S-triazine derivative and remedy for estrogen-dependent disease containing said derivative as effective component

• US 5,489,591 A
• Filed: 08/29/1994
• Issued: 02/06/1996
• Est. Priority Date: 02/28/1992
• Status: Expired due to Fees

• Current Assignee: Zenyaku Kogyo Kabushiki Kaisha
• Original Assignee: Zenyaku Kogyo Kabushiki Kaisha
• Inventors: Fukuda, Seiichi, Kobayashi, Hideshi, Izumisawa, Yasuhiro, Nakagane, Tsutomu, Ogose, Naohito, Takahashi, Masayuki, Tsuchida, Yoshio, Yaguchi, Shinichi, Kato, Masanobu, Komatsu, Toshihiko, Ono, Hajime
• Primary Examiner(s): Ford, John M.
• Application Number:
  US08/290,870
• Time in Patent Office: 526 Days
• Field of Search: 544/198, 544/113, 544/60, 544/83, 514/245, 514/227.8, 514/232.2, 514/236.2
• US Class Current: 514/245
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Abstract

s-Triazine (1,3,5-triazine) is chemically modified to obtain s-triazine derivative effective for prevention and treatment of estrogen-dependent diseases.

Claims

1. An s-triazine compound having the formula (1) or a pharmaceutically-acceptable acid addition salt thereof:

##STR6## wherein;

(1) when R₁ and R₂ are independent of each other or R₃ and R₄ are independent of each other, or both;

R₁ and R₃ are each lower alkyl;

R₂ and R₄ are each lower alkyl or phenyl which is unsubstituted or substituted with halogen, nitro or amino;

with the proviso that at least one of R₂ or R₄ is phenyl which is unsubstituted or substituted with halogen, nitro or amino;

(2) when R₁ and R₂ or R₃ and R₄, or both, are, respectively, coupled with an neighboring nitrogen atom to form a cyclic amino group;

NR₁ R₂ is 1-pyrrolidinyl;

piperidino which is unsubstituted or substituted with phenyl;

1-piperazinyl which is unsubstituted or substituted with lower alkyl or phenyl;

morpholino;

or thiomorpholino;

NR₃ R₄ is 1-aziridinyl which is unsubstituted or substituted with lower alkyl;

1-pyrrolidinyl which is unsubstituted or substituted with lower alkoxycarbonyl;

piperidino which is unsubstituted or mono- or di-substituted with hydroxy, hydroxyl lower alkyl, lower alkoxycarbonyl, lower alkyl, cyano, phenyl or ethylenedioxy;

1-piperazinyl which is unsubstituted or substituted with lower alkyl, benzyl, phenyl which is unsubstituted or substituted with halogen, nitro or amino, pyridyl or pyrimidinyl;

morpholino which is unsubstituted or mono- or di-substituted with lower alkyl;

3-thiazolidinyl;

thiomorpholino;

1-imidazolyl which is unsubstituted or mono- or di-substituted with lower alkyl;

or 1, 2, 4-triazole-1-yl.

2. The compound according to claim 1, wherein NR₁ R₂ is morpholino or thiomorpholino.

3. The compound according to claim 1, wherein NR₃ R₄ is morpholino, thiomorpholino or 1-imidazolyl.

4. The compound according to claim 1, wherein NR₁ R₂ is morpholino or thiomorpholino, and

(1) when R₃ and R₄ are independent of each other,

R₃ is lower alkyl;

R₄ is lower alkyl;

or phenyl which is unsubstituted or substituted with halogen, nitro or amino, or

(2) when R₃ and R₄ are coupled to form cyclic amino together with a neighboring nitrogen atom,

NR₃ R₄ is 1-aziridinyl which is unsubstituted or substituted by lower alkyl;

1-pyrrolidinyl which is unsubstituted or substituted with lower alkoxy carbonyl;

piperidino which is mono- or di-substituted with hydroxy, hydroxy lower alkyl, lower alkoxycarbonyl, lower alkyl, cyano, phenyl or ethylenedioxy;

1-piperazinyl which is unsubstituted or substituted with benzyl, or phenyl or each of benzyl and phenyl substituted with halogen, nitro, or amino;

pyrridyl or pyrimidinyl;

morpholino which is unsubstituted or di-substituted with lower alkyl;

3-thiazolidinyl;

thiomorpholino;

or 1-imidazolyl.

5. The compound according to claim 1, wherein NR₃ R₄ is morpholino, thiomorpholino or 1-imidazolyl, and

(1) when R₁ and R₂ are independent of each other,

R₁ is lower alkyl;

R₂ is lower alkyl;

or phenyl which is unsubstituted or substituted by halogen, nitro or amino, or

(2) when R₁ and R₂ are coupled to form cyclic amino together with a neighboring nitrogen atom,

NR₁ R₂ is 1-pyrrolidinyl;

piperidino which is unsubstituted or substituted with phenyl;

1-piperazinyl which is unsubstituted or substituted with lower alkyl or phenyl;

morpholino;

or thiomorpholino.

6. The compound according to claim 1, wherein said pharmaceutically-acceptable acid addition salt is a salt of an acid selected from the group consisting of hydrochloric, sulfuric, hydrobromic, nitric, phosphoric, acetic, oxalic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, methanesulfonic, benzenesulfonic, p-toluenesulfonic and salicylic acids.

7. A pharmaceutical composition for inhibiting aromatase enzymes, which comprises an effective amount of one or more s-triazine compounds having the formula (I) or a pharmaceutically-acceptable acid addition salt thereof:

##STR7## wherein;

(1) when R₁ and R₂ are independent of each other or R₃ and R₄ are independent of each other, or both;

R₁ and R₃ are each lower alkyl;

R₂ and R₄ are each lower alkyl or phenyl which is unsubstituted or substituted with halogen, nitro or amino;

with the proviso that at least one of R₂ or R₄ is phenyl which is unsubstituted or substituted with halogen, nitro or amino;

(2) when R₁ and R₂ or R₃ and R₄, or both are, respectively, coupled with an neighboring nitrogen atom to form a cyclic amino group;

NR₁ R₂ is 1-pyrrolidinyl;

piperidino which is unsubstituted or substituted with phenyl;

1-piperazinyl which is unsubstituted or substituted with lower alkyl or phenyl;

morpholino;

or thiomorpholino;

NR₃ R₄ is 1-aziridinyl which is unsubstituted or substituted with lower alkyl;

1-pyrrolidinyl which is unsubstituted or substituted with lower alkoxycarbonyl;

piperidino which is unsubstituted or mono- or di-substituted with hydroxy, hydroxyl lower alkyl, lower alkoxycarbonyl, lower alkyl, cyano, phenyl or ethylenedioxy;

1-piperazinyl which is unsubstituted or substituted with lower alkyl, benzyl, phenyl which is unsubstituted or substituted with halogen, nitro or amino, pyridyl or pyrimidinyl;

morpholino which is unsubstituted or mono- or di-substituted with lower alkyl;

3-thiazolidinyl;

thiomorpholino;

1-imidazolyl which is unsubstituted or mono- or di-substituted with lower alkyl;

or 1, 2, 4-triazole-1-yl and a pharmaceutically acceptable diluent or carrier.

8. The composition according to claim 7, wherein NR₁ R₂ is morpholino or thiomorpholino.

9. The composition according to claim 7, wherein NR₃ R₄ is morpholino, thiomorpholino or 1-imidazolyl.

10. The composition according to claim 7, wherein NR₁ R₂ is morpholino or thiomorpholino, and

(1) when R₃ and R₄ are independent of each other,

R₃ is lower alkyl;

R₄ is lower alkyl;

or phenyl which is unsubstituted or substituted with halogen, nitro or amino, or

(2) when R₃ and R₄ are coupled to form cyclic amino together with a neighboring nitrogen atom,

NR₃ R₄ is 1-aziridinyl which is unsubstituted or substituted by lower alkyl;

1-pyrrolidinyl which is unsubstituted or substituted with lower alkoxy carbonyl;

piperidino which is mono- or di-substituted with hydroxy, phenyl or ethylenedioxy;

1-piperazinyl which is unsubstituted or substituted with benzyl, or phenyl or each of benzyl and phenyl substituted with halogen, nitro, or amino;

pyrridyl or pyrimidinyl;

morpholino which is unsubstituted or di-substituted with lower alkyl;

3-thiazolidinyl;

thiomorpholino;

or 1-imidazolyl.

11. The composition according to claim 7, wherein NR₃ R₄ is morpholino, thiomorpholino or 1-imidazolyl, and

(1) when R₁ and R₂ are independent of each other,

R₁ is lower alkyl;

R₂ is lower alkyl;

or phenyl which is unsubstituted or substituted by halogen, nitro or amino, or

(2) when R₁ and R₂ are coupled to form cyclic amino together with a neighboring nitrogen atom,

NR₁ R₂ is 1-pyrrolidinyl;

piperidino which is unsubstituted or substituted with phenyl;

1-piperazinyl which is unsubstituted or substituted with lower alkyl or phenyl;

morpholino;

or thiomorpholino.

12. The composition according to claim 7, wherein said pharmaceutically-acceptable acid addition salt is a salt of an acid selected from the group consisting of hydrochloric, sulfuric, hydrobromic, nitric, phosphoric, acetic, oxalic, propionic, glycollic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, methanesulfonic, benzenesulfonic, p-toluenesulfonic and salicylic acids.