Boronic ester and acid compounds

• US 5,780,454 A
• Filed: 10/27/1995
• Issued: 07/14/1998
• Est. Priority Date: 10/28/1994
• Status: Expired due to Term

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: ProScript, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Baevsky, Matthew, Adams, Julian, Grenier, Louis, Plamondon, Louis, Ma, Yu-Ting, Stein, Ross
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US08/549,318
• Time in Patent Office: 991 Days
• Field of Search: 544/229, 514/64
• US Class Current: 514/64
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06 Dipeptides
• CPC Class Codes: C07K 5/06043 Leu-amino acid
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0808 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/0827 : containing heteroatoms different from O, S, or N

Abstract

Disclosed herein is a method for reducing the rate of degradation of proteins in an animal comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed herein are novel boronic ester and acid compounds, their synthesis and uses.

Claims

1. A compound having the formula:

##STR60## or a pharmaceutically acceptable salt thereof;

wherein P is R⁷ --C(O)-- or R⁷ --SO₂ --, where R⁷ is pyrazinyl;

X² is --C(O)--NH--;

R is hydrogen or alkyl;

R² and R³ are independently hydrogen, alkyl, cycloalkyl, aryl, or --CH₂ --R⁵ ;

R⁵, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or --W--R⁶, where W is a chalcogen and R⁶ is alkyl;

where the ring portion of any of said aryl, aralkyl, or alkaryl in R², R³ and R⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6 alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, C_6-10 arylsulfonyl, C_6-10 aryl, C_1-6 alkyl(C_6-10) aryl, and halo(C_6-10)aryl;

Z¹ and Z² are independently one of hydroxy, alkoxy, or aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and

A is zero.

2. The compound of claim 1, wherein:

A is zero;

X is --C(O)--NH--;

R is hydrogen or C_1-8 alkyl; and

R₃ is C_1-6 alkyl.

3. The compound of claim 2, wherein R₃ is C₄ alkyl.

4. The compound of claim 1, wherein P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl.

5. The compound of claim 1, wherein R is hydrogen or C_1-8 alkyl.

6. The compound of claim 1, wherein:

R² and R³ are each independently one of hydrogen, C_1-8 alkyl, C_3-10 cycloalkyl, or C_6-10 aryl, or --CH₂ --R⁵ ;

R⁵, in each instance, is one of C_6-10 aryl, C_6-10 ar(C_1-6)alkyl, C_1-6 alk(C_6-10)aryl, C_3-10 cycloalkyl, C_1-8 alkoxy, or C_1-8 alkylthio;

where the ring portion of any of said aryl, aralkyl, or alkaryl groups of R², R³ and R⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6 alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, C_6-10 arylsulfonyl, C_6-10 aryl, C_1-6 alkyl(C_6-10)aryl, and halo(C_6-10)aryl.

7. The compound of claim 1, wherein R₃ is C_1-12 alkyl.

8. The compound of claim 1, wherein R₃ is C_1-6 alkyl.

9. The compound of claim 1, wherein R₃ is C₄ alkyl.

10. The compound of claim 1, wherein R³ is isobutyl.

11. The compound of claim 1, wherein R² is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl.

12. The compound of claim 1, wherein Z¹ and Z² are independently one of hydroxy, C_1-6 alkoxy, or C_6-10 aryloxy.

13. The compound of claim 12, wherein Z¹ and Z² are both hydroxy.

14. The compound of claim 1, wherein together Z¹ and Z² form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.

15. The compound of claim 1, wherein:

P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl;

A is zero;

X² is --C(O)--NH--;

R is hydrogen or C_1-8 alkyl;

R² and R³ are each independently one of hydrogen, C_1-8 alkyl, C_3-10 cycloalkyl, C_6-10 aryl, C_6-10 ar(C_1-6 )alkyl, pyridylmethyl, or quinolinylmethyl; and

Z¹ and Z² are both hydroxy, C_1-6 alkoxy, or C_6-10 aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.

16. The compound of claim 1, wherein:

P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl;

A is zero;

X² is --C(O)--NH--;

R is hydrogen or C_1-8 alkyl;

R³ is isobutyl;

R² is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl; and

Z¹ and Z² are independently one of hydroxy, C_1-6 alkoxy, C_6-10 aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol and diethanolamine.

17. The compound of claim 1, wherein said compound is one of:

N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid,

N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid,

N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid,

N-(4-morpholine)carbonyl- O-(2-pyridylmethyl)!-L-tyrosine-L-leucine boronic acid;

or isosteres, pharmaceutically acceptable salts or boronate esters thereof.

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

22. The pharmaceutical composition of claim 20 or 21, wherein said compound is present in an amount effective to inhibit the proteasome function in a mammal.

18. The compound N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, or a pharmaceutically acceptable salt or boronate ester thereof.

19. A compound having the formula:

##STR61## or a pharmaceutically acceptable salt thereof;

wherein P is R⁷ --C(O)-- and R⁷ is pyrazinyl;

X² is --C(O)--NH--;

R is hydrogen or alkyl;

R² and R³ are independently hydrogen, alkyl, cycloalkyl, aryl, or --CH₂ --R⁵ ;

R⁵, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or --W--R⁶, where W is a chalcogen and R⁶ is alkyl;

where the ring portion of any of said aryl, aralkyl, or alkaryl in R², R³ and R⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6 alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, C_6-10 arylsulfonyl, C_6-10 aryl, C_1-6 alkyl (C_6-10)aryl, and halo(C_6-10)aryl;

Z¹ and Z² are independently one of hydroxy, alkoxy, or aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and

A is zero.

21. A pharmaceutical composition, comprising a compound of claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.