Phosphinic alkanoic acid derivatives

• US 6,071,965 A
• Filed: 12/31/1997
• Issued: 06/06/2000
• Est. Priority Date: 06/17/1996
• Status: Expired due to Fees

• Current Assignee: Eisai Incorporated (Eisai Medical Research Incorporated)
• Original Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Inventors: Tsukamoto, Takashi, Li, Weixing, Slusher, Barbara S., Tays, Kevin L., Jackson, Paul F., Maclin, Keith M.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US09/002,147
• Time in Patent Office: 888 Days
• Field of Search: 562/8, 562/24, 562/10, 514/75, 435/184
• US Class Current: 514/574
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 31/665 having oxygen as a ring hetero atom, e.g. fosfomycin
• CPC Class Codes: A61K 31/67 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: C07F 9/301 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3211 Esters of acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3826 Acyclic unsaturated acids
• CPC Class Codes: C07F 9/4075 Esters with hydroxyalkyl compounds
• CPC Class Codes: C07F 9/4465 of aliphatic amines
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/6552 the oxygen atom being part of a six-membered ring
• CPC Class Codes: C07F 9/655345 : the sulfur atom being part of a five-membered ring

Abstract

The present invention relate to phosphinic alkanoic acid derivatives that inhibit N-Acetylated α-Linked Acidic Dipeptidase (NAALADase) enzyme activity, pharmaceutical compositions comprising the same, and methods of using the same to inhibit NAALADase activity and to treat glutamate abnormalities and prostate diseases.

Claims

1. A compound of formula I:

##STR14## or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein;

X is CR₆ R₇, O or NR₈ ;

R₁ is selected from the group consisting of C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₁ is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar;

R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar;

provided that when X is --CH₂ --, R₁ is --(CH₂)₂ --, R₂ is --(CH₂)₂ COOCH₂ C₆ H₅, R₃ is benzyl, and R₄ is hydrogen, then R₅ is not benzyl; and

Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, [2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,] benzyl and phenyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, phenoxy, benzyloxy, and amino.

2. The compound of claim 1, wherein X is CH₂.

3. The compound of claim 2, wherein:

R₂ is --(CH₂)₂ COOR₉ ; and

R₉ is selected from the group consisting of hydrogen, C_l -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₉ is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar.

4. The compound of claim 3, wherein R₃, R₄, R₅, and R₉ are hydrogen.

5. The compound of claim 3, which is selected from the group consisting of:

2-[[2-carboxypropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[2-carboxybutyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxypentyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxy-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[2-carboxy-3-naphthylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[2-[[2-carboxy-3-pyridylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

]

2-[[2-benzyloxycarbonyl)-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[2-methoxycarbonyl)-3-phenylpropyl)hydroxyphosphiryl]methyl]pentanedioic acid;

2-[[(3-carboxy-2-methoxycarbonyl)propyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-carboxy-2-methoxycarbonyl)butyl)hydroxyphosphinyl]methyl]pentanedioic acid; and

pharmaceutically acceptable salts, hydrates and prodrugs thereof.

6. The compound of claim 5, which is 2-[[2-carboxypropyl)hydroxyphosphinyl]-methyl]pentanedioic acid, or a pharmaceutically acceptable salt, hydrate or prodrug thereof.

7. A method of inhibiting NAALADase enzyme activity in an animal, comprising administering to said animal an effective amount of a compound of formula I:

##STR15## or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein;

X is CR₆ R₇, O or NR₈ ;

R₁ is selected from the group consisting of C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₁ is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar;

R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, C₁ -C₉ straight or branched chair alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar; and

Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, [2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,] benzyl and phenyl, therein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₃ -C₆ straight or branched chain alkenyl, C_l -C₆ alkoxy, C₂ -C₆ alkenyloxy, phenoxy, benzyloxy, and amino.

8. The method of claim 7, wherein the compound is administered in combination with at least one additional therapeutic agent.

9. The method of claim 7, wherein X is CH₂.

10. The method of claim 9, wherein:

R₂ is --(CH₂)₂ COOR₉ ; and

R₉ is selected from the group consisting of hydrogen, C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, (C₅ -C₇ cycloalkenyl and Ar, wherein said R₉ is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar.

11. The method of claim 10, wherein R₃, R₄, R₅, and R₉ are hydrogen.

12. The method of claim 10, wherein the compound is selected from the group consisting of:

2-[[(2-carboxypropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxybutyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxypentyl)hydroxyphosphinyl]methyl]pentanedoic acid;

2-[[(2-carboxy-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxy-3-naphthylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[2-[[(2-carboxy-3-pyridylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

]

2-[[(2-benzyloxycarbonyl)-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-methoxycarbonyl)-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3 -carboxy-2-methoxycarbonyl)propyl) hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-carboxy-2-methoxycarbonyl)butyl)hydroxyphosphinyl]methyl]pentanedioic acid; and

pharmaceutically acceptable salts, hydrates and prodrugs thereof.

13. The method of claim 12, wherein the compound is 2-[[(2-carboxypropyl)hydroxyphosphinyl]methyl]pentanedioic acid, or a pharmaceutically acceptable salt, hydrate or prodrug thereof.

14. A pharmaceutical composition comprising:

(i) A therapeutically effective amount of a compound of formula I;

##STR16## or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein;

X is CR₆ R₇, O or NR₈ ;

R₁ is selected from the group consisting of C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₁ is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar;

R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₆ -C₇ cycloalkenyl and Ar, wherein said R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are independently unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar; and

Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, [2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,] benzyl and phenyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, phenoxy, benzyloxy, and amino; and

(ii) a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein X is CH₂.

16. The pharmaceutical composition of claim 15, wherein:

R₂ is --(CH₂)₂ COOR₉ ; and

R₉ is selected from the group consisting of hydrogen, C₁ -C₉ straight or branched chain alkyl, C₂ -C₉ straight or branched chain alkenyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl and Ar, wherein said R₉ is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, carbonyl, C₃ -C₈ cycloalkyl, C₅ -C₇ cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C₁ -C₆ straight or branched chain alkyl, C₂ -C₆ straight or branched chain alkenyl, C₁ -C₉ alkoxy, C₂ -C₉ alkenyloxy, phenoxy, benzyloxy, amino, and Ar.

17. The pharmaceutical composition of claim 15, wherein R₃, R₄ , R₅, and R₉ are hydrogen.

18. The pharmaceutical composition of claim 15, wherein the compound is selected from the group consisting of:

2-[[(2-carboxypropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxybutyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxypentyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-carboxy-3-phenylpropyl)hydroxyphosphinyl]methtyl]pentanedioic acid;

2-[[(2-carboxy-3-naphthylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[2-[[(2-carboxy-3-pyridylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

]

2-[[(2-benzyloxycarbonyl)-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(2-methoxycarbonyl)-3-phenylpropyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(3-carboxy-2-methoxycarbonyl)propyl)hydroxyphosphinyl]methyl]pentanedioic acid;

2-[[(4-carboxy-2-methoxycarbonyl)butyl)hydroxyphosphinyl]methyl]pentanedioic acid; and

pharmaceutically acceptable salts, hydrates and prodrugs thereof.

19. The pharmaceutical composition of claim 18, wherein the compound is 2-[[(2-carboxypropyl)hydroxyphosphinyl]methyl]pentanedioic acid, or a pharmaceutically acceptable salt, hydrate or prodrug thereof.

20. The pharmaceutical composition of claim 14, wherein the amount of the compound of formula I is effective for inhibiting NAALADase enzyme activity in an animal.