹ are preferably halogen, nitro, lower alkyl, halogeno lower alkyl, -0 H, -0-lower. A group selected from alkyl, -0-halogeno lower alkyl, -S-lower alkyl, -COR, -O-aryl and -O-lower alkylene-aryl, more preferably halogen, lower alkyl and -0. -A group selected from lower alkyl.

[0028] The substituent in the optionally substituted "monocyclic saturated heterocyclic group" in R ⁴ is preferably a group selected from halogen, lower alkyl, and -0-lower alkyl.

[0029] Preferred embodiments of the present invention are described below.

(a) R is preferably —H.

(b) R ¹ is preferably lower alkyl, optionally substituted phenyl, or optionally substituted monocyclic heteroaryl, more preferably methyl, ethyl, isopropyl Or phenyl, even more preferably methyl, ethyl or phenyl, and particularly preferably methyl.

(c) R ² is preferably —H, —F or —OH, more preferably —H.

(d) R ³ is preferably cyclohexyl or cyclopropylmethyl, and more preferably cyclohexyl.

(e) R ⁴ is preferably isopropyl, 3-pentyl, cyclopentyl or 2,2-dimethyl-

1.3-dioxane-4-yl, more preferably isopropyl, 3-pentyl, or cyclopentyl, and more preferably 3-pentyl or cyclopentyl.

(f) X is preferably _CH =.

(g) Y is preferably -F.

(h) n is preferably 1 or 2, and more preferably 2.

As another preferred embodiment, an embodiment is preferably a compound comprising a combination of each preferred group described in (a) to (h) above.

Further, another preferred embodiment of the compound of the present invention represented by the general formula (I) is shown below.

Yes

(1) The compound according to the general formula (I) or a salt thereof, wherein X is —CH═.

(2) The compound or salt thereof according to (1), wherein Y is -F.

(3) The compound or a salt thereof according to (2), wherein R ³ is cyclohexyl or cyclopropylmethyl.

(4) The compound or salt thereof according to (3), wherein R ² is —H.

(5) The compound or salt thereof according to (4), wherein R is -H.

(6) The compound or salt thereof according to (5), wherein R ⁴ is isopropyl, 3-pentyl or cyclopentyl.

(7) The compound or salt thereof according to (6), wherein n is 2.

(8) The compound or a salt thereof according to (7), wherein R ¹ is methyl, ethyl or phenyl.

(9) (4R) -4-({[7_ (Cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-

1.4-dihydroquinoline-3-yl] carboninole} amino) hexanoic acid,

(4R) -4-({[7_ (Cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4 -Dihydroquinoline-3-yl] carbonyl} amino) pentanoic acid,

(4R) -4-({[7_ (Cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) pentanoic acid,

(4S) _4-[({7- [(Cyclopropylmethyl) amino] -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl} carbonyl ) Amino] -4-phenylbutanoic acid,

(4R) -4-[({7_ [(Cyclopropylmethinole) amino] -6-fluoro-l-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl} carbonyl) amino] pentane Acid,

(4R) -4-({[7_ (Cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) hexanoic acid ,as well as,

(4S) _4-({[7- (Cyclohexylamino) -6-Fluoro-l-Isopropyl-4-oxo-l, 4-Dihydr quinoline-3-yl] carbol} amino) -4 -Phenylbutanoic acid

Or a pharmaceutically acceptable compound thereof, which is selected from the group consisting of:

[0031] The compound of the present invention may have other tautomers and geometric isomers depending on the kind of the substituent. In the present specification, only one form of these isomers may be described, but the present invention includes these isomers, and also includes a separated isomer or a mixture thereof.

In addition, compound (I) may have asymmetric carbon atoms or axial asymmetry, and optical isomers such as (R) and (S) isomers may exist based on this. The present invention includes all of these optical isomers and mixtures thereof.

Furthermore, the present invention includes pharmacologically acceptable prodrugs of Compound (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, OH, COH or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

In addition, the compound of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent, and as long as the salt is a pharmaceutically acceptable salt, the present invention Is included. Specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, p

-Acid addition salts with organic acids such as toluenesulfonic acid, aspartic acid or glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, methylamine, ethylamine, ethanolamine, lysine, ornithine, etc. Examples include salts with organic bases and ammonium salts.

Furthermore, the present invention also includes various hydrates and solvates of the compound of the present invention and pharmaceutically acceptable salts thereof, and polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0033] (Production method)

The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is a case. Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups, and examples of their protecting groups include Greene and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999). The protective group described in “Year)” can be cited, and these may be appropriately selected and used according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary.

Similarly to the protecting group, the prodrug of compound (I) can be produced by introducing a specific group at the raw material or intermediate stage, or by reacting with the obtained compound (I). The reaction can be accomplished by applying a method known by those skilled in the art, such as normal esterification, amidation, dehydration, etc., with a force S.

Hereafter, the typical manufacturing method of this invention compound is demonstrated. The production method of the present invention is not limited to the examples shown below.

[0034] (First manufacturing method)

[Chemical 6]

This production method is a method in which the compound (1) and the compound (2) are amidated to obtain the compound (I) of the present invention. In particular, condensation of carbonyldiimidazole (CDI), 1-ethyl-3- (3_dimethylaminopropyl) carpositimide hydrochloride (WSOHC1), dicyclohexyl carpositimide, diphenyl phosphoryl azide, jet phosphoryl cyanide, etc. A method using an agent, a method using isobutyl chloroformate, ethyl chloroformate, etc., via a mixed acid anhydride, a method using thionyl chloride or phosphorus oxychloride, etc., and a method via an acid halide are suitable. It is. The reaction conditions can be appropriately selected depending on the reactive derivative and condensing agent used, and are usually halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, and aromatic hydrocarbons such as benzene, toluene and xylene. , Ethers such as jetyl ether, tetrahydrofuran (THF), dioxane, etc., in a solvent inert to the reaction such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO). The reaction is performed at room temperature, from room temperature to under heating. Depending on the reaction, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (carbonic acid) It may be advantageous to carry out in the presence of potassium, cesium carbonate or the like.

(Second manufacturing method)

[Chemical 7]

Ia This production method is a method for obtaining the compound (Ia) of the present invention by reducing the double bond of the compound (3).

As the double bond reduction reaction, a double bond reduction reaction usually used by those skilled in the art can be used. For example, as a catalyst, palladium monocarbon, Raney nickel, platinum or the like is used, and the above-mentioned aromatic hydrocarbons, esters such as ethyl acetate, ethers, halogenated hydrocarbons, etc. under atmospheric pressure to pressurized hydrogen atmosphere. Alcohols such as methanol and ethanol, DMF, N, N-dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP), acetic acid, etc. You can also Depending on the compound, it may be advantageous to carry out the reaction in the presence of an acid (preferably hydrochloric acid, acetic acid, etc.) to facilitate the reaction.

[0036] (3rd manufacturing method)

[Chemical 8]

(I-b)

(In the formula, represents lower alkyl. The same shall apply hereinafter.)

This production method is a method for obtaining the present compound (I-c) by hydrolyzing the present compound (I-b).

As the hydrolysis reaction, an ester hydrolysis reaction commonly used by those skilled in the art can be used. For example, in the presence of mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid, organic acids such as formic acid and acetic acid; or lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, carbonic acid The reaction can be carried out under cooling to heating in the presence of a base such as cesium or ammonia. As the solvent, solvents such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water, or the above-mentioned acids can be used as the solvent.

[0037] (4th manufacturing method)

This production method is a method for obtaining the compound (Ic) of the present invention by hydrolyzing the cyan group of the compound (4).

As the hydrolysis reaction, a hydrolysis reaction of a cyan group usually used by those skilled in the art can be used. For example, the reaction can be performed in the presence of an acid such as sulfuric acid, hydrochloric acid, or hydrobromic acid; or in the presence of a base such as sodium hydroxide or potassium hydroxide, under cooling to heating. As the solvent, ethers, alcohols, DMF, DMA, NMP, DMSO, water or the like, or the aforementioned acids can be used.

[0038] Further, some of the compounds represented by the formula (I) are usually employed by those skilled in the art such as known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, etc. from the compounds obtained as described above. It can also be produced by arbitrarily combining the possible processes.

[0039] (Synthesis of raw material compounds)

The starting compound used in the production of the compound (I) of the present invention can be synthesized by using the following method, a known method, or a modified method thereof.

[0040] (Raw material synthesis 1)

[Chemical 10]

Compound (3) can be obtained by amidating compound (1) and compound (5). Amidation can be carried out by the same method as described in the first production method. Compound (1) can be obtained, for example, by the method described in Patent Document 7 or a modified method thereof.

(Raw material synthesis 2)

[Chemical 11]

-Means the remainder of the Emmons or Wittig reagent,

Means a single bond or a double bond. The same applies below. )

(First step)

In this step, compound (1) and compound (6) are amidated to obtain compound (7).

The amidation reaction can be carried out by the same method as described in the first production method.

(Second process)

In this step, compound (7) is oxidized to obtain compound (8).

As the oxidation reaction, an oxidation reaction of an alcohol usually used by those skilled in the art can be employed. For example, in a solvent inert to the reaction, such as ethers and halogenated hydrocarbons, under cooling, using an oxidizing agent generated in the system by DMSO and oxalyl dichloride (Swern oxidation) Power S can be. (Third process)

This step is a step of obtaining the compound (3) from the compound (8) by the Horner-Emmons reaction or the Wittig reaction.

For the Horner-Emmons reaction or Wittig reaction, it is possible to employ a method that can be usually used by those skilled in the art. For example, in the presence of Horner-Emmons reagent or Wietzig reagent, reaction in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, acetonitrile, under cooling or heating. It can be performed. Depending on the type of Horner-Emmons reagent or Wittig reagent, the reaction is preferably carried out in the presence of a base such as alkyllithium such as potassium carbonate, tert-butoxypotassium, sodium hydride, n-butyllithium.

(Raw material synthesis 3)

[Chemical 13]

Compound (4) can be obtained by amidating compound (1) and compound (10).

Amidation can be carried out by the same method as described in the first production method.

(Raw material synthesis 4)

[Chemical 14]

(Four)

(First step)

In this step, compound (1) and compound (11) are amidated to obtain compound (12).

(Second process)

In this step, the hydroxyl group of compound (12) is converted to a cyan group to obtain compound (4).

A conversion reaction to a cyano group is carried out by converting a hydroxyl group to a leaving group (preferably halogen, sulfonyloxy such as methanesulfonanoloxy, p-toluenesulfonyloxy, etc.), In the presence of an agent, the reaction can be carried out in a solvent such as alcohols, DMF, DMA, NMP, DMSO, water, etc., under cooling to heating.

Conversion of a hydroxyl group to a leaving group can be performed by a method commonly used by those skilled in the art. For example, the conversion to a sulfonyloxy group can be carried out by using ethers, aromatic hydrocarbons, and sulfoylating agents such as methanesulfonyl chloride and p-toluenesulfonyl chloride in the presence of bases such as triethylamine and pyridine. The reaction can be carried out in a solvent such as halogenated hydrocarbons under cooling to heating.

The compounds of the present invention are isolated and purified as free compounds, pharmaceutically acceptable salts, hydrates, solvates, or crystalline polymorphic substances. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting it to a conventional salt formation reaction.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be separated by selecting an appropriate raw material compound or utilizing the difference in physicochemical properties between isomers. For example, optical isomers can be obtained by stereochemically pure isomers by general optical resolution methods (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Can lead to. It can also be produced from a suitable optically active raw material compound.

The pharmacological activity of the compound of the present invention was confirmed by the following test.

Test method (1) Human platelet aggregation inhibitory activity measurement test

Blood was collected from a healthy person (adult male) using a syringe containing 1/10 volume of 3.8% sodium citrate solution, and centrifuged at 160 X g for 10 minutes to obtain platelet-rich plasma (PRP) ). The remaining blood from which PRP was collected was centrifuged at 1,800 Xg for 10 minutes! / Immature platelet plasma (PPP) was separated. After the platelet count in PRP was measured with an automatic hemocytometer (MEK-6258, Nippon Koden), the platelet count was adjusted to 3 X 10 ⁸ / ml by adding PPP to PRP and used for the following tests. ADP, a platelet aggregation-inducing agent, used a product of MMC Medical. Platelet aggregation was measured using a platelet aggregometer (MCM Hematracer 212; M'C 'Medical Co.). That is, add PRP 80 μ1 with platelet count 3 X 10 ⁸ / ml and test compound solution or solvent (10% DMSO or 10% DMSO_9% hydroxypropyl- / 3-cyclodextrin-4.5% d_mannitol) 10 μΐ. After incubation at 37 ° C for 1 minute, platelet aggregation was induced by adding 10 µl of ADP (50 ^ M), and the change in transmitted light was recorded for 5 minutes. The inhibition rate was calculated using the area under the platelet aggregation curve as an index. Table 1 shows the results of the compound of the present invention at 10% (final concentration). In the table, Rf represents the reference compound number and Ex represents the example compound number. Reference Examples 1 and 2 are the Example compounds described in Patent Document 7, and were produced according to the method described in Patent Document 7.

Reference Example 1 (Example 467 of Patent Document 7)

4 _ ({[7- (Cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) butanoic acid

Reference Example 2 (Example 526 of Patent Document 7)

4 _ ({[7- (Cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4-dihy Droquinoline-3-yl] carboninole

[0046] [Table 1]

[0047] Test method (2) Substitution test for binding of human P2Y12 to 2-methylthio-ADP (2-MeS_ADP)

C6-15 cells in a 10 cm dish are seeded with DMEM medium to become 1 × 10 ⁶ cells, cultured for 1 day, then plasmid 8 ag of pEF- BOS-dhfr-human P2Y12 and 0.8 μg of pEF -BOS-neo (Nucleic Acid Res., 18,5322,1990) was transfected using a transfection reagent (LipofectAMINE 2000; manufactured by GIBCO BRL).

After 24 hours from the above gene transfer operation, the cells into which the gene has been transferred are collected, suspended in DMEM medium containing 0.6 mg / ml G418 (GIBCO BRL), and then diluted serially to a 10 cm petri dish. Sowed. Colonies that appeared after 2 weeks were individually obtained and used as P2Y12 protein-expressing C6-15 cells in the following experiment (WO 02/36631, Mol. Pharmacol., 60, 432, 2001).

P2Y12 protein expression After C6-15 cells were cultured, the cells were collected. Cells were washed with PBS, suspended in ²⁰ mM Tris-HCl (pH 7.4) containing 5 mmol / 1 EDTA and protease inhibitor cocktail set Complete ™ (Boehringer Mannheim), and homogenized with Polytron. . After ultracentrifugation, the precipitate was suspended in 50 mM Tris_HCl (pH 7.4) containing 1 mM EDTA, 100 mM NaCl and Complete ™, and this was used as a membrane fraction.

[0048] P2Y12 protein expression C6-15 cell membrane fraction (100 μg / ml) prepared as described above 100 1.5 Test compound solution 1.5 n 1 and 0.75 nM [ ³ H] -2- MeS- ADP (80 Ci / mmol , Amersham Pharmaci a Biotech) or 0.75 nM [P] -2-MeS_ADP (2100 Ci / mmol, PerkinElmer) 50 a 1 is added, and 50 mM Tris-HCl containing 100 mM NaCl and 50 mM MgCl (pH 7. After incubation for 1 hour at room temperature in 4), the cells were collected on a glass filter with a cell harvester. A micro scintillator was added to the glass filter, and the radioactivity was measured with a liquid scintillation force counter. At the same time, radioactivity was measured by adding the solvent alone and adding 1.5 μl of 250 M ADP as the total binding amount and non-specific binding amount, respectively, in the above test. The inhibition rate (%) of the test compound was calculated with the total binding amount and non-specific binding amount being 0% and 100%, respectively. The results for the compound of the present invention at 30 nM (final concentration) are shown in Table 2.

[0049] [Table 2]

[0050] Test method (3) Rat platelet aggregation inhibition test and measurement of plasma test compound concentration

The compound of the present invention 0.5% methylcellulose aqueous solution (prepared by adding sodium hydroxide aqueous solution and methylcellulose aqueous solution to the present compound) and fasted for 12 hours or more in male SD rats (5-7 weeks old) using a sonde 30 mg / Orally administered in kg. Two hours after compound administration, blood was collected using a syringe containing 1/10 volume of a 3.8% sodium citrate solution. In the same manner as in the test method (1), PPP and PRP having a platelet count of X 10 ⁸ / ml were prepared. Incubate PRP 90 a 1 with a platelet count of 3 X 10 ⁸ / ml at 37 ° C for 1 minute, then add 10 μ1 of ADP (50 μΜ) to induce platelet aggregation and change the transmitted light for 5 minutes. Recorded. The inhibition rate was calculated using the area under the platelet aggregation curve as an index.

Using the sputum prepared above, the plasma concentration was measured. To draw a standard curve, Separately, the PPP of SD rats that have not been administered a product is prepared, and the PPP compound of the present invention is sequentially diluted with this PPP (selected as appropriate depending on the final concentration of 30 a M to 0.0003 a M compound). An equal amount of distilled water was added to 1001 of the rat administered with the compound of the present invention and PPP containing the diluted compound of the present invention, and further 5% triclo oral acetic acid was added and mixed. After standing in ice for 10 minutes, the mixture was centrifuged and the supernatant was collected. The supernatant was neutralized by adding 311 1 of 2M Tris base and mixing. P2Y12 protein expression C6-15 cell membrane fraction (200 〃 / ½1) 50 1 and PPP 50 1 treated with this triclonal acetate (depending on the compound, 50 mM Tris_HCl (pH 7. (Use PPP diluted in 4)). Furthermore, 0.75 nM [ ³ H] -2-MeS-ADP (80 Ci / mmol, manufactured by Amersham Pharmacia Biotech) or 0.75 nM [ ³³ P] -2-MeS-ADP (2100 Ci / mmol, manufactured by PerkinElmer) After adding 50 μ \ and incubation in 50 mM Tris-HCl (pH 7.4) containing 100 mM NaCl and 50 mM MgCl at room temperature for 1 hour, the cells were collected on a glass filter with a cell harvester. A micro scintillator was added to the glass filter, and the radioactivity was measured with a liquid scintillation counter. Using the binding inhibition curve calculated from the measurement results derived from PPP containing the serially diluted compound of the present invention as a standard curve, the concentration of the compound of the present invention in PPP was converted from the measurement results derived from PPP of rats administered with the compound of the present invention. did.

The results are shown in Table 3. As a result of evaluation by the above-described method, it was revealed that the compound of the present invention exhibits a good platelet aggregation inhibitory activity and a good pharmacokinetics upon oral administration.

[Table 3]

Test method (4) Monkey platelet aggregation inhibition test and measurement of plasma test compound concentration

Male male tubers (2-11 years old) fasted for 12 hours or longer with rubber oral tube The compound aqueous solution of the present invention (prepared by adding sodium hydroxide aqueous solution to the compound of the present invention) was orally administered at 3 mg / kg. Before and 4 hours after administration of the compound of the present invention, blood was collected from the femoral vein using a syringe containing 1/10 volume of a 3.8% sodium quenate solution. In the same manner as in the test method (1), PPP and PRP having a platelet count of X 10 ⁸ / ml were prepared. Platelet count 3 X 10 ⁸ / ml PRP 90 μ 1 37. After incubation at C for 1 minute, platelet aggregation was induced by adding 10 μl of ADP (50 μΜ), and the change in transmitted light was recorded for 5 minutes. The inhibition rate was calculated using the area under the platelet aggregation curve as an index.

Using the sputum prepared above, the plasma concentration was measured. Samples for calibration curve (final concentration 0.5 ng / ml to 2000 ng / ml) were added to 25 1 obtained by serially diluting the compound of the present invention with 50% acetonitrile to 100 1 collected from monkeys not administered the compound of the present invention. ). 50% acetonitrile 25 1 was added to PPP 100 1 of monkeys to which the compound of the present invention was administered to prepare a measurement sample. For samples that are expected to exceed the upper limit of the calibration curve, administer the compound! /, NA! /, Dilute appropriately using PPP collected from monkeys, add 50 μl acetonitrile 25 μ 1, A measurement sample was obtained. After adding 50 μl of 50% acetonitrile solution of the internal standard compound to the measurement sample and the calibration curve sample, 3 ml of tert-butyl methyl ether was added and stirred well. Centrifugation was performed and the supernatant was collected, and then the supernatant was dried with a nitrogen stream. 20 mM ammonium acetate aqueous solution / acetonitrile (40:60 ν / ν δΟ ^ Ι) was added thereto, and 101 was measured by LC / MS / MS method. According to the retention time of the obtained peak and the mass number of the monitor ion The compound of the present invention and an internal standard compound were identified, and the concentration of the compound of the present invention in soot was quantified using a calibration curve formula calculated based on the internal standard method based on the peak area ratio.

Yes

As a result of evaluation by the above-mentioned method, it was revealed that the compound of the present invention exhibited a good platelet aggregation inhibitory activity for oral administration and a good pharmacokinetics.

As a result of the above tests, it was confirmed that the compound of the present invention has an excellent P2Y12 inhibitory action, platelet aggregation inhibitory action and pharmacokinetics. Therefore, the compound of the present invention is a cardiovascular disease closely related to thrombus formation due to platelet aggregation, such as unstable angina pectoris, acute myocardial infarction and its secondary prevention, hepatic artery bypass surgery, PTCA surgery or stent placement. Ischemic diseases such as postoperative reocclusion and restenosis, promotion of hepatic artery thrombolysis and prevention of reocclusion; Cerebrovascular disorders such as transient ischemic attack (TIA) cerebral infarction, subarachnoid hemorrhage (vasospasm); peripheral arterial diseases such as chronic arterial occlusion; preventive and / or therapeutic drugs, and cardiac surgery or Useful as an adjuvant during vascular surgery.

Formulations containing one or more of the compounds (I) or salts thereof of the present invention as active ingredients are usually used using pharmaceutical carriers, excipients and the like that are usually used in this field! /, Can be prepared by the method.

Administration is oral by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intraarticular, intravenous, intramuscular, suppositories, eye drops, eye ointments, transdermal solutions. Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, It is mixed with bull pyrrolidone and / or magnesium aluminate metasilicate. The composition contains an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as carboxymethyl starch sodium, a stabilizer, and a solubilizing agent according to a conventional method. Also good. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, etc., commonly used inert diluents such as purified Contains water or ethanol. In addition to the inert diluent, the liquid composition may contain solubilizers, wetting agents, suspending agents and other adjuvants, sweeteners, flavors, fragrances and preservatives.

Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of the water-insoluble solvent include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia name). Such compositions further comprise isotonic agents, preservatives, wetting agents, milk An agent, dispersant, stabilizer, or solubilizer may be included. These are sterilized by, for example, filtration through a battery retaining filter, blending of a bactericide, or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. A dry powder inhaler or the like can use a dry powder or a powder-containing capsule which can be used for single or multiple administrations. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

In general, in the case of oral administration, the appropriate daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Administer once or in 2 to 4 divided doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and should be administered once to several times a day. As a transmucosal agent, administer about 0.001 to 100 mg / kg per body weight once or multiple times a day. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex, etc. Yes

[0056] The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for diseases for which the compound of the present invention is considered effective. The combination may be administered simultaneously, separately in succession, or at desired time intervals. Co-administered products can be formulated separately, even if they are combination drugs!

Example

[0057] Hereinafter, the production method of the compound (I) of the present invention will be described in more detail based on Examples. The compounds of the present invention are not limited to the compounds described in the following examples. The production method of the raw material compound is shown in the production examples.

[0058] Production Example 1

Suspend 500 mg of 7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 8 ml of methylene chloride and cool with ice. Lower triethylamine 1961 and isobutyl chloroformate 1821 were added. After stirring for 30 minutes, (2R) -2-amino-2-phenylethanol (275 mg) was added, and the mixture was stirred for 2 hours under ice-cooling. Water was added to the reaction solution, followed by extraction with black mouth form, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 7- (cyclohexylamino) -1- (1_ethylpropyl) -6-phenoleo-N-[(lR) -2-hydroxy-1-phenylethyl] 599 mg of 4-oxo-1,4-dihydroquinoline-3-canolepoxamide was obtained.

[0059] Production Example 2

Methyl (2E, 4R) -4-[(tert-butoxycarboninole) amino] pent-2-enoate To a solution of 2.76 g of chloroform with 15 ml was added 15 ml of trifluoroacetic acid at room temperature and stirred for 4 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and jetyl ether were added to the resulting residue. The resulting insoluble material was collected by filtration and dried to obtain 2.93 g of methyl (2E, 4R) -4-aminopent-2-enoatotrifluoroacetate.

[0060] Production Example 3

To a solution of 4.0 g of 3,4,5-trifluoroaniline and 3.6 ml of cyclopentanone in 150 ml of dichloroethane and 3.1 ml of acetic acid, add 11.5 g of sodium triacetoxyborohydride under ice cooling. The mixture was gradually added, warmed to room temperature, and stirred for 3.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with black mouth form, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 5.4 g of N-cyclopentyl-3,4,5-trifluoroaniline.

[0061] Production Example 4

To 3.3 g of N-cyclopentyl-3,4,5-trifluoroaniline, 3.2 ml of jetyl (ethoxymethylene) malonate was added and stirred at 130 ° C for 4 hours. Purification by silica gel column chromatography gave 2.2 g of jetinole {[cyclopentyl (3,4,5-trifluorophenyleno) amino] methylene} malonate.

[0062] Production Example 5

5.7 g of polyphosphoric acid was added to 2.2 g of jetinole {[cyclopentyl (3,4,5-trifluorophenenole) amino] methylene} malonate and stirred at 140 ° C. for 40 minutes. The reaction solution was poured into ice water, and insoluble materials were collected by filtration. This was dissolved in black mouth form, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.4 g of ethyl 1-cyclopentyl-5,6,7-trifluoro-4-4-oxo-1,4-dihydroquinoline-3-carboxylate.

[0063] Production Example 6

Ethyl 1-cyclopentyl-5,6,7-trifluoro-4-ethyl-1,4-dihydroquinoline-3-carboxylate (1.1 g) was added with 42% borohydrofluoric acid and heated at 90 ° C. for 20 hours. Water was added to the reaction solution, and the resulting insoluble material was collected by filtration and dried to obtain 1.4 g of a boron compound. DMSO 15 ml and cyclohexylamine 0.97 ml were added to 1.4 g of this boron compound, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and insoluble matters were collected by filtration. After drying, 30 ml of ethanol and 15 ml of 1M aqueous sodium hydroxide solution were added and stirred at 80 ° C. for 1.5 hours. After completion of the reaction, the insoluble material was removed by filtration, water and jetyl ether were added to the filtrate, liquid separation was performed, and 1M hydrochloric acid was added to the aqueous layer. The resulting precipitate was collected by filtration and dried to give 7- (cyclohexylamino) -1-cyclopentyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.0 g Got.

[0064] Production Example 7

N_Butyllithium (1.60M) in benzyl alcohol 0.58 ml in THF 2.4 ml solution under ice-cooling Hexane solution) 3.2 ml was added and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 8.0 ml of toluene was added for suspension. 400 _mg of 7- (cyclohexylamino) -1-cyclopentyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid prepared in a separate container was added to the prepared suspension. In addition to the toluene suspension, the mixture was stirred at room temperature for 6 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, insoluble matter was collected by filtration, and dried to give 5- (benzyloxy) -7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1 400 mg of 1,4-dihydroquinoline-3-carboxylic acid was obtained.

[0065] Production Example 8

(4R) -4-({[7_ (Cyclohexylamino) -1- (1_ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino ) To a solution of 1.1 g of pentanoic acid in 22 ml of DMF, 395 mg of 1,1'-carbonyldiimidazole was added and heated at 80 ° C. The reaction solution was poured into ice water, and insoluble materials were collected by filtration. The obtained solid was dried and then dissolved in a mixed solution of 22 ml of THF and 11 ml of water, 97 mg of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. 7- (Cyclohexylamino) -1- (1_ethynolepropyl) -6-fluoro-N-[(1R) _4-hydroxy -1 -Methylbutyl] -4-oxo-1,4-dihydroquinoline-3-carboxamide 500 mg was obtained.

[0066] Production Example 9

7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-N-[(1R) _4-hydroxy-1-methylbutyl] -4-oxo-1,4-dihydroquinoline-3-carboxamide To an 8 ml solution of 410 mg of methyl chloride, 0.19 ml of triethylamine and 0.10 ml of methanesulfonyl chloride were added under ice cooling, and the mixture was stirred for 30 minutes at room temperature under ice cooling. Saturated saline was added to the reaction solution, extracted with chloroform, and washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. To the obtained residue, 10 ml of DMF and 109 mg of sodium cyanide were added and stirred at 60 ° C. for 6 hours. Water was added to the reaction solution, followed by extraction with jetyl ether. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain N-[(lR) -4-ciano-1-methylbutyrate. Nore] -7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide was obtained.

[0067] Production Example 10

Dissolve 7.00 g of benzyl [2-hydroxy-1- (hydroxymethinole) ethinole] rubamate in 100 ml of methyl chloride and add 390 mg of pyridinium paratoluenesulfonate and 38 ml of 2,2-dimethoxypropane. Stir at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction solution, and the mixture was extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 8.00 g of benzyl (2,2-dimethyl-1,3-dioxan-5-yl) strength rubamate. .

[0068] Production Example 11

400 mg of palladium-carbon (10%) was added to 80 ml of ethanol solution of 4.00 g of benzanol (2,2-dimethyl-1,3-dioxane-5-inole) strength rubamate, and the mixture was stirred in a hydrogen atmosphere. After filtration through Celite, the filtrate obtained was poured into a separately prepared ethyl 2- (2-chromo-4,5-difluo-benzoyl) -3-ethoxyatalylate 3.84 g in 50 ml of ether and stirred at room temperature. Stir for hours. Saturated saline was added to the resulting reaction solution, followed by extraction with black mouth form, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was added to a suspension of sodium hydride (55%) 658 mg in dioxane 80 ml, and the mixture was stirred at 60 ° C. overnight. The obtained reaction solution was cooled to room temperature, poured into 100 ml of 1M hydrochloric acid, and the resulting insoluble material was collected by filtration, dried, and ethyl 1- (2,2-dimethyl-1,3-dioxane-5-i. L) -6,7-difluoro-4 oxo-1,4-dihydroquinoline-3-carboxylate 1.10 g was obtained.

[0069] Production Example 12

To a solution of DMSO (16.3 ml) and methylene chloride (300 ml) was added 10 ml of oxalyl dichloride at _78 ° C and stirred for 30 minutes. 8.52 g of tert-butyl [(lR) -2-hydroxy-1-methylethyl] strength rubamate was added and stirred for 1 hour. 46.9 ml of diisopropylethylamine was added, and the mixture was stirred at −78 ° C. for 30 minutes and with ice cooling for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with black mouth form, and the organic layer was washed successively with a saturated saline solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in 360 ml of chloroform, add methyl (triphenyl phosphora). Julidene) acetate (19.3 g) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, hexane-ethyl acetate (2: 1) was added, and the insoluble material was removed by filtration. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 8.91 g of methyl (2E, 4R) -4-[(tert-butoxycarboninole) amino] pent-2-enoate.

[0070] Production Example 13

(3R) -3-[(tert-Butoxycarbonyl) amino] butanoic acid To a solution of 1.18 g of DMF in 10 ml was added 971 mg of sodium bicarbonate and 0.54 ml of methyl iodide, and the mixture was stirred at room temperature overnight. 1.61 g of potassium carbonate and 0.54 ml of methyl iodide were added, and the mixture was stirred overnight at room temperature. Insoluble material was removed by filtration, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 995 mg of methyl (3R) -3-[(tert_butoxycarbonyl) amino] butanoate.

[0071] Production Example 14

6,7-Difluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 941 mg in DMSO 8 ml suspension, 1.53 ml diisopropylethylamine and 0.37 ml aminomethylcyclopropane And heated at 80 ° C. for 11 hours. Water and dilute hydrochloric acid were added, and insoluble matters were collected by filtration and dried. To the obtained solid, 4 ml of 80% aqueous acetic acid was added and heated to reflux. After stirring under ice-cooling, insoluble matter was collected by filtration and dried to give 7-[(cyclopropylmethyl) amino] -6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline. -1.05 g of 3-carboxylic acid was obtained.

Production Examples 1 to; Compounds of Production Examples 15 to 68 shown in the table below were produced in the same manner as in the method of 14. The structures, production methods, and physicochemical data of the production example compounds are shown in Tables 4 to 15;

Yes

[0073] Example 1

Methyl (2E, 4S) -4-({[7- (cyclohexylamino) -1- (1_ethylpropyl) -6-fluor-4-oxo-1,4-dihydroquinoline-3-yl] carboxy Nore} amino) -4-phenolbuta-2-enoate 415 mg was dissolved in a mixed solution of 5 ml of methanol and 5 ml of ethyl acetate, 50 mg of palladium-carbon (10%) was added, and then hydrogen atmosphere 2 Stir for hours. After filtration through celite, the filtrate was concentrated under reduced pressure, and methyl (4S) _4-({[7- (cyclohexylamino) -1- (1_ethyl). Mouth pill) -6-fluor mouth-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) -4-phenylbutanoate 403 mg was obtained.

[0074] Example 2

Methyl (4R) -4-({[7_ (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-inole] carboninore} amino) pentanoate To a mixed solution of 190 mg of methanol 5 ml and THF 5 ml, 1.2 ml of 1M aqueous sodium hydroxide solution was added and stirred at room temperature for 5 hours. Jetyl ether and water were added for liquid separation, and 1M hydrochloric acid was added to the aqueous layer. The resulting solid was collected by filtration and dried to obtain (4R) -4-({[7_ (cyclohexylamino) -1-cyclopentyl-6-fluoroc-4-oxo-1,4-dihydroquinoline. 140 mg of 3-yl] carbonyl} amino) pentanoic acid was obtained.

[0075] Example 3

N-[(1R) _4-Ciano-1-methylbutyl] -7- (cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide To 10 ml of 212 mg ethanol solution, 0.34 ml of 4M aqueous sodium hydroxide solution was added and heated to reflux. After completion of the reaction, water and jetyl ether were added for liquid separation, and 1M hydrochloric acid was added to the resulting aqueous layer. The resulting insoluble material was collected by filtration and dried to give (5R) -5 _ ({[7- (cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-4-oxo-1,4 -Dihydroquinoline-3-yl] carbonyl} amino) hexanoic acid 200 mg was obtained.

[0076] Example 4

tert-butyl 4- [7_ (cyclohexylamino) -6-fluoro_3-({[(lS) -4-methoxy-4-oxo-1-phenylbutinole] amino} carbonyl) -4-oxoquinoline-1 ( 4H) _yl] piperidine-1-force Noreboxylate in 5 ml suspension in ethyl acetate was added 4M hydrogen chloride ethyl acetate solution in 0.57 ml and methanol in 5 ml and stirred for 4 days. After distilling off the solvent under reduced pressure, jetinole ether and diisopropyl ether were added. The insoluble material was collected by filtration and dried to obtain methyl (4S) _4-({[7- (cyclohexylamino) -6-fluoroxy-4-oxo-1-piperidine-4-yl-1 , 4-Dihydroquinoline-3-yl] carbonyl} amino) -4-phenylbutanoate hydrochloride 4 20 mg was obtained.

[0077] Example 5 Methyl (4S) _4-({[7- (Cyclohexylamino) -6-Fluoro-Oxo-4-oxo-1-piperidin-4-yl-1,4-dihydroquinoline-3-yl] carbo Diyl} amino) -4-phenylbutanoate hydrochloride 10 3 mg was added THF 5 ml, sodium acetate 51 mg, 37% honolemarin aqueous solution 64 μ1, acetic acid 0.4 ml and sodium triacetoxyborohydride 92 mg, Stir at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with black mouth form, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain methyl (4S) _4-({[7- (cyclohexylamino) -6-fluoro- 1- 95 mg of (1_methylpiperidine-4-yl) -4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) -4-phenenolebutanoate was obtained.

[0078] Example 6

(4R) -4-({[7_ (Cyclohexylamino) -1- (2,2-dimethyl-1,3-dioxane-5-yl) -6-fluoro-4-oxo-1,4 -Dihydroquinoline-3-yl] carbon} amino) pentanoic acid (100 mg) was added with 90% aqueous acetic acid (2.30 ml) and stirred at 60 ° C overnight. The obtained reaction solution was cooled to room temperature, water was added, insoluble matter was collected by filtration, and dried to give (4R) -4-[({7_ (cyclohexylamino) -6-fluorine-1_ [ 45 mg of 2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinolin-3-yl} carbonyl) amino] pentanoic acid was obtained.

[0079] Example 7

(3R) -3-[(tert-Butoxycarbonyl) amino] butanoic acid To a solution of 462 mg of black mouth form is added 5 ml of trifluoroacetic acid under ice-cooling, and stirred at room temperature for 2 hours. Distilled off to obtain an amine compound. In a separate container, 7- (cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 703 mg methylene chloride 30 ml Under ice-cooling, 0.34 ml of triethylamine and 0.25 ml of isobutyl chloroformate were added to the suspension and stirred for 1 hour. 0.95 ml of triethylamine and 5 ml of methylene chloride and 5 ml of DMF of the above synthesized amine were added and stirred at room temperature for 3 hours. 1M hydrochloric acid was added, extracted with black mouth form, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain (3R) -3-({[7- (cyclohexylamino) -1- (1-ethylpropyl)- 6-Fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) butanoic acid 774 mg was obtained. [0080] Example 8

tert-Butyl (3S) -3 _ ({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-ynole] carboninole} Amino) butanoate To a solution of 121 mg of Kuroguchi Form 3 ml of trifluoroacetic acid was added under ice cooling and stirred at room temperature for 10.5 hours. The solvent was distilled off under reduced pressure, and jetyl ether and hexane were added to the resulting residue. The insoluble material was collected by filtration and dried to obtain (3S) -3 _ ({[7- (cyclohexylamino) -1- (1_ethenorepropyl) -6-fluoro-4-4-oxo-1,4 96 mg of -dihydroquinoline-3-yl] carbonyl} amino) butanoic acid were obtained.

[0081] Example 9

7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1273 mg of methylene chloride in 100 ml suspension was cooled with ice Lower triethylamine 1137 1 and isobutyl chloroformate 463 1 were added, and the mixture was stirred as it was for 2 hours. 1 ml of the prepared reaction solution was added to 6.8 mg of 3-amino-3_ (4-methoxyphenyl) propanoic acid and triethylamine 61 and stirred at room temperature. To the reaction solution, 70 mg of polystyrene methyl isocyanate (PS-NCO, 1.58 mmol / g) was added and stirred, and then water was added and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC, and 3-({[7_ (cyclohexylamino) -1- (1_ethylpropyl) -6-fluorine-4-oxo-1 , 4-Dihydr quinoline-3-yl] carbonyl} amino) -3_ (4-methoxyphenyl) propanoic acid 22 mg was obtained.

[0082] Example 10

(4R) -4-({[7_ (Cyclohexylamino) -1- (ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) pentane To a solution of 899 mg of acid in 15 ml of acetic acid, 2.5 ml of 25% hydrobromic acetic acid solution was added and stirred overnight. The solvent was distilled off under reduced pressure, 10 ml of ethyl acetate was added to the resulting residue, and the mixture was heated to reflux. The mixture was stirred under ice-cooling, and the insoluble material was collected by filtration and dried to give (4R) -4-({[7_ (cyclohexylamino) -1- (ethylpropyl) -6-fluoro-4-oxo- 1.03 g of 1,4-dihydroquinoline-3-yl] carbonyl} amino) pentanoic acid hydrobromide was obtained.

[0083] In the same manner as in the methods of! To 10, the compounds of Examples 11 to 153 shown in the table below were prepared. Each was produced using the corresponding raw material. The structure and production method of each Example compound are shown in Tables 16 to 46, and the physicochemical data are shown in Tables 47 to 52.

[0084] The following abbreviations are used in the tables below.

PEx: Production example, Ex: Example, MS: m / z value in mass spectrometry (EI: EI-MS, FAB: FAB-MS, ESI: ESI_MS, + after ionization method is a positive ion-is a negative ion Unless otherwise specified, (M + H) ⁺ for a cation, (MH) — for an anion) NMR1: δ in ¹ H NMR in DM SO-d (ppm), Syn: Manufacturing method

6

It shows that it manufactured using the corresponding raw material similarly to the Example compound which has as. If there is P before the number, it indicates that it was produced using the corresponding raw material in the same manner as in the production example compound having that number as the production example number. If there are multiple numbers, it indicates that the reaction was carried out in the same manner. ). In the structural formula, HC1 indicates a hydrochloride, HBr indicates a hydrobromide, and TFA indicates a trifluoroacetate.

[0085] [Table 4]

]

]

]

]

1]

2]

]

]

Five]

]

0

8

]

]

[0119] [Table 38]

]

]

]

9]

0] + + + + + + + + +

lPZL0 / L00Zd £ / L d 18 0Z./.Z90/800Z: O / A Ex Syn Data

146 9 ESI + 568

147 9 ESI + 590

148 9 ESI + 550

149 9 ESI + 628

150 9 ESI + 629

151 9 ESI + 528

152 9 ESI + 538

153 9 ESI + 600 Industrial applicability

Since the compound of the present invention has an excellent P2Y12 inhibitory action, it is useful as a pharmaceutical, particularly as a platelet aggregation inhibitor. Therefore, the compound of the present invention is a cardiovascular disease closely related to thrombus formation due to platelet aggregation, such as unstable angina, acute myocardial infarction and its secondary prevention, hepatic artery bypass surgery, PTCA surgery or stent placement. Ischemic diseases such as subsequent reocclusion and restenosis, promotion of hepatic artery thrombolysis and prevention of reocclusion; transient cerebral ischemic attack (TIA) cerebral infarction, subarachnoid hemorrhage (vasospasm), etc .; It is useful as a prophylactic and / or therapeutic drug for peripheral arterial disease such as chronic arterial occlusion; and as an adjuvant during cardiac surgery or vascular surgery.

Claims

The scope of the claims

A quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.

R: -H or lower alkyl.

R ² : -H, halogen or -OH.

R ³ : cycloalkyl or cycloalkylmethyl.

R ⁵ : the same or different, lower alkyl or lower alkylene-OH.

X: —CH = Mata

Y: No, Rogen.

n: l, 2 or 3. )

[2] The compound or a salt thereof according to claim 1, wherein X is —CH═.

[3] The compound or a salt thereof according to claim 2, wherein Y is —F.

[4] The compound or a salt thereof according to claim ^{3, wherein} R ³ is cyclohexyl or cyclopropylmethyl.

[5] The compound or a salt thereof according to claim 4, wherein R ² is —H.

[6] The compound or a salt thereof according to claim 5, wherein R is —H.

[7] The compound according to claim 6, wherein R ⁴ is isopropyl, 3-pentyl or cyclopentyl. Or its salt.

[8] The compound or a salt thereof according to claim 7, wherein n is 2.

[9] The compound or a salt thereof according to claim 8, wherein R ¹ is methyl, ethyl or phenyl.

[10] (4R) -4-({[7_ (Cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbodi Nore} amino) hexanoic acid,

(4R) -4-({[7_ (Cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino ) Pentanoic acid,

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[11] A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[12] The pharmaceutical composition according to claim 11, which is a platelet aggregation inhibitor.

[13] The pharmaceutical composition according to claim 11, which is a P2Y12 inhibitor.

[14] Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for producing a platelet aggregation inhibitor or a P2Y12 inhibitor.