2-arylthiazole derivatives and pharmaceutical composition thereof

• US 5,614,520 A
• Filed: 01/30/1995
• Issued: 03/25/1997
• Est. Priority Date: 11/30/1990
• Status: Expired due to Term

• Current Assignee: Teijin Limited
• Original Assignee: Teijin Limited
• Inventors: Yamaguchi, Hisao, Kondo, Shiro, Fukushima, Hisashi, Osada, Yoshio, Komoriya, Keiji, Tsuchimoto, Masahiro, Nagata, Ikuo, Hasegawa, Masaichi
• Primary Examiner(s): POWERS, FIONA
• Application Number:
  US08/380,214
• Time in Patent Office: 785 Days
• Field of Search: 514/365, 514/236, 514/8, 514/252, 514/326, 514/342, 514/4, 548/188, 548/200, 548/201, 544/133, 544/367, 546/209, 546/280
• US Class Current: 514/236.8
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Pharmaceutical compositions for treating gout or hyperuricemia and containing a new categorized compound, i.e. 2-arylthiazole derivatives, as an active ingredient, are provided. The 2-arylthiazole derivatives in the present invention are represented by the following formula (I): ##STR1## wherein Ar is an unsubstituted or substituted pyridyl, thienyl, furyl, naphthyl or phenyl group;

X is a hydrogen atom, alkyl group or carboxyl group which may be protected, and

Y is a hydrogen atom, alkyl group, or a hydroxyl or carbonyl group which may be protected.

Furthermore, novel compounds included in the 2-arylthiazole derivatives and pharmaceutically acceptable salts thereof are provided.

Claims

1. A 2-arylthiazole derivative having the following formula (I), and a pharmaceutically acceptable salt thereof:

##STR71## wherein Ar is an unsubstituted or substituted furyl group;

or a group represented by the following formula (II);

##STR72## wherein R₁, R₂, and R₃ are hydrogen, a halogen atom, or a nitro, cyano or formyl group;

or a group of OR, S(O)_n R and NRR¹ (wherein n is an integer of from 1 to 2, R represents an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, R¹ represents a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R¹, taken together with the nitrogen atom bonded thereto, represent atoms forming an unsubstituted or substituted 5- or 7-membered heterocyclic ring), or a group of COR" wherein R" represents an unsubstituted or substituted C_1-10 alkyl, aryl or aralkyl group;

a hydroxyl group;

an unsubstituted or substituted C_1-10 alkoxy, aryloxy or aralkyloxy group;

an amino group;

or an unsubstituted or substituted C_1-10 alkyl (mono- or di-substituted, independently) amino, aryl (mono- or di-substituted, independently) amino or aralkyl (mono- or di-substituted, independently) amino group, or a 5- to 7-membered cyclic amino group, and at least one of R₁, R₂ or R₃ is other than hydrogen;

X is a hydrogen atom, or a C_1-14 alkyl, carboxyl, C_1-5 alkoxycarbonyl, carbamoyl or C_1-4 alkyl (mono- or di-substituted) aminocarbonyl group; and

Y represents a hydrogen atom or a C_1-4 alkyl, carboxyl, C_1-5 alkoxycarbonyl, carbamoyl or C_1-4 alkyl (mono- or di-substituted) aminocarbonyl group, with the proviso that when at least one group of R₁, R₂ and R₃ represents a halogen atom, or an alkoxy, alkylamino or nitro group, at least one group of the two other groups represents a group other than a hydrogen atom;

when at least one group of R₁, R₂ and R₃ is a halogen atom and another group is a hydrogen atom, a remaining group is a group other than a halogen atom, or an alkoxy, alkylamino or acylamino group, with the additional proviso that when any one of R₁, R₂ or R₃ is OR, one of the remaining groups cannot represent hydrogen while the other group represents OR, or the remaining two groups cannot both represent OR at the same time, nor do all of R₁ -R₃ represent halogen;

with the further proviso that both X and Y do not represent carboxyl, C_1-5 alkoxycarbonyl, carbamoyl or C_1-4 alkyl (a mono- or di-substituted) aminocarbonyl group at the same time.

2. A 2-arylthiazole derivative of the formula (I) and a pharmaceutically acceptable salt thereof in accordance with claim 1 wherein Ar represents a group of the formula (II), and R₁ is a halogen atom, or a nitro, cyano or formyl group, R₂ is a member of the group consisting of OR, S(O)_n R and NRR'"'"' wherein n is an integer of from 0 to 2, R represents an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, R¹ represents a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R¹ taken together with the nitrogen atom bonded thereto, represent atoms forming an unsubstituted or substituted 5- to 7-membered heterocyclic ring), and R₃ represents a hydrogen or halogen atom.

3. A 2-arylthiazole derivative and a pharmaceutically acceptable salt thereof in accordance with claim 2, wherein X is a carboxyl, C_1-5 alkoxy-carbonyl, carbamoyl or C_1-4 alkyl (mono- or di-substituted) aminocarbonyl group;

and

Y is a hydrogen atom, or a C_1-4 alkyl group.

4. A 2-arylthiazole derivative of the formula (I) and a pharmaceutically acceptable salt thereof, in accordance with claim 1, wherein Ar represents a group of the formula (II), and R₁ represents an m-nitro or m-cyano group, R₂ represents a member of the group consisting of OR, S(O)_n R and NRR'"'"' wherein n is an integer of from 0 to 2, R represents an unsubstituted or substituted alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, R'"'"' represents a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R'"'"', taken together with the nitrogen atom bonded thereto, represent atoms forming an unsubstituted or substituted 5- to 7-membered heteroxyclic ring, and R₃ represents a hydrogen atom;

X represents a carboxyl, C_1-5 alkoxycarbonyl, carbamoyl or C_1-4 alkyl (mono-or di-substituted aminocarbonyl group; and

Y represents a hydrogen atom, or a C_1-4 alkyl group.

5. A 2-arylthiazole derivative of the formula (I) and a pharmaceutically acceptable salt thereof in accordance with claim 1 wherein Ar represents a group of the formula (II), and R¹ represents an m-halogen atom, R₂ represents a member of the group consisting of OR, S(O)_n R and NRR'"'"' wherein n is an integer of from 0 to 2, R represents an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, R'"'"' represents a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R'"'"', taken together with the nitrogen atom bonded thereto, represent atoms forming an unsubstituted or substituted 5-to 7-membered heterocyclic ring, and R₃ represents a hydrogen or halogen atom.

6. A 2-arylthiazole derivative of the formula (I) and a pharmaceutically acceptable salt thereof in accordance with claim 1, wherein Ar represents a group of the formula (II), and R₁ represents an m-halogen atom, R₂ represents a group of OR, S(O)_n R and NRR'"'"' wherein n is an integer of from 0 to 2, R represents an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, R'"'"' represents a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R'"'"', taken together with the nitrogen atom bonded thereto, represent atoms forming an unsubstituted or substituted 5- to 7-membered heterocyclic ring, and R₃ represents a hydrogen or halogen atom;

X represents a carboxyl, C_1-5 alkoxycarbonyl, carbamoyl or C_1-4 alkyl (mono- or di-substituted)-aminocarbonyl group; and

Y represents a C_1-4 alkyl group.

7. A 2-arylthiazole derivative of the following formula (I-a) and a pharmaceutically acceptable salt thereof in accordance with claim 1:

##STR73## wherein R_1-a is a C_2-8, alkoxy group and R_2-a is a nitro group;

R_1-a is a morpholino, 4-N-methylpiperazine-1-yl or piperidino group and R_2-a is a nitro group;

R_1-a is a morpholino, 4-N-methylpiperazine-1-yl or piperidino group and R_2-a is a cyano group;

R_1-a is a C_2-8 alkoxy group and R_2-a is a cyano group;

or

R_1-a is an unsubstituted benzoyl group or a benzoyl group substituted by one or two groups selected from the group consisting of a methyl group, chlorine atom or methoxy group, and R_2-a is a hydrogen atom.

8. An 2-arylthiazole derivative of the following formula (I-b) and a pharmaceutically acceptable salt thereof in accordance with claim 2:

##STR74## wherein R_1-b is OR or SR group wherein R represents a C_2-8 alkyl, morpholino, 4-N-methyl piperazine-1-yl or piperidino group;

R_2-b represents a nitro, trifluoromethyl or cyano group, and Y_b represents a hydrogen atom or a methyl group;

or

R_1-b represents a group of the formula ##STR75## wherein R_3-b represents an unsubstituted or substituted phenyl group and R_4-b represents a hydroen atom or a methyl group.

9. The 2-arylthiazole derivative of claim 1 wherein when X represents a carboxyl group, Y represents a hydrogen atom or a C_1-4 alkyl group.

11. A pharmaceutical composition comprising an effective amount of the 2-arylthiazole derivative of claim 1.

12. A pharmaceutical composition in accordance with claim 11 wherein Ar is a group of the formula (II), and at least one group of R₁, R₂ and R₃ is a halogen atom, or a nitro, cyano or formyl group;

or a group of OR, S(O)_n R or NRR'"'"' (wherein n is an integer of from 0 to 2, R is an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, and R'"'"' is a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R'"'"' taken together with the nitrogen atom bonded thereto, are atoms forming an unsubstituted or substituted 5- to 7- membered heterocylic ring), or a group of COR" (wherein R" is an unsubstituted or substituted C_1-10 alkyl, aryl or aralkyl group, a hydroxyl group, an unsubstituted or substituted C_1-10 alkoxy, aryloxy or aralkyloxy group, an amino group, or an unsubstituted or substituted C_1-10 alkyl (mono- or di-substituted, independently) amino, aryl (mono- or di-substituted, independently) amino or aralky (mono- or di-substituted, independently) amino group, or a 5- to 7- membered cyclic amino group);

X is a carboxyl, C_1-5 alkoxycarbonyl, carbamoyl or C_1-4 alkyl (mono- or di-substituted) aminocarbonyl group.

13. The pharmaceutical composition of claim 11 wherein when X represents a carboxyl group, Y represents a hydrogen atom or a C_1-4 alkyl group.

15. A method for treating a patient afflicted with gout or hyperuricemia which comprises administering to said patient a uric acid-lowering effective amount of the pharmaceutical composition of claim 11.

10. A 2-arylthiazole derivative having the following formula (I), and a pharmaceutically acceptable salt thereof:

##STR76## wherein Ar represents a group of the formula (II) ##STR77## wherein R₁ represents COR" wherein R" represents an unsubstituted or substituted C_1-10 alkyl, aryl or aralkyl group;

wherein at least one member of the group of R₂ and R₃ is a hydrogen, a halogen atom, or a nitro, cyano or formyl group;

or a member selected from the group consisting of OR, S(O)_n R and NRR¹ wherein n is an integer of 1 to 2, R represents an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group, R¹ represents a hydrogen atom, or an unsubstituted or substituted C_1-10 alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl group;

or R and R¹ taken together with the nitrogen atom bonded thereto, represent atoms forming an unsubstituted or substituted 5- to 7-membered heterocyclic ring or COR" wherein R" represents an unsubstituted or substituted C_1-10 alkyl, aryl or aralkyl group;

a hydroxyl group;

an unsubstituted or substituted C_1-10 alkoxy, aryloxy or aralkyloxy group;

an amino group;

or an unsubstituted or substituted C_1-10 alkyl (mono- or disubstituted) amino, aryl (mono- or di-substituted) amino or aralkyl (mono-or di-substituted) amino group, or a 5- to 7-membered cyclic amino group;

X represents a carboxyl, C^1-5 alkoxycarbonyl carbamoyl or C_1-4 alkyl (mono- or di-substituted) aminocarbonyl group; and

y represents a hydrogen atom, or a C_1-4 alkyl group.

14. A pharmaceutical composition comprising an effective amount of the 2-arylthiazole derivative of claim 10.