Morpholine compound

1. A compound represented by the formula (1)

wherein

ring A is aryl having substituent(s), or heteroaryl optionally having substituent(s),

ring B is arylene optionally having substituent(s), divalent heterocyclic group optionally having substituent(s), or C 3-8 cycloalkylene optionally having substituent(s),

m is an integer of 0 to 2,

n is an integer of 1 to 5,

X is a bond, —NH—, —NR 1 — wherein R 1 is C 1-6 alkyl optionally having substituent(s), —CO—, —CO 2 —, —OCO—, —CONR a — wherein R a is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR a CO—, —NR 2 CONR 3 — wherein R 2 and R 3 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s), or R 2 and R 3 in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR a SO 2 —, —SO 2 NR a —, C 1-6 alkylene optionally having substituent(s), C 2-6 alkenylene optionally having substituent(s), C 2-6 alkynylene optionally having substituent(s), —O—X a — wherein X a is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X a —O—, —CO—X a —, —X a —CO—, —CONR a —X a —, —X a —CONR a —, —NR a CO—X a —, —X a —NR a CO—, —S—X a —, —X a —S—, —SO—X a —, —X a —SO—, —NR a —X a —, —X a —NR a —, —SO 2 —X a —, —X a —SO 2 —, —C(═N—CO 2 —R 1 )—, —C(═N—SO 2 —R 1 )—, —C(═N—SO 2 NH 2 )—, —C(═CH—NO 2 )—, —C(═N—CN)— or C 3-8 cycloalkylidene group optionally having substituent(s),

Y is a bond, —NH—, —NR 4 — wherein R 4 is C 1-6 alkyl optionally having substituent(s), hereinafter the same, —CO—, —CO 2 —, —OCO—, —CONR b — wherein R b is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR b CO—, —NR 5 CONR 6 — wherein R 5 and R 6 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s), or R 5 and R 6 in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR b SO 2 —, —SO 2 NR b —, C 1-6 alkylene optionally having substituent(s), C 2-6 alkenylene optionally having substituent(s), C 2-6 alkynylene optionally having substituent(s), —O—X b — wherein X b is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X b —O—, —CO—X b —, —X b —CO—, —CONR b —X b —, —X b —CONR b —, —NR b CO—X b —, —X b —NR b CO—, —S—X b —, —X b —S—, —SO—X b —, —X b —SO—, —NR b —X b —, —X b —NR b —, —SO 2 —X b —, —X b —SO 2 —, —C(═N—CO 2 —R 4 )—, —C(═N—SO 2 —R 4 )—, —C(═N—SO 2 NH 2 )—, —C(═CH—NO 2 )— or —C(═N—CN)—, and

Z is hydrogen atom, halogen atom, C 1-6 alkyl optionally having substituent(s), C 3-8 cycloalkyl optionally having substituent(s), aryl optionally having substituent(s), heterocyclic group optionally having substituent(s), hydroxy, nitro, amino, cyano, C 1-6 alkoxy optionally having substituent(s), mono- or di-C 1-6 alkylamino optionally having substituent(s), C 1-7 acylamino optionally having substituent(s), sulfonylamino optionally having substituent(s), hydrazino optionally having substituent(s), guanidino optionally having substituent(s) or amidino optionally having substituent(s),

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein ring B is arylene optionally having substituent(s), or divalent heterocyclic group optionally having substituent(s), and

X is a bond, —NH—, —NR 1 — wherein R 1 is C 1-6 alkyl optionally having substituent(s), —CO—, —CO 2 —, —OCO—, —CONR a — wherein R a is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR a CO—, —NR 2 CONR 3 — wherein R 2 and R 3 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s), or R 2 and R 3 in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR a SO 2 —, —SO 2 NR a —, C 1-6 alkylene optionally having substituent(s), C 2-6 alkenylene optionally having substituent(s), C 2-6 alkynylene optionally having substituent(s), —O—X a — wherein X a is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X a —O—, —CO—X a —, —X a —CO—, —CONR a —X a —, —X a —CONR a —, —NR a CO—X a —, —X a —NR a CO—, —S—X a —, —X a —S—, —SO—X a —, —X a —SO—, —NR a —X a —, —X a —NR a —, —SO 2 —X a —, —X a —SO 2 —, —C(═N—CO 2 —R 1 —, —C(═N—SO 2 —R 1 —, —C(═N—SO 2 NH 2 )—, —C(═CH—NO 2 )— or —C(═N—CN)—, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein, in the formula (1), m is 0 or 2, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein, in the formula (1), m is 0, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein, in the formula (1), X is a bond, —NH—, —NR 1 — wherein R 1 is C 1-6 alkyl optionally having substituent(s), —CO—, —CO 2 —, —OCO—, —CONR a — wherein R a is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR a CO—, —NR 2 CONR 3 — wherein R 2 and R 3 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR a SO 2 —, —SO 2 NR a —, C 2-6 alkenylene optionally having substituent(s), —CO—X a — wherein X a is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X a —CO—, —CONR a —X a —,

—X a —CONR a —, —NR a CO—X a —, —X a —NR a CO— or C 3-8 cycloalkylidene optionally having substituent(s), or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein, in the formula (1), X is a bond, —CO—, —CONR a — wherein R a is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR a CO—, —CO—X a — wherein X a is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X a —CO—, —CONR a —X a —, —X a —CONR a —, —NR a CO—X a — or —X a —NR a CO—, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein, in the formula (1), Y is a bond, —NH—, —NR 4 — wherein R 4 is C 1-6 alkyl optionally having substituent(s), —CO—, —CO 2 —, —OCO—, —CONR b — wherein R b is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR b CO—, —NR 5 CONR 6 — wherein R 5 and R 6 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR b SO 2 —, —SO 2 NR b —, —CO—X b — wherein X b is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X b —CO—, —CONR b —X b —, —X b —CONR b —, —NR b CO—X b — or —X b —NR b CO—, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein, in the formula (1), Y is a bond, —CO—, —CONR b — wherein R b is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR b CO—, —CO—X b — wherein X b is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X b —CO—, —CONR b —X b —, —X b —CONR b —, —NR b CO—X b — or —X b —NR b CO—, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein, in the formula (1), Z is hydrogen atom, halogen atom, C 1-6 alkyl optionally having substituent(s), C 3-8 cycloalkyl optionally having substituent(s), aryl optionally having substituent(s), heterocyclic group optionally having substituent(s), hydroxy, nitro, amino, cyano, C 1-6 alkoxy optionally having substituent(s), mono- or di-C 1-6 alkylamino optionally having substituent(s), C 1-7 acylamino optionally having substituent(s), sulfonylamino optionally having substituent(s), hydrazino optionally having substituent(s), guanidino optionally having substituent(s), or amidino optionally having substituent(s), or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein, in the formula (1), Z is hydrogen atom, hydroxy, amino, C 1-6 alkyl optionally having substituent(s), C 1-6 alkoxy optionally having substituent(s), aryl optionally having substituent(s) or heterocyclic group optionally having substituent(s), or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , which is represented by the formula (1a)

wherein ring C is aryl optionally having substituent(s) or heteroaryl and other symbols are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein, in the formula (1), ring A is phenyl having substituent(s), or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein, in the formula (1), n is 1 to 3, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein, in the formula (1), the absolute configuration at the 2-position of morpholine is S configuration, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , which is selected from the group consisting of

(2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-[4-(3-aminophenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-[4-(3-carbamoyl-4-hydroxyphenyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(pyridin-4-yl)thiazol-2-ylthio]acetamide,

(2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(3,4-dimethoxyphenyl)thiazol-2-ylthio]acetamide,

(2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)- {4-[(2-amino-2-oxoethyl)aminocarbonyl]thiazol-2-ylthio}-N- {[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-ylthio]acetamide,

(2S)-(5-amino-8H-indeno[1,2-d]thiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(4-carboxyphenylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin -2-yl]methyl}acetamide,

(2S)-{4-[(2-amino-2-oxoethyl)aminocarbonyl]phenylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-{4-[(2-carboxyethyl)aminocarbonyl]thiazol-2-ylthio}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(5-acetamino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-4-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}butyramide,

(2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-[4-(1H-tetrazol-5-yl)thiazol-2-ylthio]acetamide,

(2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)acetamide,

(2S)-(E)-[4-(2-carbamoylethen-1-yl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-[4-(carbamoylmethyl)thiazol-2-ylthio]-N-{[4-(4-fluorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(4-carboxy-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(4-carbamoyl-5-methylthiazol-2-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(4-carbamoylthiazol-2-ylthio)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-[4-(2-amino-2-oxoethyl)aminocarbonylthiazol-2-ylthio]-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3-chlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-(5-amino-1,3,4-thiadiazol-2-ylthio)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-(pyrimidin-2-ylthio)acetamide,

(2S)-(3-acetyl-2-oxo-2H-chromen-6-ylthio)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide,

(2S)-N-{[4-(3,4-difluorobenzyl)morpholin-2-yl]methyl}-(6-oxo-1,6-dihydropyridazin-3-ylthio)acetamide,

(2S)-[6-(carbamoylmethyl)pyrazin-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide, and

(2S)-4-(cyclopentanesulfonyl)-N-{[4-(3-chloro-4-fluorobenzyl)morpholin-2-yl]methyl}butyramide, or a pharmaceutically acceptable salt thereof.

16. A CCR3 antagonist comprising, as an active ingredient, the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 , which is an agent for the treatment of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

19. A method for the treatment of a disease selected from the group consisting of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease and rheumatoid arthritis, which comprises administering an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof to an animal having the disease.

20. A production method of a compound represented by the formula (1)

wherein

ring A is aryl having substituent(s), or heteroaryl optionally having substituent(s),

ring B is arylene optionally having substituent(s), divalent heterocyclic group optionally having substituent(s), or C 3-8 cycloalkylene optionally having substituent(s),

m is an integer of 0 to 2,

n is an integer of 1 to 5,

X is a bond, —NH—, —NR 1 — wherein R 1 is C 1-6 alkyl optionally having substituent(s), —CO—, —CO 2 —, —OCO—, —CONR a — wherein R a is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR a CO—, —NR 2 CONR 3 — wherein R 2 and R 3 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s),

or R 2 and R 3 in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR a SO 2 —, —SO 2 NR a —, C 1-6 alkylene optionally having substituent(s), C 2-6 alkenylene optionally having substituent(s), C 2-6 alkynylene optionally having substituent(s), —O—X a — wherein X a is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X a —O—, —CO—X a —, —X a —CO—, —CONR a —X a —, —X a —CONR a —, —NR a CO—X a —, —X a —NR a CO—, —S—X a —, —X a —S—, —SO—X a —, —X a —SO—, —NR a —X a —, —X a —NR a —, —SO 2 —X a —, —X a —SO 2 —, —C(═N—CO 2 —R 1 )—, —C(═N—SO 2 —R 1 )—, —C(═N—SO 2 NH 2 )—, —C(═CH—NO 2 )—, —C(═N—CN)— or C 3-8 cycloalkylidene optionally having substituent(s),

Y is a bond, —NH—, —NR 4 — wherein R 4 is C 1-6 alkyl optionally having substituent(s), hereinafter the same, —CO—, —CO 2 —, —OCO—, —CONR b — wherein R b is hydrogen atom or C 1-6 alkyl optionally having substituent(s), hereinafter the same, —NR b CO—, —NR 5 CONR 6 — wherein R 5 and R 6 may be the same or different and each is hydrogen atom or C 1-6 alkyl optionally having substituent(s), or R 5 and R 6 in combination optionally form, together with the atoms bonded thereto, a ring optionally having substituent(s), oxygen atom, sulfur atom, —SO—, —SO 2 —, —NR b SO 2 —, —SO 2 NR b —, C 1-6 alkylene optionally having substituent(s), C 2-6 alkenylene optionally having substituent(s), C 2-6 alkynylene optionally having substituent(s), —O—X b — wherein X b is C 1-6 alkylene optionally having substituent(s), hereinafter the same, —X b —O—, —CO—X b —, —X b —CO—, —CONR b —X b —, —X b —CONR b —, —NR b CO—X b —, —X b —NR b CO—, —S—X b —, —X b —S—, —SO—X b —, —X b —SO—, —NR b —X b —, —X b —NR b —, —SO 2 —X b —, —X b —SO 2 —, —C(═N—CO 2 —R 4 )—, —C(═N—SO 2 —R 4 )—, —C(═N—SO 2 NH 2 )—, —C(═CH—NO 2 )— or —C(═N—CN)—, and

Z is hydrogen atom, halogen atom, C 1-6 alkyl optionally having substituent(s), C 3-8 cycloalkyl optionally having substituent(s), aryl optionally having substituent(s), heterocyclic group optionally having substituent(s), hydroxy, nitro, amino, cyano, C 1-6 alkoxy optionally having substituent(s), mono- or di-C 1-6 alkylamino optionally having substituent(s), C 1-7 acylamino optionally having substituent(s), sulfonylamino optionally having substituent(s), hydrazino optionally having substituent(s), guanidino optionally having substituent(s) or amidino optionally having substituent(s),

or a salt thereof, which comprises reacting a compound represented by the formula (6)

wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula (8)

wherein ring A is as defined above, or a salt thereof.

21. (2S)-[4-(carboxymethyl)thiazol-2-ylthio]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide.

22. A pharmaceutical composition comprising the compound of claim 21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22 , which is an agent for the treatment of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease or rheumatoid arthritis.

24. A method for the treatment of a disease selected from the group consisting of asthma, sinusitis, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, allergic myelitis, ulcerative colitis, Crohn's disease and rheumatoid arthritis, which comprises administering an effective amount of the compound of claim 21 , or a pharmaceutically acceptable salt thereof to an animal having the disease.