WO2005123697A1

WO2005123697A1 - Quinazoline derivatives

Info

Publication number: WO2005123697A1
Application number: PCT/JP2005/011174
Authority: WO
Inventors: Noriyuki Kawano; Noriko Ishikawa; Hiroyuki Kaizawa; Naoyuki Masuda; Wataru Hamaguchi; Yohei Koganemaru; Koji Kato; Takahiro Miyazaki
Original assignee: Astellas Pharma Inc.
Priority date: 2004-06-21
Filing date: 2005-06-17
Publication date: 2005-12-29
Also published as: JP2007269629A

Abstract

A compound useful as a preventive or a remedy for inflammatory diseases, allergic diseases or autoimmune diseases in which CC chemokine receptor 4 (CCR4) participates, i.e., a quinazoline derivative having an anilino or cycloalkylamino group at the 4-position and a cyclic amino group substituted by a nitrogen-containing heterocyclic group or an amino group via carbonyl such as piperazino at the 2-position. Because of having a favorable activity as a CCR4 function controller, the above-described compound is useful as a remedy or a preventive for inflammatory diseases, allergic diseases or autoimmune diseases, in particular, dermatitis, etc.

Description

Specification

Quinazoline derivatives

Technical field

The present invention relates to a novel quinazoline derivative and a medicament containing the same as an active ingredient, particularly a therapeutic agent for inflammatory diseases.

Background art

[0002] Chemokines, which are cell chemotactic factors, are broadly classified into two types, CXCZ chemokines and CCZ iS chemokines, depending on their structural characteristics. In addition, these chemokine receptors belong to the family of seven transmembrane G-protein coupled receptors, and are composed of CXC chemokine receptor and CC chemokine receptor (Pharmacological Reviews, 52, 145, 2000).

CC chemokine receptor 4 (CCR4) is clawed from T lymphocytes and thymus (Biochemical and Biophysical Research Communications, 218, 337, 1996, European Journal of Immunology, 26, 3021, 1996), and is initially referred to as a Th2 type T cell. It was mainly reported to be expressed (Journal of Experimental Medicine, 187, 875, 1998). And subsequent detailed analysis showed that CCR4 was widely present in ThE and Th2 efecta 'memory T cells (Journal of Immunology, 166, 103, 2001; The Journal of Clinical Investigation, 108, 1331, 2001). More recent studies have also shown that CCR4 is present on most skin-directed T cells (Nature, 400, 776, 1999) and monocytes. Macrophages, dendritic cells, and NK cells. (Arthritis & Rheumatism, 44, 1022, 2001).

Thymus and activation-regulated chemokine (1'AR) and Macrophage-derived chemokine (MDC) are CCR4 specific ligands (Journal of Biologi cal Chemistry, 272, 15036, 1997, Journal of Biological Chemistry, 273, 1764, 1998). TARC was discovered as a T cell chemotactic factor (Journal of Biological Chemistry, 271, 21514, 1996), and MDC was discovered as a chemotactic factor for monocytes, macrophages, and ΝΚ cells (Journal of Experimental Medicine, 185, 1595, 1997). Both chemokines are known to have the characteristics of both inflammatory and homeostatic chemokines (Immunology Today, 20, 254, (1999)

Numerous reports have suggested that CCR4 and its ligands, TARC and MDC, are involved in various diseases such as inflammatory diseases, allergic diseases, and autoimmune diseases. For example, asthma (The Journal of Clinical Investigation, 107, 1357, 2001), atopic dermatitis (Journal of Investigative Dermatology, 115, 640, 2000), psoriasis (Laboratory Investigat ion, 81, 335, 2001), rheumatoid arthritis (Arthritis & Rheumatism, 44, 2750, 2001), inflammatory bowel disease (Clinical & Experimental Immunology, 132, 332, 2003) and the like. Therefore, CCR4 function modulators are expected as preventive or therapeutic agents for these diseases and the like. Various drugs such as steroids have been used as prophylactic or therapeutic agents for the above-mentioned inflammatory diseases, allergic diseases, autoimmune diseases, etc., but in view of their therapeutic effects and side effects, a new mechanism of action has been proposed. There is a strong need for the development of drugs based on this.

For example, it has been reported that the compound represented by the following general formula has a function of regulating the function of TARC or MDC (Patent Document 1).

[Chemical 1]

(Where A, B, D, E, X and Y are N or C, J and K are C, L is 0, NH or S, M is CH or N, P is a bond or C = 0, Z is-(CFG) R ² (F is 0, H, alkyl, etc., G is 0, N or

2

Indicates a bond], n is 0-4, R ¹ is halogen, -CN, etc., R ² is heterocyclyl containing at least one nitrogen atom, R ³ is halogen, -CN, etc., R ⁴ and R ⁵ is a ring such connexion formed H or together, R ^1Q represents H, alkyl or the like. See the gazette for details. )

The application contains specific disclosures of 5 'conjugates, which are pyrido [2,3-d] pyrimidine or tetrahydroisoquinoline conjugates.

Further, for example, it has been reported that a compound represented by the following general formula has a function of regulating CCR4 function (Patent Document 2). [Chemical 2]

(In the formula, m and n are the same or different and are each an integer of 1 to 3 (where m + n is 4 or less), R ¹ is -NR ⁴ R ⁵ [where R ⁴ and R ⁵ are H, Aralkyl etc.], r is an integer of 0-4, s is 0-substitutable number, G is a nitrogen atom, CH, etc., q is an integer of 0-2, E is A single bond, -C (= 〇)-, etc., R ^1Q represents an ^optionally substituted alicyclic heterocyclic group, etc., A represents a single bond, -C (= 0)-, etc., and R ³ represents H Quinazoline derivatives represented by the following general formula have IgE antagonistic activity and are useful as therapeutic agents for allergic diseases and cartilage disorders. It has been reported (Patent Document 3).

[Formula 3]

Wherein G is CH or N, R ¹ and R ² are H, optionally substituted alkyl, optionally substituted alkoxy, halogen, etc., and R ³ and R ⁴ are H, substituted R ⁵ is substituted with a group selected from alkyl, alkaryl, alkyl, cycloalkyl, aryl, heterocyclic group, alkanol, arylcarbonyl, alkoxycarbol, and alkamoyl. The group which may be shown below.

In addition, a compound having a cyclic amino group such as piperazine at the 2-position and an arino group at the 4-position has been reported. For example, a compound having an α-blocking effect (Non-Patent Document 1), a compound having an antitumor activity (Patent Document 4), a compound having a Rho-kinase inhibitory activity (Patent Document 5), and the like can be mentioned. However, in any of the documents, compounds in which a cyclic amino group substituted at the 2-position is further substituted with a nitrogen-containing heterocyclic ring or an amino group via a carbonyl group are described. No disclosure. There is no disclosure or suggestion of CCR4 inhibitory activity.

Patent Document 1: US Patent Application Publication No. 2004Z0048865

Patent Document 2: International Publication No. 03Z104230 pamphlet

Patent Document 3: JP-A-2000-281660

Patent Document 4: International Publication No. 92Z14716 pamphlet

Patent Document 5: International Publication No. 02Z076976 pamphlet

Non-Patent Document l: Khimiko-Farmatsevticheskii Zhurnal, Soviet Union, 1987, Vol. 21, No. 7, p.802-807

Disclosure of the invention

Problems to be solved by the invention

[0008] An object of the present invention is to provide a safe and powerful preventive / therapeutic agent for inflammatory diseases, allergic diseases, autoimmune diseases and the like, which has a function of regulating CCR4 function and replaces conventional steroids. .

Means for solving the problem

[0009] The present inventors have diligently studied compounds having a CCR4 function regulating action. As a result, a quinazoline derivative having an arino or cycloalkylamino group at the 4-position and a cyclic amino group at the 2-position such as piperazino substituted with a carbonyl at the amino group such as a nitrogen-containing heterocycle is a CCR4 derivative. The inventors have found that they are useful as function regulators, and have completed the present invention. The compound of the present invention differs from the compound described in Patent Document 1 in that a ring group is directly bonded to the 4-position of the quinazoline ring via a nitrogen atom. Also, Patent Document 1 describes a quinazoline conjugate in concept, but specifically describes only a pyrido [2,3-d] pyrimidine or tetrahydroisoquinoline compound. There is no specific disclosure of the quinazoline-dani product. Similarly, the structure of the compound of the present invention is different from that of the compound described in Patent Document 2 in that quinazoline is used as a mother nucleus. Furthermore, the compound of the present invention differs from the compound of Patent Document 3 in that the compound of the present invention has a structure containing a nitrogen atom via a carbonyl group on a nitrogen atom of a cyclic amino group substituted at the 2-position of the quinazoline ring. . Patent Document 3 does not describe CCR4, TARC, or MDC.

That is, the present invention provides a novel quinazoline derivative represented by the following general formula (I) or a pharmaceutical product thereof. The present invention relates to a pharmaceutical composition comprising a physiologically acceptable salt and a pharmaceutically acceptable carrier, particularly a pharmaceutical composition effective as a prophylactic / therapeutic agent for asthma, atopic dermatitis and rheumatoid arthritis.

[Formula 4]

(The symbols in the formula have the following meanings.

R ¹ :-R °, -OH, -OR °, halogen, halogeno-substituted lower alkyl, -CN, -0- (nodogeno-substituted lower alkyl), -R °° -OH, -SR °, -SO -R °, -NO or -NR ⁹ (R ^{1 ()} ),

twenty two

R °: lower alkyl,

R ^QQ : lower alkylene,

m: 0, 1 or 2,

A: Substituted !, may be, may be, or may be substituted, monocyclic cycloalkyl, R ² and R ³ : the same or different, H or -R °,

n: l or 2,

X: bond or lower alkylene,

B: The group G is substituted with one to three selected groups, and may be a monocyclic or bicyclic nitrogen-containing heterocyclic group, or —CR ⁵ (R ⁶ ) —NR ⁷ (R ⁸ ),

Group G: alkyl, alkaryl, halogen, halogeno-substituted lower alkyl, -Y-0H, -Y-0-R. , -Y-NR ⁹ (R ¹⁰ ), — Y—CO Η, — Υ—CO—R °, — Υ—CN, — Υ— 0—CO—R °, — Υ— NR ^U —CO—R. ,

twenty two

^{^{- Y- CO- NR 9 (R 10}} ), - Y- C (0H) - R. . -0H,-Y-C (C0H) -R. . -CO H,-CO-R. ,-0- (Halo

twenty two

Geno-substituted lower alkyl), -Y-S-R. , -Y-SO-R. ,-Y- NR ¹¹ -CO- NR ⁹ (R ¹⁰ ),-Y- O- CO-

2

NR ⁹ (R ¹⁰ ),-Y-NR ¹¹ -CO-Z-substituted

, A monocyclic heterocyclic group which may be -Z-substituted, -Z-substituted / !, cycloalkyl or -Z-substituted !, also! /, Cycloalkenyl,

R ⁹ , R ^1Q and R ¹¹ : same or different, H or -R °,

Y: bond, -R °°-or lower alkelene,

Z: bond, - R °° -, - 0- , - 0- R °° -, - S -, - S- R °° -, -SO -, - NR 11 -, - NR U - R °° -,-NR ^U -C

2

^{0 -, - NR 11 - CO-} R °° -, - NR 11 - CO- R °° -, - 0- CO -, - NR 11 - CO- NR 9 -, - NR 11 - SO- also

2 2 - SO- NR ¹¹ -,

2

k: 0, 1, 2, or 3,

R ⁵ and R ⁶ : same or different, H, -R °, halogeno-substituted lower alkyl, cycloalkyl, -CO H, -CO -R °, -CN, -R °°-0H, -R °° -0- R °,-R °°-CO-NR ⁹ (R ^{1 (>} ),-R. ⁰ -C

twenty two

N, -R. . -NR ⁹ (R ¹⁰ ), an optionally substituted file, -R. . -An optionally substituted file,-R °°-0- R °°-an optionally substituted file,-R °°-CO-an optionally substituted file.

2

-R °° -C0 -R °° -Feelable or optionally substituted

2

Cyclic heteroaryl,

R ⁷ and R ⁸ : the same or different, H, -R °, -R ° -0-R ° or monocyclic cycloalkyl. The same applies hereinafter. )

The present invention also relates to a pharmaceutical composition comprising the quinazoline derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition is a CCR4 or TARC and Z or MDC function modulator, which is an inflammatory disease, an allergic disease or an autoimmune disease, more preferably asthma, atopic dermatitis or The above-mentioned pharmaceutical composition which is an agent for preventing or treating rheumatoid arthritis. In another embodiment, the general formula (I) for producing a CCR4 or TARC and Z or MDC function modulator, or a prophylactic or therapeutic agent for an inflammatory disease, an allergic disease or an autoimmune disease is provided. Or a pharmaceutically acceptable salt thereof, which comprises administering to a patient an effective amount of the quinazoline derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. , An inflammatory disease, an allergic disease or an autoimmune disease.

The invention's effect

The quinazoline derivative of the present invention is used to regulate the function of CCR4 or TARC and Z or MDC. It has the advantage of having potent effects in models of inflammatory, allergic or autoimmune diseases.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the present specification, “lower alkyl” and “alkyl” mean a straight or branched hydrocarbon group. “Lower alkyl” refers to a C 1-6 (hereinafter abbreviated as C) carbon atom.

1-6

Alkyl, more preferably C alkyl, still more preferably methyl, ethyl and

1-4

And a propyl group.

“Alkyl” means C alkyl, the lower power of the above “lower alkyl”,

1-12 7-12 Incl. "Alkyl" is preferably C alkyl, more preferably branched

1-8

3 or less.

1-8

“Alkyl” is a group having one or more double bonds at any position of the above “alkyl”, preferably C alkenyl, more preferably C alkyl having a branching power of ¾ or less.

2-8 2-8, and more preferably a C-alkyl having one or two double bonds.

2-8

“Lower alkylene” means a divalent group (C alkylene) obtained by removing one arbitrary hydrogen atom from the above “lower alkyl”, preferably C alkylene, and more preferably methyl alkylene.

1-6 1-4

Tylene, ethylene, trimethylene and propylene.

"Lower alkylene" means one or more double bonds at any position of C lower alkylene.

2-6

A group having a bond, preferably a C-alkylene, more preferably a biylene or a

2-4

Bealene, buterene, 2-methylprobelene and 1,3-butagelene.

“Halogen” refers to F, Cl, Br and I. “Halogeno-substituted lower alkyl” preferably means C alkyl substituted with one or more halogens, more preferably one or more

1-6

C is a C alkyl substituted with F, more preferably fluoromethyl, difluoro

1-6

Tyl, trifluoromethyl and trifluoroethyl.

[0013] "Cycloalkyl" is a C-cyclic saturated hydrocarbon ring group having a bridge

3-10

Is also good. Preferred are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo [2.2.1] heptyl groups. Preferred as "monocyclic cycloalkyl" are cyclopentyl, cyclohexyl and cycloheptyl groups. “Cycloalkenyl” is a group having one double bond at any position of “cycloalkyl”, preferably cyclopentyl, cyclohexenyl, cyclohepturyl and bicyclo [2.2.1] heptulyl. is there. Preferred as "monocyclic cycloalkenyl" are cyclopentyl, cyclohexyl and cyclohepturyl groups.

A "monocyclic heterocyclic group" is a monocyclic 3- to 8-membered, preferably 5- to 7-membered ring group containing 1 to 4 heteroatoms selected from 0, S and N forces, "Monocyclic heteroaryl" which is aromatic, "monocyclic saturated heterocyclic group which is aliphatic and does not contain an unsaturated bond", and "monocyclic which is aliphatic and partially has an unsaturated bond" Formula unsaturated heterocyclic group ". The ring atom S or N may be oxidized to form an oxoxide-dioxide. As the "monocyclic heteroaryl", pyridyl, pyrazur, pyrimidyl, pyridazyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl And oxadiazolyl groups. As the "monocyclic saturated heterocyclic group" or "monocyclic unsaturated heterocyclic group", preferably pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydroviranyl, tetrahydrothiopyran L, 1,3-dioxolanyl, morpholinyl and thiazolidyl groups. In the “monocyclic saturated heterocyclic group” and the “monocyclic unsaturated heterocyclic group”, any carbon atom may be substituted with an oxo group. The “monocyclic nitrogen-containing heterocyclic group” includes, among the above “monocyclic heterocyclic groups”, particularly one containing one N atom and further containing one or more heteroatoms having N, S and O forces. And a monocyclic 3- to 8-membered, preferably 5- to 7-membered ring group. As the “monocyclic nitrogen-containing heterocyclic group”, preferably pyridyl, pyrazur, pyrimidyl, pyridazyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, Examples include thiadiazolyl, oxaziazolyl, pyrrolidinyl, piperidyl, piperazinyl, azepar, diazepar, morpholinyl, and thiomorpholinyl groups. It is preferably an aliphatic and saturated ring group, more preferably a pyrrolidyl, piperidyl, piperazyl and azepar group, particularly preferably a pyrrolidinyl group.

The “bicyclic nitrogen-containing heterocyclic group” is the same as the above “monocyclic nitrogen-containing heterocyclic group”, or a ring formed by condensing a file or cycloalkyl with the “monocyclic nitrogen-containing heterocyclic group”. Ring group More preferably, they are indolyl, isoindolyl, indazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, tetrahydroquinolyl, tetrahydridoisoquinolyl, indoleyl, and octahydroindolel.

[0015] The term "optionally substituted" means "unsubstituted" or "having 1 to 5 identical or different substituents".

For example, “optionally substituted fuel”, “optionally substituted monocyclic heteroaryl”, and “optionally substituted or unsubstituted monocyclic heterocyclic group (monocyclic heterocyclic group)” The substituent in “heteroaryl”) is preferably -R °, halogen, halogeno-substituted lower alkyl, -OH ゝ -0-R. ,-CN ゝ-NR ⁹ (R ¹⁰ ),-R. . -OH, -R. . -O-R. ,-S-R. , NO,-O- (ノヽ口

2

Geno-substituted lower alkyl), -SO-R °, -CO H, -R °° -CO H, -CO-R °, -R °° -CO-R. ,-

2 2 2 2 2

O- CO- R °, - CO- NR 9 (R 10), - R °° - CO- NR 9 (R 10), - CO- R. And more preferably -R. , Halogen, halogeno-substituted lower alkyl, -OH, -0-R °, -CN. In addition, “substituted V or may be cycloalkyl”, “substituted or may be monocyclic cycloalkyl”, “substituted or may be cycloalkyl”, and “substituted The substituent in the monocyclic heterocyclic group (which is a monocyclic saturated heterocyclic group or a monocyclic unsaturated heterocyclic group) J is preferably -R ° , Halogen, halogeno-substituted lower alkyl, -OH, -0-R °, oxo, -NR ⁹ (R ¹⁰ ), -R.-OH, -R.-O-R., -O- ( Halogeno-substituted lower alkyl), -CO H,-C

Two

O-R °, -R °° -CO-R °, -CO-NR ⁹ (R ¹⁰ ), more preferably -R °, halogen, halogeno

twenty two

Substituted lower alkyl, -OH, -0-R °, oxo.

When m force ¾ or more, there are a plurality of groups R ¹ , which may be the same or different.

Preferred embodiments of the compound of the present invention represented by the general formula (I) are shown below:

[1] A compound in which A is substituted! Or may be a phenyl.

[2] The compound according to [1], wherein X is a bond or methylene.

[3] The compound of the above-mentioned [2], wherein B is preferably a monocyclic nitrogen-containing heterocyclic group which may be substituted with one to three groups which also select group G.

[4] The compound according to [3], wherein the monocyclic nitrogen-containing heterocyclic group is a pyrrolidinyl, piperidyl, piperazyl, azepal, diazepar or morpholinyl group. [5] The compound according to the above [3], wherein the monocyclic nitrogen-containing heterocyclic group is a pyrrolidinyl or piperidyl group.

[6] The compound of the above-mentioned [5], which is more preferably 1 or 2.

[7] The compound according to the above [6], wherein n is preferably 1.

[8] Particularly preferably, at least one compound selected from the following group: N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2- [4- (pyrrolidine-2-ylacetyl) ) Piperazine-1-yl] quinazoline-4-amine, N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2- [4- (piperidin-2-ylacetyl) Piperazine-1-yl] quinazoline-4-amine, 4-[(4-chloro-2-fluorophenyl) amino] -2- [4- (pyrrolidine-2-ylacetyl) pidazine- 1-yl] quinazoline-7-carbo-tolyl, N- (4-chloro-2-fluorophenyl) -6-fluoro-7-methoxy-2- [4- (pyrrolidine-2-ylacetyl) pi Razine-1-yl] quinazoline-4-amine, 4-[(4-chloro-2-fluorophenyl) amino] -6-methoxy-2- [4- (pyrrolidine-2-ylacetyl) pidazine -1-yl] quinazoline-7-carbo-tolyl, N- (4-chloro-2-fluoro (Yel) -2- [4-({1- [2- (Dimethylamino) -1-methylethyl] pyrrolidine-2-yl} carbonyl) pyrazine-1-yl] -6,7-dimethoxy Quinazoline-4-amine, 2- {2-[(4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} piperazine-1- Yl) carbonyl] pyrrolidine-1-yl} pupan-1-ol, N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2- [4- (pyrrolidine-2 -Ylcarbonyl) piperazine-1-yl] quinazoline-4-amine, N- (4-chloro-2-fluorophenyl) -2- (4-{[1- (1H-imidazole-2- Ylmethyl) pyrrolidine-2-yl] acetyl} piperazine-1-yl) -6,7-dimethoxyquinazoline-4-amine, 4- {2- [2- (4- {4-[(4-chloro Mouth-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} piperazine-1-yl) -2-oxoethyl] pyrrolidine-1-yl} pen Acid, 3- {2- [2- (4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} piperazine-1-y L) -2-oxoethyl] pyrrolidine-1-yl} propane-1,2-diol, N- (4-chloro-2-fluorophenyl)-2- [4-({1- [2- (Dimethylamino) -1-methylethyl] pyrrolidine-2-yl} acetyl) pyrazine-1-yl]-6,7-dimethoxyquinazoline-4-amine, 3- {2-[(4- {4- [(4-Chloro-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} piperazine-1-yl) carbol] pyrrolidine-1-yl} butane-1- All and 2- {2- [2- (4- {4-[(4-chloro-2-fluorophenyl) amino]-6,7-di Methoxyquinazoline-2-yl} piperazin-1-yl) -2-oxoethyl] pyrrolidine-1-yl} pu-pan-tool.

Preferred substituent embodiments of the compound of the present invention represented by the general formula (I) are as follows:

(1) As a substituent of the optionally substituted phenyl group in A, halogen, -CN or -R ° is preferable.

(2) R ¹ is preferably -R °, halogen, -CN, -OR ° or halogeno-substituted lower alkyl, and halogen, -CN or -OR. Is more preferred.

(3) As R ² and R ³ , both are preferably H.

(4) Substituents shown in Group G include C alkyl, C alkyl, cyclopentyl,

1-8 1-8

Cyclohexyl, cyclopent - Le, cyclohexane xenon - le, halogen, halogeno-substituted lower § alkyl, tetrahydronaphthalene Vila sulfonyl, tetrahydronaphthyl Chio Villa ^{alkenyl, - OH, - R QQ -} OH, -OR °, -R 00 - OR 0 ^{, - R 00 - CH (OH} ) - R 00 - OH, - R 00 - CO H, -R °° -CH (CO H) -R °° -CO H, - R 00 - NR 9 (R 10

2 2 2

Preference is given to -R ° -S-R ° or lower alkyl substituted by a monocyclic heterocyclic group which also selects pyrrolyl, imidazolyl, pyridyl, 2-hydroxypyridyl, pyrimidyl and 2-aminopyrimidyl forces.

(5) and R ⁶ are preferably H.

(6) As R ⁷ and R ⁸ , an H, methyl or ethyl group is preferable.

The compound (I) of the present invention may have a geometrical isomer or a tautomer depending on the type of the substituent. The present invention includes a separated form or a mixture of these isomers. Is done.

Further, the compound (I) may have an asymmetric carbon atom, and an (R) -form or (S) -form optical isomer based on this may exist. The present invention includes all of the optical isomers as a mixture or an isolated one.

Further, the compound (I) also includes a pharmacologically acceptable prodrug. A pharmacologically acceptable prodrug is defined as the NH4 of the present invention by solvolysis or under physiological conditions.

Two

It is a compound having a group that can be converted to OH, COH, and the like. As a base to form a prodrug

2

For example, the groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. Compound (I) may form an acid addition salt or a salt with a base depending on the type of the substituent. The strong salt is a pharmaceutically acceptable salt, specifically, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propion. Acid addition salts with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium And inorganic bases such as potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortin; and ammonium salts.

Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of compound (I) and salts thereof.

[0020] (Manufacturing method)

The compound (I) 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 the substituent. At that time, depending on the type of the functional group, it is necessary to protect the functional group with an appropriate protecting group at the stage of raw materials or intermediates, or to replace the functional group with a group that can be easily transferred to the functional group. May be effective. Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like, and their protecting groups include, for example, those described in Protective Groups in Organic Synthesis (TW Greene and PGM Wuts). 3rd edition, 1999) ", and these may be appropriately selected and used according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protective group and carrying out a reaction, and then removing the protective group or converting it to a desired group as necessary.

Further, the prodrug of the compound (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate or by carrying out a reaction using the obtained compound (I) as in the case of the above-mentioned protective group. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.

[0021] First manufacturing method

[Formula 5]

(The symbols in the formula have the same meanings as described above. The same applies hereinafter.)

This production method is a method for producing the present compound (I) by an amidation reaction from a quinazoline derivative (II) having an amino group and a carboxylic acid conjugate (III).

The reaction is carried out by using an equivalent amount of the quinazoline derivative (II) and the carboxylic acid conjugate (III) or one of them in excess, and using a condensing agent (for example, dicyclohexylcarposimide (DCC), Isopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1-carbylbis-1H-imidazole (CDI), etc. In the presence of an agent (eg, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), etc.), stirring is performed under cooling to heating, preferably at room temperature, usually for 1 hour to 1 day. be able to. Instead of these reagents, it is also possible to use a solid phase reagent carrying a functional group having an equivalent action (for example, PS-carposimide (Argonaut Technologies, USA)). Alternatively, the active ester of the compound (III) and the above-mentioned additive may be once isolated and then reacted with the compound (II). The solvent is not particularly limited as long as it is inert to the reaction.For example, aromatic hydrocarbons such as benzene, toluene and xylene, getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dioxane Ethers such as methoxyethane and 1,2-diethoxytan, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, Ν, Ν-dimethylformamide (DMF), N-methylpyrrolidone (NMP), Dimethyl sulfoxide (DMSO) and the like. These solvents are used alone or in combination of two or more. It may be advantageous to carry out the reaction in the presence of a base such as triethylamine, diisopropylethylamine (DIPEA), pyridine or the like in order to make the reaction proceed smoothly.

Second manufacturing method [Formula 6]

(IV)

(In the formula, L represents a leaving group. The same applies hereinafter.)

1

In this production method, the quinazoline derivative (IV) having a leaving group at the 2-position is ipso-substituted with the cyclic amine compound (V) to produce the compound (I) of the present invention.

Examples of the leaving group represented by L include a halogen, an alkylsulfiel group, an alkylsulfol

1

And the like. The reaction is carried out by subjecting compound (IV) to a solvent inert to the reaction, in the presence or absence of a base or acid (preferably hydrogen chloride), using an equivalent or excess amount of (V) under cooling to heating to reflux. Usually one hour to one day. The solvent is not particularly limited as long as it is inert to the reaction.For example, aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol, ethanol, _2- propanol, butanol, DMF, NMP , DMSO and the like. Examples of bases include organic bases such as triethylamine, DIPEA, 1,8-diazabicyclo [5.4.0] -7-indene (DBU), 2,6-lutidine, sodium carbonate, potassium carbonate, cesium carbonate, and hydrogen. Bases such as sodium hydride, potassium hydride and potassium tert-butoxy are preferred.

Third manufacturing method

Group B in the general formula (I),

Compounds having various substituents on R ⁵ or R ⁶ , or on ring group A can be prepared by subjecting compound (I) of the present invention as a raw material to a reaction obvious to those skilled in the art or a modification thereof. Can be easily synthesized. For example, the following reaction can be applied.

(1) Alkylation

The compound of the present invention having a secondary or tertiary amino group can be produced by alkylating the compound of the present invention having a primary or secondary amino group. The reaction is a reductive alkylation reaction For example, a method described in “Experimental Chemistry Lecture (4th edition)”, edited by The Chemical Society of Japan, Vol. 20 (1992) (Maruzen) can be used.

(2) Hydrolysis

The compound of the present invention having a carboxyl group can be produced by hydrolyzing the compound of the present invention having an ester group. For the reaction, a conventional hydrolysis method can be used. For example, the method described in the above-mentioned “Protective Groups in Organic Synthesis (3rd edition)” for the carboxyl group deprotection reaction can be applied.

[0024] Raw material synthesis

(In the formula, P represents H or an amino-protecting group. The same applies hereinafter.)

The starting compounds (II) and (IV) can be produced by the above reaction route. In the above reaction route, the same conditions as in the second production method can be applied to the ipso substitution reaction. When P is a protecting group for an amino group, the group used as P and its removal method are described in the aforementioned “Protective Groups in Organic Synthesis (3rd edition, 1999)”.

[0025] Deprotection

(Villa) (Va) The cyclic aminy conjugate (V) can be produced by the method shown in the above formula. The amidation reaction can be carried out under the same conditions as in the first production method described above, or under the usual method of Amido-dani. (Maruzen) and the like.

[0026] The reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced by subjecting it to a usual salt-forming treatment.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

Various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between the isomers. For example, the optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. The optical isomer can be produced from an appropriate optically active starting compound.

[0027] The pharmacological activity of the compound of the present invention was confirmed by the following test.

1. Effects on [ ³⁵ S] GTP y S binding test via CCR4

(1) Acquisition of human CCR4-expressing cell line

A vector (containing a neomycin resistance gene) having the human CCR4 gene inserted downstream of the EF-1a promoter was prepared, and transfected into mouse pre B cell line B300-19 cells by electoporation. These cells were cultured in a medium supplemented with G418, and a single cell line that constantly and stably expresses human CCR4 was obtained by the limiting dilution method.

(2) Preparation of membrane fraction of human CCR4-expressing cell line

After collecting human CCR4 expressing cells and washing with PBS, Lysis Buffer (10 mM Hepes pH 7.5, The suspension was suspended in 2 mM EDTA (protainase inhibitor). After placing the suspension on ice for 15 minutes, the cells were disrupted with a homogenizer and centrifuged (20000 rpm, 10 min, 4 ° C). _{0 The} supernatant was ultracentrifuged (22K, 30 min, 4 ° C). Thereafter, the pellet suspended in PBS was used as a membrane fraction in subsequent experiments.

(3) GTP y S binding test

Test compounds were prepared at 20 mM Hepes pH 7.05, 100 mM NaCl, 5 mM MgCl, GD

Two

PM, Human MDC ゝ [ ³⁵ S] GTPyS 150 pM, Wheatgerm agglutinin SPA beads 1 mg, Human CCR4 expressing cell line membrane fraction 1 μg Reaction mixture containing 1 h 30 min at room temperature Radioactivity was measured.

The following are examples of Example compounds that exhibited 50% or more inhibitory activity at a concentration of 100 nM: Examples 2, 3, 4, Ί, 108, 120, 124, 126 to 128, 130, 147, 190, 203, 242, 251, 285, 286, 295, 314, 378, 387, 412, 415-417.

The IC values of typical compounds are shown below in nM.

50

Example 2: 83, Example 4: 63, Example 120: 37, Example 124: 67, Example 128: 10, Example 147: 89, Example 251: 57, Example 285: 35, Example 387: 34, Example 415: 68

The above test revealed that the compound of the present invention has strong CCR4 inhibitory activity.o

2.Effects on mouthoxazolone-induced contact dermatitis

The effect on mouthoxazolone-induced contact dermatitis was confirmed by the following method. The abdomen of Balb / c mice (6 to 10 weeks old, female, Nippon Charles' Riva Co., Ltd.) is sensitized by applying a 3% oxazolone / ethanol solution 150 1 (Sigma-Aldrich Japan). Six days after sensitization, apply 1% oxazolone / ethanol solution 10 1 to both sides of the right ear. The test drug is administered 12 hours after application of the oxazolone solution (test drug administration group), and the control group receives only the solvent used to dissolve the test drug. The thickness of the right pinna is measured using a thickness gauge (Mitsutoyo) before and 20 hours after application, and the swelling (thickness increase = measured after 20 hours, measured before application) is calculated. The inhibition rate was calculated by the following formula using the group to which the oxazolone solution was applied without sensitization as the normal group. Inhibition rate = (swelling of control group swelling of test drug administration group) xl00 / (swelling of control group swelling of normal group)

The compounds of the present invention showed good activity. For example, the compound of Example 126 showed an inhibitory rate of 31% after oral administration of 30 mg / kg. In addition, Examples 120 and 127 also showed good activity. The above test proved that the compound of the present invention has a good anti-inflammatory action based on the inhibition of CCR4.

The effect on oxazolone-induced contact dermatitis is also described in The Journal of Immunology, 164, 5207 (2000), and can be evaluated using this method. 3. Effects on mouse collagen-induced arthritis

The effect on mouse collagen-induced arthritis can be evaluated using the method described in The Japanese Journal of Pharmacology, 88, 332 (2002).

In addition to the above test examples, for example, mouse asthma modenole described in Immunology, 98, 345 (1999), oxazolone-induced chronic contact dermatitis model described in Journal of Investigative Dermatorogy, 111, 86 (1998), Japanese Journal of Pharmacology, 76, 175 (1998), International Archives of Allergy and Immunology, 133, 55 (2004), NC / Nga mouse atopic dermatitis model, The Journal of Experimental Medicine, 191, 1755 (2 000) The pharmacological action of the compound of the present invention can be confirmed by various evaluation models generally used for evaluating an anti-inflammatory action, such as a mouse LPS-induced TNFa production model. A preparation containing one or more of compound (I) or a salt thereof as an active ingredient is prepared using a carrier, an excipient, and other additives that are usually used for formulation.

For oral administration, tablets, pills, capsules, granules, powders, liquids, etc., or parenteral injections, such as intravenous injections, intramuscular injections, suppositories, transdermals, nasal preparations, inhalants, etc. Any of the forms may be used. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration subject.However, in the case of oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per adult per day It is administered once or in 2 to 4 divided doses. In the case of intravenous administration depending on the symptoms, the dose is usually in the range of 0.0001 mg / kg to 10 mg / kg per adult once or more times a day. In the case of inhalation, In general, for adults, the dosage is 0.0001 mg / kg to 1 mg / kg once or more times a day.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, one or more active substance (s) at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, or a solubilizer according to a conventional method. Tablets or pills may be coated with sugar coating or a gastric or enteric coating, if necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including. The composition may contain, in addition to the inert solvent, auxiliaries such as solubilizers, wetting agents and suspending agents, sweeteners, flavoring agents, fragrances and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (pharmacopoeia name). Such compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizing agent, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these are prepared by preparing a sterile solid composition, dissolving and suspending it in sterile water or a sterile injection solvent before use.

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, an excipient and as Ratatosu Ya starch, furthermore, _P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate. For administration, an appropriate inhalation or insufflation device can be used. For example, using known devices or nebulizers, such as metered dose inhalation devices, The compounds can be administered alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. A dry powder inhaler or the like can utilize a dry powder or a powder-containing capsule that can be used for single or multiple doses. 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 diacid carbon, etc. .

[0031] External preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments and the like. It 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, carboxyvul polymer, white petrolatum, salami beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl anore konore, cetyl alcohol, lauromacrogol, sonorebitan sesquioleate, and the like. No.

Example

Hereinafter, the method for producing the compound (I) of the present invention will be described in more detail with reference to Examples. The present invention is not limited only to the invention of the compounds described in the following Examples. The production methods of the starting compounds are shown in Reference Examples.

The following abbreviations are used in the following table. Ex: Example number, No: Compound number, Dat: Physical data (F: FAB-MS (M + H) \ FN: FAB-MS (M-H)-, ES: ES to MS (M + H) +, ESN: ESI-MS (M-H)-, NMR: δ (ppm) of characteristic peak in ¹ H NMR in DMSO-d, H:

6

HPLC retention time (min) [HPLC conditions: WakosiHI 5C18 AR 5 ^ M 2.0 x 30 mm, Me OH I 5 mM CF CO H—HO = 10/90 (Omin) —100/0 (4.0min)-100/0 (4.5min), flow rate

3 2 2

1.2 mL / min, 254 nm, 35.0 ° C]), Sal: salt and contained solvent (HC1: hydrochloride, no description: free form, the number before the component is, for example, 2HC1 indicates dihydrochloride), Str: Structural formula, syn: production method (the number indicates the example number produced similarly), Me: methyl, Et: ethyl, Pr: propyl, i Pr: 2-propyl, Bu: butinole, tBu: tert-butyl, Pen: pentyl, Hex: hexyl, cHex: cyclohexyl, Ph: phenol, Ac: acetyl, 2Py: 2-pyridyl, 3Py: 3-pyridyl, 4Py: 4-pyridyl, Ms: methanesulfol, Boc : t-Butoxycarbol, Ph: Fer, Bn: B Benzyl, cbz: benzyloxycarbonyl.

[0033] Reference Example 1

To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline and 4-chloro-2-fluoroaniline in ethanol was added a 1M aqueous hydrochloric acid solution, and the mixture was heated under reflux for 3 hours. The resulting precipitate is filtered and dried under reduced pressure to give 2-chloro-N- (4-chloro-2-fluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride. Was. ES: 368

Reference example 2

2,4-dichloro-6-fluoroquinazoline and 4-chloroaline are reacted in acetonitrile at 70 ° C for 16 hours in the presence of DIPEA, treated with 4M hydrogen chloride Z ethyl acetate solution, and -N- (4-chlorophenol) -6-fluoroquinazoline-4-amine hydrochloride was obtained. F: 308 Reference example 3

2-chloro-N- 6,7- (4-chloro-2-fluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride and anhydrous perazine in dioxane Thus, N_ (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2-pirazin-1-ylquinazolin-4-amine was obtained. E S: 418

Reference example 4

2-chloro-N- 6,7- (4-chloro-2-fluorophenyl) -6,7-dimethoxyquinazoline-4-amine hydrochloride and tert-butyl 1,4-diazepan-1-carboxylate The reaction was carried out in dioxane in the presence of DBU under reflux with heating to give tert-butyl 4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-y 1,4-diazepan-1-carboxylate was obtained. After reacting this compound in trifluoroacetic acid at room temperature for 1 hour, N- (4-chloro-2-fluorophenyl) -2- (1,4- Diazepan-1-yl) -6,7-dimethoxyquinazoline-4-amine dihydrochloride was obtained. F: 432

Reference Example 5

tert-Butyl 4- (chloroacetyl) piperazine-1-carboxylate and pyrrolidine are reacted in aceto nitrile in the presence of cesium carbonate at room temperature to give tert-butyl 4- (pyrrolidine-1-ylacetyl) pirate. Perazine-1-carboxylate was obtained. ES: 298

[0034] Reference Example 6 tert-Butyl 4- (pyrrolidine-1-ylacetyl) piperazine-1-carboxylate is treated with 4M hydrochloric acid in ethyl acetate solution in methanol to give 1- (pyrrolidine-1-ylacetyl) piperazine 2 The hydrochloride was obtained. ES: 198

Reference Example 7

The same operation as in Reference Example 5 was performed using tert-butyl 4- (chloroacetyl) pirazine-1-carboxylate and 3- (hydroxymethyl) piperidine to obtain tert-butyl 4-{[3- (Hydroxymethyl) piperidin-1-yl] acetyl} piperazine-1-carbosylate was obtained. The same operation as in Reference Example 6 was performed using this compound to obtain [1- (2-oxo-2-pyrazine-1-ylethyl) piperidin-3-yl] methanol dihydrochloride. ES: 242

Reference Example 8

Methyl 2-amino-5-fluoro-4-methoxybenzoate is reacted with potassium cyanate in acetic acid at 100 ° C. for 4 days to give 6-fluoro-7-methoxyquinazoline-2,4- (1Η, 3Η )-Dione was obtained. ES: 211.

Reference Example 9

A mixture of 6-fluoro mouth-7-methoxyquinazoline-2,4 (1H, 3H) -dione, phosphorus pentachloride and oxychlorine was heated under reflux for 13 hours to give 2,4-dichloro-6-fluoro mouth-7. -Methoxyquinazoline was obtained. ES: 247 ₀

Reference example 10

Reaction of 2,4-dichloro-6-fluoro-7-methoxyquinazoline and 4-chloro-2-fluoroaniline in ΤHF in the presence of potassium tert-butoxide at room temperature to give 5-bromo-2- (2-chloro-6-fluoro-quinazoline-4-ylamino) -benzo-tolyl was obtained. ES: 356.

Reference Example 11

DBU was added to a DMF solution of 2-aminoterephthalate-tolyl and stirred overnight at room temperature under a carbon dioxide atmosphere. The reaction solution was added to a 1M aqueous hydrochloric acid solution, and the resulting precipitate was filtered and dried under reduced pressure to obtain 7-cyanoquinazoline-2,4 (1H, 3H) _dione. FN: 186.

Reference Example 12

A mixture of 7-cyanoquinazoline-2,4 (1H, 3H) -dione, phosphorus oxychloride, N ,,,-getyla-line is heated to reflux and heated to give 2,4-dichloro-7-cyanoquinazoline. Obtained. FN: 223 ₀ Reference Example 13

Potassium tert-butoxide was added to a solution of dimethyl 2-fluoro-5-troterephthalate in methanol-THF at 0 ° C, followed by reaction at 50 ° C for 3 hours, and dimethyl 2-methoxy-5-nitro Terephthalate was obtained. ES: 270

Reference Example 14

Dimethyl 2-methoxy-5-nitroterephthalate was stirred in a mixed solvent of ethanol and THF in the presence of 10% palladium-carbon under a hydrogen atmosphere at room temperature to obtain dimethyl 2-amino-5-methoxyterephthalate. ES: 240

Reference Example 15

Methyl 6-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate is reacted with phosphorus oxychloride in toluene in the presence of tripropylamine at 100 ° C for 3 days to give methyl 2 , 4-Dichloro-6-methoxyquinazoline-7-carboxylate was obtained. ES: 287.

Reference Example 16

To a mixed solution of methyl 2,4-dichloro-6-methoxyquinazoline-7-carboxylate in methanol-THF was added 1M aqueous sodium hydroxide solution, and the mixture was allowed to react at room temperature for 22 hours. 4-chloro-2-fluorophenyl) amino] -6-methoxyquinazoline-7-carboxylic acid was obtained. In a THF solution of this compound, salted oxalil and DMF were stirred at room temperature for 5 hours. After the reaction solution was concentrated, it was added to a saturated aqueous ammonia solution to obtain 2-chloro-4-[(4-chloro-2-fluorophenyl) amino] -6-methoxyquinazoline-7-carboxamide. ES: 381

Reference Example 17

2-chloro- 4-[(4-chloro-2-fluorophenyl) amino] -6-methoxyquinazoline-7-carboxamide, trifluoroacetic anhydride in THF solution of DIPEA at -20 ° C Thereafter, the mixture was reacted at 0 ° C. for 17 hours to obtain 2-chloro-4-[(4-chloro-2-fluorophenyl) amino] -6-methoxyquinazoline-7-carbo-tolyl. ES: 363

Reference Example 18

After adding WSC hydrochloride to a THF solution of N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2-piperazine-1-ylquinazoline-4-amine and 3-bromopropanoic acid At room temperature to give 2- [4- (3-bromopropanoyl) pirazin-1-yl] -N- (4-chloro-2-fluoro (Fenyl) -6,7-dimethoxyquinazolin-4-amine was obtained. ES: 554

Reference Examples 19 to 24

The compound of Reference Example 19 was obtained in the same manner as in the method of Reference Example 8, the compound of Reference Examples 20 to 21 was obtained in the same manner as in the method of Reference Example 10, and the compounds of Reference Examples 22 to 24 were obtained in the same manner as in the method of Reference Example 3. Were produced using the corresponding raw materials. Table 1 shows the structures and physicochemical data of the compounds of Reference Examples 19 to 24.

Example 1

1- (Pyrrolidine-1-ylacetyl) in a solution of 400 mg of 1,2-dioxetane in 400 mg of 2-mg-N- (4-methyl mouth) -6-fluoroquinazoline-4-amine hydrochloride Piperazine dihydrochloride (3 50 mg) and DBU (0.74 ml) were added, and the mixture was stirred at 110 ° C for 16 hours. To the residue obtained by evaporating the solvent of the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (form-form-methanol-28% aqueous ammonia) to give N- (4-form-methyl) -6-fluoro-2- [4- ( There was obtained 220 mg of pyrrolidine-1-ylacetyl) pyrazine-1-yl] quinazoline-4-amine as an orange amorphous solid. The compound was dissolved in 5 ml of methanol, and 0.5 ml of a 4M hydrogen chloride / ethyl acetate solution was added to form a hydrochloride, and the solvent was distilled off. The obtained crystals were recrystallized from ethanol-acetonitrile to give N- (4-chlorophenol) -6-fluoro-2- [4- (pyrrolidine-1-ylacetyl) pyrazine-1-yl] 188 mg of quinazoline-4-amine dihydrochloride was obtained as pale orange crystals.

Example 2

To a solution of 6.6 mg of N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2-piperazine-1-ylquinazoline-4-amine and 2.6 mg of HOBt in 0.5 mL of DMF was added 3-dimethyla. A solution of 3.1 mg of minopropion hydrochloride in 0.04 mL of NMP was added, and 42 mg of PS-carboimide (manufactured by Arbonaut Technologies, 1.35 mmol / g) was added thereto, followed by stirring at room temperature for 1 day. 55 mg of PS-trisamine (manufactured by Argonaut Technologies, 4.36 mmol / g) and 22 mg of PS-isocyanate (manufactured by Argonaut Technologies, 1.47 mmol / g) were added to the reaction solution, followed by stirring at room temperature for 2 hours. The solution obtained by filtering the reaction solution was subjected to HPLC (column: Symmetry, registered trademark), C18, 5 M 19 × 100 mm; solvent: MeOH / 0.1% HCOOH-HO = 10/90 (0 min) -10/90 (1 min)-100/0 (9 min)-100/0 (12 min); 30 mL / min flow rate; Fluorophenyl) -2- {4- [3- (dimethylamino) propanoyl] piperazin-1-yl} -6,7-dimethoxyquinazoline-4-amine 0.7 mg was obtained.

Example 3

Using N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2-piperazine-1-ylquinazoline-4-amine 6.3 mg and Boc-L-j8-homoproline 3.4 mg as described above. By performing the same operation as in Example 1, tert-butyl (2S) -2- [2- (4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7-dimethoxy Quinazoline-2-yl} piperazine-1-yl) -2-oxoethyl] pyrrolidine-1-carboxylate was obtained. This compound was dissolved in 0.2 mL of 1,4-dioxane, 0.2 mL of a 4M HC1 I 1,4-dioxane solution was added, and the mixture was stirred at room temperature for an hour. The residue obtained by evaporating the solvent of the reaction solution was subjected to HPLC (column: Symmetry, registered trademark, C18, 5M19X100mm; solvent: MeOH / 0.1% HCOOH-H0 = 10/90 ( 0 min)-10/90 (1 min)-100

2

/ 0 (9 min)-100/0 (12 min); flow rate 30 mL / min), and perform N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy- 2.7 mg of 2- {4-[(2S) _pyrrolidine-2-ylacetyl] piperazine-1-yl} quinazoline-4-amine was obtained.

Example 4

N- (4-chloro-2-fluorophenyl) -2- (1,4-diazepan-1-yl) -6,7-dimethoxyquinazoline-4-amine dihydrochloride 505 mg DMF 10 ml To the solution were added (S)-[l- (tert-butoxycarbol) pyrrolidine-2-yl] acetic acid (343 mg), WSC hydrochloride (290 mg), HOBt (135 mg), and triethylamine (0.28 ml), and the mixture was stirred at room temperature for 16 hours. To the residue obtained by evaporating the solvent of the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (form-methanol-28% aqueous ammonia) to give tert-butyl (S) -2- [2- (4- {4-[(4-chloroform Mouth-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} -1,4-diazepan-1-yl) -2-oxoethyl] pyrrolidine-1-carboxylate 220 mg pale Obtained as yellow crystals. This compound was dissolved in 5 ml of ethanol, 1 ml of a 4 M hydrogen chloride Z-ethyl acetate solution was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and the resulting crystals were recrystallized from ethanol-ethyl ether to give (S) -N- (4-chloro-2 -Fluorophenyl) -6,7-dimethoxy-2- [4- (pyrrolidine-2-ylacetyl) -1,4-diazepan-1-yl] quinazoline-4-amine dihydrochloride 126 mg pale yellow Obtained as crystals.

Examples 5 to 201

The compounds of Examples 5 to 201 shown in Tables 2 to 10 below were produced in the same manner as in the methods of Examples 1 to 4, using the corresponding raw materials.

Example 202

2- [4- (3-Bromopropanoyl) pirazin-1-yl] -N- (4-chloro-2-fluorophenyl) -6,7-dimethoxyquinazoline-4-amine 6.0 mg Isopropylamine in 0.5 mL of DMF

A solution of 1.5 mg of NMP in 0.05 mL, potassium iodide 2.5 mg and potassium carbonate 2.1 mg were added, and the mixture was stirred overnight at room temperature. The filtrate obtained by filtering the reaction solution was subjected to HPLC (column: Symmetry, registered trademark), C18, 5 ^ 19 × 100 mm; solvent: MeOH I 0.1% HCOOH-HO.

Two

= 10/90 (0 min)-10/90 (1 min)-100/0 (9 min)-100/0 (12 min); flow rate 30 mL / min), N- (4-chloro-2-fluorophenyl) -2- {4- [3- (isopropylamino) propanoyl] pirazin-1-yl} -6,7-dimethoxyquinazoline-4-amine 0.5 mg was obtained. Example 203

N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2- {4-[(2S) -pyrrolidine-2-ylacetyl] pyrazine-1-yl} quinazoline-4 To a solution of 10.6 mg of -amine in 0.5 mL of DMF was added a solution of 2.2 mg of 1-hydroxyacetone in 0.1 mL of NMP, 0.05 mL of acetic acid, and 34 mg of MP-triacetoxyborohydride (Arbonaut Technologies, 2.05 mmol / g). The mixture was stirred at room temperature for 1 晚. To the reaction mixture was added 27 mg of PS-isocyanate (manufactured by Argonaut Technologies, 1.47 mmol / g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the resulting solution was subjected to HPLC (force: Cosmosil [COSMOSIL] , Registered trademark], C18, 5M 20 x 250mm; solvent: MeCN I 0.1% TFA-HO = 10/90 (0 min)-10/90 (0.6 min)-60/40 (24.8 min)- 95/5 (25 min) —

2

95/5 (28min)-10/90 (28.1min)-10/90 (30min); flow rate 20 mL / min) to purify 2-((2S)-2- [2- (4 -{4-[(4-chloro-2-fluorophenyl) amino]-6,7-dimethoxyquinazolin-2-yl} piperazin-1-yl) -2-oxoethyl] pyrrolidine-1-y 2.1 mg of propane-1-ol were obtained.

In the same manner as in Examples 3, 202 and 203, Example 204 shown in Tables 11 to 24 below is used. ~ 576 compounds were each prepared using the corresponding starting materials.

The structures and physical data of the compounds of Examples 1 to 576 are shown in Tables 2 to 24. Table 25 shows the structure of another compound of the present invention. These can be easily synthesized by using the above-mentioned production methods and the methods described in the Examples and methods obvious to those skilled in the art, or modified methods thereof.

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Industrial applicability

Since the quinazoline derivative of the present invention has a function to regulate the function of CCR4 or TARC and Z or MDC, various inflammatory diseases, allergic diseases, autoimmune diseases and the like (for example, asthma, allergic rhinitis, allergic conjunctivitis, Hay fever, dermatitis (atopic skin Inflammation, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, insulin-dependent diabetes mellitus (IDDM), organ transplant rejection, cancer, inflammatory bowel disease (ulcerative colitis, clone Disease), interstitial cystitis, sepsis, pain]. In particular, it can be expected as a preventive / therapeutic agent for asthma, atopic dermatitis or rheumatoid arthritis.

Claims

The scope of the claims

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

[Formula 9]

(The symbols in the formula have the following meanings.

R ¹ : -R °, -OH, -OR °, halogen, halogeno-substituted lower alkyl, -CN, -0- (nodogeno-substituted lower alkyl), -R ° -0H, -SR °, -SO -R °, -NO or -NR ⁹ (R ¹⁰ ),

twenty two

R °: lower alkyl,

R ^QQ : lower alkylene,

m: 0, 1 or 2,

n: l or 2,

X: bond or lower alkylene,

twenty two

Genomic substituted lower alkyl), - Y- S- R °, -Y-S0 - R °, - Y- NR 11 - CO- NR 9 (R 1 (>), - Y- 0- CO-

2

NR ⁹ (R ¹⁰ ),-Y-NR ¹¹ -CO-Z-substituted

Or -Z-substituted monocyclic heterocyclic group, -Z-substituted! /, Cycloalkyl or -Z-substituted! Yeah! /, Cycloalkal, R ⁹ , R ^1Q and R ¹¹ : same or different, H or -R °,

Y: bond, -R °°-or lower alkenylene,

2

2 2 - SO- NR ¹¹ -,

2

k: 0, 1, 2, or 3,

twenty two

2

-R °° -C0 -R °° -Feelable or optionally substituted

2

Cyclic heteroaryl,

R ⁷ and R ⁸ : the same or different from each other, H, -R °, -R °° -0-R ° or monocyclic cycloalkyl o)

[2] The derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein A is an optionally substituted file.

[3] The derivative according to claim 2, wherein X is a bond or methylene, or a pharmaceutically acceptable salt thereof.

[4] B-force G-group power The derivative according to claim 3, which is a monocyclic nitrogen-containing heterocyclic group optionally substituted with one to three selected groups, or a pharmaceutically acceptable derivative thereof. Salt.

5. The derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein the monocyclic nitrogen-containing heterocyclic group is pyrrolidinyl or piperidyl.

[6] N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2- [4- (pyrrolidine-2-ylacetyl) pidazine-1-yl] quinazoline-4-amine , N- (4-chloro-2-fluorophenyl) -6,7-dimethoxy-2- [4- (piperidine-2-ylacetyl) piperazine-1-yl] quinazoline-4-amine, 4 -[(4-Chloro-2-fluorophenyl) amino]-2- [4- (pyrrolidine-2-ylacetyl) pyrazine-1-yl] quinazoline-7-carbonitrile, N- (4 -Chloro- 2-fluorophenyl) -6-fluoro-7-methoxy-2- [4- (pyrrolidine-2-ylacetyl) pidazine-1-yl] quinazoline-4-amine, 4-[(4-chloro-2-fluorophenyl) amino] -6-methoxy-2- [4- (pyrrolidine-2-ylacetyl) pyrazine-1-yl] quinazoline-7-carboni Tolyl, N- (4-chloro-2-fluorophenyl) -2- [4-({1- [2- (dimethylamino) -1-methylethyl] pyrrolidine-2-yl} carbol) piperazine- 1-yl] -6,7-dimethoxyquinazoline-4-amine, 2- {2-[(4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7- Dimethoxyquinazoline-2-yl} piperazin-1-yl) carbol] pyrrolidine-1-yl} propan-1-ol, N- (4-chloro-2-fluorophenyl) -6, 7-dimethoxy-2- [4- (pyrrolidine-2-ylcarbol) pidazine-1-yl] quinazoline-4-amine, N- (4-chloro-2-fluorophenyl) -2- (4-{[1- (1H-imidazole-2-ylmethyl) pyrrolidine-2-yl] acetyl} piperazine-1-yl) -6,7-dimethoxyquinazoline-4-a 4- {2- [2- (4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7-dimethoxyquinazoline-2-yl} piperazine-1-yl ) -2-oxoethyl] pyrrolidine-1-yl} pentanoic acid, 3- {2- [2- (4- {4-[(4-chloro-2-fluorophenyl) amino] -6,7 -Dimethoxyquinazoline-2-yl} piperazine-1-yl) -2-oxoethyl] pyrrolidine-1-yl} propane-1,2-diol, N- (4-chloro-2-fluorophene) )-2- [4-({1- [2- (dimethylamino) -1-methylethyl] pyrrolidine-2-yl} acetyl) piperazin-1-yl] -6,7-dimethoxyquinazoline-4- Amine, 3- {2-[(4- {4-[(4-chloro-2-fluorophenol) amino] -6,7-dimethoxyquinazoline-2-yl} piperazine-1-yl) [Carbol] pyrrolidine-1-yl} butan-1-ol and 2- {2- [2- (4- {4-[(4-chloro-2-fluorophenyl) amino] -6 , 7-Dimethoxyquinazoline-2_yl} Perazine - 1-I) -2-Okisoechiru] pyrrolidine emissions -1- I le} propan - 1 derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the selected all-force group consisting force.

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

[8] The derivative according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which is a CCR4 or TARC and a functional regulator of Z or MDC. The pharmaceutical composition according to claim 7, wherein

[9] The pharmaceutical composition according to claim 8, which is an agent for preventing or treating an inflammatory disease, an allergic disease or an autoimmune disease.

[10] The pharmaceutical composition according to claim 9, which is an agent for preventing or treating asthma.

[11] The pharmaceutical composition according to claim 9, which is a prophylactic or therapeutic agent for atopic dermatitis.

12. The pharmaceutical composition according to claim 9, which is a prophylactic or therapeutic agent for rheumatoid arthritis.

[13] Use of the derivative according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic or therapeutic agent for an inflammatory disease, an allergic disease or an autoimmune disease.

[14] Prevention of an inflammatory disease, an allergic disease or an autoimmune disease, comprising administering to a patient a therapeutically effective amount of the derivative according to claim 1 or a pharmaceutically acceptable salt thereof. Or a method of treatment.