Nitrogen-containing condensed cyclic compound having a pyrazolyl group as a substituent group and pharmaceutical composition thereof

• US 7,074,801 B1
• Filed: 04/25/2002
• Issued: 07/11/2006
• Est. Priority Date: 04/26/2001
• Status: Expired due to Fees

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Inventors: Shirato, Manabu, Takase, Yasutaka, Miyamoto, Mitsuaki, Sakuma, Yoshinori, Shimokubo, Daiya, Miyazaki, Futoshi, Yokohama, Hiromitsu, Suzuki, Shuichi, Yoneda, Naoki, Yoshida, Ichiro, Kamata, Junichi, Ohashi, Yoshiaki, Seshimo, Hidenori
• Primary Examiner(s): Saeed, Kamal A.
• Assistant Examiner(s): Paviglianiti, Anthony J.
• Application Number:
  US10/475,585
• Time in Patent Office: 1,538 Days
• Field of Search: 546/121, 546/122, 546/167, 546/144, 546/118, 514/266.23, 514/307, 514/314
• US Class Current: 514/266.23
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 493/04 : Ortho-condensed systems
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention discloses compounds and compositions of formula (I):

having inhibitory activity on activation of STAT6, wherein X represents quinoline, isoquinoline, quinazoline or imidazopyridine; Y represents phenyl, piperazine, pyridine, thiophene, thiazole, oxathiazole or oxathiadiazole; and variables Z, n, R¹, R², R³ and R⁴ are as defined in the claims.

Claims

1. A compound represented by the following formula (I), or a salt thereof or a hydrate thereof:

2. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), X is quinoline or isoquinoline.

3. The compound according to claim 1 or 2, a salt thereof or a hydrate of them, wherein in the formula (I), X is quinazoline or imidazopyridine.

4. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), n in the substituent groups (R⁴)_n is 0, 1 or 2, and the substituent groups R⁴ independently represent a hydrogen atom, halogen atom, cyano group, hydroxyl group, amino group, a C_1-6 alkyl group, a halogenated C_1-6 alkyl group, an N—

(C_1-6 alkyl)amino group or a C_1-6 alkoxy group.

5. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), Y is thiophene, thiazole, oxadiazole or oxathiadiazole.

6. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), R² is a hydrogen atom, trityl group, tetrahydropyranyl group, t-butyldimethylsilyl group, t-butoxycarbonyl group or pivaloyloxymethyl group,

R³ is a hydrogen atom, and

n in the substituent groups (R⁴)_n is 0, 1 or 2, and each of the substituent groups R⁴ independently represents a hydrogen atom, halogen atom, cyano group, carbamoyl group, C_1-6 alkyl group or halogenated C_1-6 alkyl group.

7. The compound according to claim 5, a salt thereof or a hydrate thereof, wherein in the formula (I),

n in the substituent groups (R⁴)_n is 0, 1 or 2, the substituent groups R⁴ independently represent a hydrogen atom, halogen atom, carbamoyl group or C_1-6 alkyl group,

R² is a hydrogen atom or trityl group, and

R³ is a hydrogen atom.

8. The compound according to any one of claims 5 to 7, a salt thereof or a hydrate thereof, wherein R¹ represents (1) hydrogen, (2) halogen atom, (3) nitro group, (4) cyano group, (5) C_1-6 alkyl group, (6) C_2-6 alkenyl group, (7) halogenated C_1-6 alkyl group, (8) C_2-6 alkenyl group substituted with a hydroxyl or cyano group, (9)—

CONR⁷R⁸, (10) —

NR⁷R^{, (}11) —

(CH₂)_mR⁹, (12) —

(CH₂)_m—

O—

CH₂)_n—

R⁹, (13) —

COOR⁷ whereupon n and m independently represent 0, 1, 2 or 3, R⁷ and R⁸ are the same or different and each represent a hydrogen atom, C_1-6 alkyl group or C_3-8 cycloalkyl group, and R⁹ groups are the same or different and represent a hydrogen atom, C_1-6 alkyl group, hydroxyl group, cyano group, or

     1) C_3-8 cycloalkyl group,

     2) C_4-8 cycloalkenyl group,

     3) phenyl group,

     4) 5- to 10-membered non-aromatic heterocyclic group,

     5) 5- to 6-membered aromatic heterocyclic ring, each of which may be substituted with 4 or less groups selected independently from the substituent group P¹, or (14) (a) C_3-8 cycloalkyl group, (b) C_3-8 cycloalkenyl group, (c) 5- to 10-membered non-aromatic heterocyclic group, (d) phenyl group or (e) 5- to 10-membered aromatic heterocyclic group which may be arbitrarily substittued substituted with 3 or less groups selected independently from the substituent group P¹ and with 1 or less group selected independently from the substituent group P²,

the above-mentioned substituent group P¹ represents an oxo group, halogen atom, hydroxyl group, amino group, cyano group, nitro group, azido group, cyano group, carboxyl group, C_1-6 alkyl group, halogenated C_1-6 alkyl group, C_1-6 alkyl group substituted with a hydroxyl or cyano group, C_2-6 alkenyl group, C_2-6 alkynyl group, halogenated C_2-6 alkenyl group, halogenated C_1-6 alkoxy group, —

OR⁷, —

NR⁷R⁸, —

NR⁷COR⁸, —

COR⁷, —

CONR⁷R⁸, —

SOR⁷, —

SO₂R⁷, —

NR⁷SO₂R⁸, or —

SO₂NR⁷R⁸, whereupon R⁷ and R⁸ are the same or different and each represent a hydrogen atom, C_1-6 alkyl group or C_3-8 cycloalkyl group, and

the substituent group P² represents —

CH₂NR⁷R⁸, —

OCH₂CONR⁷R⁸, —

O—

(CH₂)_m—

R¹⁰, —

NR⁷COR¹⁰, —

NR⁷COOR¹⁰, C_3-7 cycloalkyl group, C_4-7 cycloalkenyl group, phenyl group, 5- to 6-membered aromatic heterocyclic group, 5- to 7-membered non-aromatic heterocyclic group, C_3-7 cycloalkyloxy group, phenoxy group, heteroallyloxy group, methylene dioxy group or ethylene dioxy group, whereupon m is 0, 1, 2 or 3, R⁷ and R⁸ are the same or different and each represent a hydrogen atom, C_1-6 alkyl group or C_3-8 cycloalkyl group, R¹⁰ represents a hydrogen atom, C_1-6 alkyl group, C_3-8 cycloalkyl group, phenyl group, 5- to 10-membered non-aromatic heterocyclic group, or 5- to 6-membered aromatic heterocyclic group.

9. The compound according to any one of claims 5 to 7, a salt thereof or a hydrate thereof, wherein in the formula (I), (Z)n represent n (Z) groups bound to Y, n is 0, 1, 2 or 3, Z groups independently represent formula —

J—

R¹¹ wherein J is a single bond, —

(CH₂)_m—

, —

CHR⁵CHR⁶—

, —

(CH₂)_m—

CR⁵R⁶—

(CH₂)_n—

, —

CR⁵≡

CR⁶—

, —

C≡

C—

, —

CR⁵═

CR⁶—

CO—

, —

(CH₂)_m—

O—

(CH₂)_n—

, —

O—

(CH₂)_n—

CR⁵R⁶—

, —

(CH₂)_m—

S—

(CH₂)_n—

, —

SO(CH₂)_m—

, —

SO₂(CH₂)_m—

, —

CO(CH₂)_m—

, —

COO—

, —

CONR⁷—

, —

CONR⁷CHR⁵—

, —

CONR⁷—

CR⁵R⁶—

, CONR⁷—

(CH₂)_m—

, —

NR⁷—

, —

NR⁷CO—

CR⁵R⁶—

, NR⁷CO—

CR⁵R⁶—

CO—

, —

NR⁷CO—

(CH₂)_m—

, —

NR⁷SO₂(CH₂)_m—

, —

SO₂NR⁷—

(CH₂)_m—

, —

SO₂NR⁷—

CR⁵R⁶—

, —

NR⁷CONR⁸—

, or —

NR⁷CSNR⁸—

whereupon n and m are independently 0, 1, 2 or 3, or R⁵ and R⁶ are the same or different and each represent

     1) hydrogen atom,

     2) halogen atom,

     3) hydroxyl group,

     4) cyano group,

     5) C_1-6 alkyl group,

     6) C_1-6 alkyl group substituted with a halogen atom, hydroxy group or cyano group,

     7) C_3-8 cycloalkyl group,

     8) phenyl group which may be substituted with 3 or less groups selected from the substituent group Q,

     9) 5- to 6-membered aromatic heterocyclic group which may be substituted with 3 or less groups selected from the substituent group Q, or

     10) C_3-8 cycloalkyl group formed by combining R⁵ with R⁶, and R⁷ and R⁸ are the same or different and each represent a hydrogen atom, C_1-6 alkyl group or C_3-8 cycloalkyl group, R¹¹ represents a hydrogen atom, halogen atom, hydroxyl group, cyano group, carboxyl group, C_1-6 alkyl group, C_1-6 alkoxy group, halogenated C_1-6 alkyl group, C_3-8 cycloalkyl group, C_3-8 cycloalkenyl group, phenyl group, 5- to 6-membered aromatic heterocyclic group or 5- to 6-membered non-aromatic heterocyclic group, provided that each of the C_3-8 cycloalkyl group, C_3-8 cycloalkenyl group, phenyl group, 5- to 6-membered aromatic heterocyclic group and 5- to 6-membered non-aromatic heterocyclic group may be arbitrarily substituted with 3 or less substituent groups selected independently from the substituent group P³ and with 1 or less substituent group selected independently from the substituent group P⁴,

the above-mentioned substituent group P³ represents an oxo group, halogen atom, hydroxyl group, amino group, cyano group, nitro group, azido group, cyano group, carboxyl group, C_1-6 alkyl group, halogenated C_1-6 alkyl group, C_1-6 alkyl group substituted with a hydroxyl or cyano group, C_2-6 alkenyl group, C_2-6 alkynyl group, halogenated C_2-6 alkenyl group, halogenated C_1-6 alkoxy group, —

OR⁷, —

NR⁷R⁸, —

NR⁷COR⁸, —

COR⁷, —

CONR⁷R⁸, —

SOR⁷, —

SO₂R⁷, —

NR⁷SO₂R⁸, or —

SO₂NR⁷R⁸, whereupon R⁷ and R⁸ are the same or different and each represent a hydrogen atom, C_1-6 alkyl group or C_3-8 cycloalkyl group, and

the substituent group P⁴ represents a C_3-7 cycloalkyl group, C_4-7 cycloalkenyl group, phenyl group, 5- to 6-membered aromatic heterocyclic group, 5- to 7-membered non-aromatic heterocyclic group, C_3-7 cycloalkyloxy group, phenoxy group, heteroaryloxy group, methylene dioxy group or ethylene dioxy group, each of which is a group binding to the cyclic group Y.

10. The compound according to any one of claims 5 to 7, a salt thereof or a hydrate of them, wherein in the formula (I), R¹ is (1) hydrogen, (2) halogen atom, (3) nitro group, (4) cyano group, (5) C_1-6 alkyl group, (6) C_2-6 alkenyl group, (7) halogenated C_1-6 alkyl group, (8) phenyl group, (9) 5- to 6-membered aromatic heterocyclic group, (10) 5- to 7-membered non-aromatic heterocyclic group, provided that (8) phenyl group, (9) 5- to 6-membered aromatic heterocyclic group and (10) 5- to 7-membered non-aromatic heterocyclic group may be substituted arbitrarily with 3 or less substituent groups selected independently from the substituent group P⁵ and with 1 or less substituent group selected independently from the substituent group P⁶,

the substituent group P⁵ represents an oxo group, halogen atom, hydroxyl group, amino group, cyano group, nitro group, azido group, cyano group, carboxyl group, C_1-6 alkyl group, halogenated C_1-6 alkyl group, C_1-6 alkyl group substituted with a hydroxyl or cyano group, C_2-6 alkenyl group, C_2-6 alkynyl group, halogenated C_2-6 alkenyl group, halogenated C_1-6 alkoxy group, —

OR⁷, —

OCH₂CONR⁷R⁸, —

NR⁷R⁸, —

NR⁷COR⁸, —

COR⁷, —

CONR⁷R⁸, —

SOR⁷, —

SO₂R⁸, —

NR⁷SO₂R⁸ or —

SO₂NR⁷R⁸ whereupon R⁷ and R⁸ are the same or different and each represent a hydrogen atom, C_1-6 alkyl group or C_3-8 cycloalkyl group,

the substituent group P⁶ represents a C_3-7 cycloalkyl group, C_4-7 cycloalkenyl group, phenyl group, 5- to 6-membered aromatic heterocyclic group, 5- to 7-membered non-aromatic heterocyclic group, C_3-7 cycloalkyloxy group, phenoxy group, heteroaryloxy group, methylene dioxy group or ethylene dioxy group; and

R², R³ and R⁴ are hydrogen atoms.

11. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), X is an imidazo[1,2-a]pyridine cyclic group, and Y is a phenyl group, piperazine, pyridine, thiophene, 1,2,4-thiadiazolyl group, 1,2,4-oxadiazolyl group, or 1,3,4-oxadiazolyl group.

12. The compound according to claim 1, a salt thereof or a hydrate of them, wherein in the formula (I), X is quinazoline and Y is a phenyl group, piperazine, pyridine, thiophene, thiazole or 1,3,4-oxadiazolyl group.

13. The compound according to claim 1 represented by the formula (I), a salt thereof or a hydrate thereof, wherein the compound is the one selected from:

6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]-3-[5-(methylsulfonyl)-2-thienyl]imidazo[1,2-a]pyridine hydrochloride, 6-[3-(2,4-difluorophenyl)-1H-pyrazol-4-yl]-3-(5-methylsulfonylthiophen-2-yl)imidazo [1,2-a]pyridine, 6-[3-(2,6-difluorophenyl)-1H-pyrazol-4-yl]-3-(5-methylsulfonylthiazol-2-yl)imidazo[1,2-a]pyridine, 3-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-6-[3-(2,4-difluorophenyl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine, 6-[3-(2,4-difluorophenyl)-1H-pyrazol-4-yl]-3-(5-methoxy[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine, 6-[3-(2,6-difluorophenyl)-1H-pyrazol-4-yl]-3-(5-methoxy[1,2,4]oxadiazol-3-yl)imidazo[1,2-a]pyridine, 3-(5-cyclopropyl-[1,2,4] oxadiazol-3-yl)-6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]-imidazo[1,2a]-pyridine hydrochloride, 3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-[3-(2,4-difluorophenyl)-1H-4-pyrazolyl]-imidazo[1,2-a]pyridine trihydrochloride, 3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-[3-(2-fluoro-4-methoxyphenyl)-1H-4-pyrazolyl]-imidazo[1,2-a]pyridine trihydrochloride, 3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-[3-(2-fluorophenyl)-1H-4-pyrazolyl]-imidazo[1,2-a]pyridine trihydrochloride, 6-[3-(4-cyclopentyloxy-2-fluorophenyl)-1H-4-pyrazolyl]-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-imidazo[1,2-a]pyridine trihydrochloride, 3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-[3-(2,6-difluorophenyl)-1H-4-pyrazolyl]-imidazo[1,2-a]pyridine trihydrochloride, 6-[3-(2,4-difluorophenyl)-1H-4-pyrazolyl]-3-(5-difluoromethyl-[1,2,4]oxadiazol-3-yl)-imidazo[1,2-a]pyridine trihydrochloride, 3-(5-difluoromethyl-[1,2,4]oxadiazol-3-yl)-6-[3-(2-fluorophenyl)-1H-4-pyrazolyl]-imidazo[1,2-a]pyridine trihydrochloride, 6-[3-(2,6-difluorophenyl)-1H-4-pyrazolyl]-3-(5-difluoromethyl-[1,2,4]oxadiazol-3-yl)-imidazo[1,2-a]pyridine trihydrochloride, N1-[(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]-2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide hydrochloride, N1-(2,4-difluorophenyl)-2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide hydrochloride, N1-(5-chloro-2-pyridyl)-2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide dihydrochloride, N1-(4-methyl-2-pyridyl)-2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide dihydrochloride, N1-(2,4-difluorophenyl)-2-chloro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide hydrochloride, N1-(5-vinyl-2-pyridyl)-2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide dihydrochloride, N1-(5-ethyl-2-pyridyl)-2-fluoro-4-[6-(1H-4-pyrazolyl)imidazo[1,2-a]pyridin-3-yl]benzamide dihydrochloride, 6-[3-(4-fluorophenyl)-1H-4-pyrazolyl]-4-[5-(methylsulfonyl)-2-thienyl]quinazoline dihydrochloride, 6-[3-(2,4-difluorophenyl)-1H-pyrazol-4-yl]-4-(5-methylsulfonylthiophen-2-yl) quinazoline, 6-[3-(4-chloro-2-fluorophenyl)-1H-pyrazol-4-yl]-4-(5-methylsulfonylthiazol-2-yl) quinazoline, 4-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-6-[3-(2,4-difluorophenyl)-1H-pyrazol-4-yl] quinazoline, 4-(5-cyclopropyl[1,3,4]thiadiazol-2-yl)-6-[3-(2,4-difluorophenyl)-1H-pyrazol-4-yl] quinazoline, 6-[3-(2,6-difluorophenyl)-1H-pyrazol-4-yl]-4-(5-methoxy[1,3,4]oxadiazol-2-yl) quinazoline, 6-(1H-pyrazol-4-yl)-4-(4-m-tolylpiperazin-1-yl)-quinazoline tri-trifluoroacetate, 4-[4-(3-methylsulfonylphenyl)piperazin-1-yl]-6-(1H-pyrazol-4-yl)quinazoline tri-trifluoroacetate, and 4-[4-(3-cyclopropylsulfonylphenyl)piperazin-1-yl]-6-(1H-pyrazol-4-yl)quinazoline tri-trifluoroacetate.

16. The compound according to claim 1 represented by the formula (I), a salt thereof or a hydrate thereof, wherein Y is the phenyl group, piperazine or pyridine.

14. A pharmaceutical composition comprising:

a compound represented by the following formula (I), a salt thereof or a hydrate of them, and

a pharmaceutically acceptable carrier;

15. The pharmaceutical composition according to claim 14, wherein in the formula (I), Y is thiophene, thiazole oxadiazole or oxathiadiazole.

17. A compound represented by the following formula (I), or a salt thereof or a hydrate thereof: