BORONIC ESTER AND ACID COMPOUNDS, SYNTHESIS AND USES

• US 20090247731A1
• Filed: 04/01/2009
• Published: 10/01/2009
• Est. Priority Date: 10/28/1994
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: MA, Yu-Ting, GRENIER, Louis, STEIN, Ross, PLAMONDON, Louis, BAEVSKY, Matthew, ADAMS, Julian
• Granted Patent: US 8,003,791 B2
• Time in Patent Office: Days
• US Class Current: 530/300
• 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:

or a pharmaceutically acceptable salt thereof;

wherein;

P is hydrogen or an amino-group-protecting moiety;

B¹, at each occurrence, is CH;

X¹, at each occurrence, is —

C(O)—

NH—

;

X² is —

C(O)—

NH—

;

R is hydrogen or alkyl, or R forms together with the adjacent R¹, or when A is zero, forms together with the adjacent R², a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, aryl, alkoxy and aryloxy;

R¹, at each occurrence, and R² and R³ are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —

CH₂—

R⁵, where the ring portion of any of said aryl or heterocycle can be optionally substituted;

R⁵, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl, or heterocycle can be optionally substituted;

provided that at least one of R¹, R², or R³ is

where R⁹ is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

wherein the alkyl is optionally substituted with one of C_1-6alkyl, halogen, monohalo(C_1-6)alkyl, and trifluoromethyl; and

wherein said cycloalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups are optionally substituted with one or two of C_1-6alkyl, C_3-8cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8alkenyl, C_2-8alkynyl, cyano, amino, C_1-6alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6alkoxy, C_6-10aryl, C_6-10aryl(C_1-6)alkyl, C_6-10aryl(C_1-6)alkoxy, hydroxy, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, C_6-10arylthio, C_6-10arylsulfinyl, C_6-10arylsulfonyl, C_6-10aryl, C_1-6alkyl(C_6-10)aryl, and halo(C_6-10)aryl;

A¹ and A² are independently one of hydrogen, halogen, C_1-6alkyl, monohalo(C_1-6) alkyl, or trifluoromethyl;

Z¹ and Z² are independently one of alkyl, 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 0, 1, or 2.

2. The compound of claim 1, wherein P is R⁷—

C(O)—

, R⁷—

SO₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

R⁷ is one of alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

, then R⁷ can also be N-morpholinyl.

3. The compound of claim 1, wherein P is R⁷—

C(O)—

or R⁷—

SO₂—

; and

R⁷ is one of C_6-10 aryl, C_6-10 ar(C_1-6)alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl(C_1-6)alkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

, R⁷ can also be N-morpholinyl.

4. The compound of claim 1, wherein one of R¹, R², or R³ is

where

A¹ and A² are independently one of hydrogen, halogen, C_1-6alkyl, monohalo(C_1-6)alkyl, or trifluoromethyl;

R⁹ is one of C_1-8 alkyl, C_3-10 cycloalkyl, C_6-10 aryl, C_6-10ar(C_1-6)alkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl(C_1-6)alkyl;

and the remaining R¹, R², and R³ are independently selected from the group consisting of alkyl and —

CH₂—

R⁵, where

R⁵, in each instance, is one of C_6-10aryl, C_6-10ar(C_1-6)alkyl, C_1-6alk(C_6-10)aryl, C_3-10cycloalkyl, C_1-8alkoxy, C_1-8alkoxy, C_1-8alkylthio, or a 5-, 6-, 9-, or 10-membered heteroaryl group, where the ring portion of any of said C_6-10aryl, C_6-10ar(C_1-6)alkyl, C_1-6alk(C_6-10)aryl, C_3-10cycloalkyl, C_1-8alkoxy, C_1-8alkoxy, C_1-8alkylthio, or a 5-, 6-, 9-, or 10-membered heteroaryl can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6alkyl, C_3-8cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8alkenyl, C_2-8alkynyl, cyano, amino, C_1-6alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6alkoxy, C_6-10aryl, C_6-10aryl(C_1-6)alkyl, C_6-10aryl(C_1-6)alkoxy, hydroxy, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, C_6-10arylthio, C_6-10arylsulfinyl, C_6-10arylsulfonyl, C_6-10aryl, C_1-6alkyl(C_6-10)aryl, and halo(C_6-10)aryl.

5. The compound of claim 1, wherein A is zero.

6. The compound of claim 1, wherein:

A is zero;

P is one of R⁷—

C(O)—

, R⁷—

SO₂—

, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

R⁷ is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl, or pyrrolyl, or when P is R⁷—

C(O)—

, R⁷ can also be N-morpholinyl;

R² is;

where

A¹ and A² are independently one of hydrogen, halogen, C_1-6alkyl, monohalo(C_1-6)alkyl, or trifluoromethyl;

R⁹ is one of C_1-8 alkyl, phenyl, benzyl, phenethyl, or pyridylmethyl;

R³ is C_1-6alkyl; and

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

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

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

or

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

or a pharmaceutically acceptable salt or boronate ester thereof.