Amine compounds and combinatorial libraries comprising same

• US 6,316,626 B1
• Filed: 09/04/1998
• Issued: 11/13/2001
• Est. Priority Date: 09/05/1997
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Sprankle, Kelly G., Swayze, Eric Edward
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US09/148,732
• Time in Patent Office: 1,166 Days
• Field of Search: 546/207, 546/208, 546/244, 546/246
• US Class Current: 546/207
• CPC Class Codes: C07D 243/08 not condensed with other rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C12Q 1/18 Testing for antimicrobial activity of a material
• CPC Class Codes: C40B 40/00 Libraries per se, e.g. arrays, mixtures
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92

Abstract

The present invention provides monocyclic, bicyclic and oligomeric amine compounds with at least two sites of diversity. These compounds are formed from monocyclic scaffolds which can be cyclized to form bicyclic amine scaffolds. These can then be reacted with building blocks to form the amine compounds of the invention. This invention further provides libraries or monocyclic, bicyclic and oligomeric amine compounds. Also provided are methods for preparing monocyclic, bicyclic and oligomeric amine compounds and libraries thereof. The present invention also provides pharmaceutical compositions of the monocyclic, bicyclic and oligomeric amine compounds.

Claims

1. A compound having the formula:

wherein;

R₁ and R_1′

are, individually CH₂, CH(R₂), C═

O, C═

S, S(═

O)₂, C(═

O)NH, C(═

S)NH or C(═

O)O;

R₂ is H, substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl, substituted or unsubstituted C₂-C₂₀ alkynyl, substituted or unsubstituted C₆-C₁₄ aryl, substituted or unsubstituted C₆-C₁₄ aralkyl, substituted or unsubstituted C₃-C₁₄ cycloalkyl, substituted or unsubstituted C₅-C₁₄ fused cycloalkyl, substituted or unsubstituted C₄-C₁₄ heterocyclyl, substituted or unsubstituted C₄-C₁₄ heterocyclylalkyl, substituted or unsubstituted C₄-C₁₄ heteroaryl;

substituted or unsubstituted C₄-C₁₄ heteroaralkyl, CH(R₇)—

NH—

R_7′

or CH(R₇)—

NH—

R_1′

—

R₃;

wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone sulfonate, sulfonamide, thiol, and thioalkoxy;

or R₁ and R₂, together, are H, or an amino protecting group;

R₃ is H;

R₄ is H, R₁-R₂ or R₁₁-R₁₂;

R₅ is, H, substituted or unsubstituted C₁-C₁ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl, substituted or unsubstituted C₂-C₂₀ alkynyl, substituted or unsubstituted C₆-C₁₄ aryl, substituted or unsubstituted C₆-C₁₄ aralkyl, substituted or unsubstituted C₃-C₁₄ cycloalkyl, substituted or unsubstituted C₅-C₁₄ fused cycloalkyl, substituted or unsubstituted C₄-C₁₄ heterocyclyl, substituted or unsubstituted C₄-C₁₄ heterocyclylalkyl, substituted or unsubstituted C₄-C₁₄ heteroaryl;

substituted or unsubstituted C₄-C₁₄ heteroaralkyl, —

R₁-R₂, or N(R₈)(R₉)—

C(═

O);

wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;

R₆ is, H, substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl, substituted or unsubstituted C₂-C₂₀ alkynyl, substituted or unsubstituted C₆-C₁₄ aryl, substituted or unsubstituted C₆-C₁₄ aralkyl, substituted or unsubstituted C₃-C₁₄ cycloalkyl, substituted or unsubstituted C₅-C₁₄ fused cycloalkyl, substituted or unsubstituted C₄-C₁₄ heterocyclyl, substituted or unsubstituted C₄-C₁₄ heterocyclylalkyl, substituted or unsubstituted C₄-C₁₄ heteroaryl;

substituted or unsubstituted C₄-C₁₄ heteroaralkyl, —

R₁-R₂, or —

C(═

O)O—

R₃;

wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;

or R₅ and R₆, together, are (CH₂)_nd, (CH₂)_nd—

O—

(CH₂)_ne, (CH₂)_nd—

N(R₁₀)—

(CH₂)_ne, or (CH₂)_nd—

S—

(CH₂)_ne;

R₇ is H, substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl, substituted or unsubstituted C₂-C₂₀ alkynyl, substituted or unsubstituted C₆-C₁₄ aryl, substituted or unsubstituted C₆-C₁₄ aralkyl, substituted or unsubstituted C₃-C₁₄ cycloalkyl, substituted or unsubstituted C₅-C₁₄ fused cycloalkyl, substituted or unsubstituted C₄-C₁₄ heterocyclyl, substituted or unsubstituted C₄-C₁₄ heterocyclylalkyl, substituted or unsubstituted C₆-C₁₄ heteroaryl;

substituted or unsubstituted C₆-C₁₄ heteroaralkyl, or a group selected from the group consisting of groups attached to the α

-position of amino acids, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;

R_7′

is H or an amino protecting group;

R₈ and R₉ are each, independently, H, substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl, substituted or unsubstituted C₂-C₂₀ alkynyl, substituted or unsubstituted C₆-C₁₄ aryl, substituted or unsubstituted C₆-C₁₄ aralkyl, substituted or unsubstituted C₃-C₁₄ cycloalkyl, substituted or unsubstituted C₅-C₁₄ fused cycloalkyl, substituted or unsubstituted C₄-C₁₄ heterocyclyl, substituted or unsubstituted C₄-C₁₄ heterocyclylalkyl, substituted or unsubstituted C₄-C₁₄ heteroaryl;

substituted or unsubstituted C₄-C₁₄ heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;

or R₈ and R₉, together, are (CH₂)_nd, (CH₂)_nd—

O—

(CH₂)_ne, (CH₂)_nd—

N (R₁₀)—

(CH₂)_ne, or (CH₂)_nd—

S—

(CH₂)_ne;

R₁₀ is substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₆-C₁₄ aryl, or substituted or unsubstituted C₆-C₁₄ aralkyl, substituted or unsubstituted C₄-C₁₄ heteroaryl;

substituted or unsubstituted C₄-C₁₄ heteroaralkyl, wherein the substituent groups are selected from the group consisting of acyl, alkoxy, alkoxycarbonyl, alkyl, alkenyl, alkynyl, amino, amido, azido, aryl, heteroaryl, carboxylic acid, cyano, guanidino, halo, haloalkyl, haloalkoxy, hydrazino, hydroxyl, alkylsulfonyl, nitro, sulfide, sulfone, sulfonate, sulfonamide, thiol, and thioalkoxy;

R₁₁ is a linker moiety;

R₁₂ is a solid support; and

nd and ne are each, independently, 1 to 4;

provided that said compound is not;

N-[1-[1,1′

-biphenyl]-4-ylsulfonyl)-5-[[[4-[(2,4-dioxo-5-thiazolidinylidene)methyl]bezoy]amino]methyl]-3-pyrrolidinyl]-4-[(3-oxo-2(3H)-isothizolyl)methyl]-, [3S-[3.alpha.,5.alpha.(E)]]-benzamide;

or

N-[(4-amino-2-pyrrolidinyl) methyl]-3-methyl-L-valyl-L-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-, (2S-trans)-, tris (trifluoroacetate)-L-glutamine;

or

N-[[1-[(1,1-dimethylethoxy) carbonyl]-4-[[(1,1-dimethyletyhoxy) carbonyl]amino]-2-pyrrolidinyl]methyl]-3-methyl-L-1,2,3,4-tetrahydor-3-isoquinolinecarbonyl-, (2S-trans)-, tris (trifluoroacetate)- L-glutamine;

or

N-[(4-amino-2-pyrrolidinyl) methyl]-3-methyl-L-valyl-L-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-, (2S-trans)-trifluoroacetate L-glutamine;

or

N-[(4-amino-2-pyrrolidinyl) methyl]-3-methyl-L-valyl-L-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-, (2S-trans)- L-glutamine;

or

3-[[[1-[(4-chlorophenyl) sulfonyl]-4-[[(4-chlorophenyl) sulfonyl]amino]-2-pyrrolidinyl]methyl]amino]-,(2S-trans)-benzoic acid;

or

4-azido-2-(azidomethyl)-1-(p-tolylsulfonyl)-, (−

)-pyrrolidine.

2. The compound of claim 1 wherein the individual stereochemical configurations at positions 3 and 5 of the piperidine rind are specifically R, specifically S, or a mixture of R and S.