Nitrogenous macrocyclic compounds

• US 6,107,482 A
• Filed: 09/19/1997
• Issued: 08/22/2000
• Est. Priority Date: 03/27/1995
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Fraser, Allister S., Cook, Phillip Dan, An, Haoyun, Kung, Pei-Pei, Guinosso, Charles J.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/913,664
• Time in Patent Office: 1,068 Days
• Field of Search: 540/472, 540/455
• US Class Current: 540/472
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 515/08 Bridged systems

Abstract

Novel macrocyclic compounds are constructed to include large cyclic structures that are interrupted by at least one ring system. Each interrupting ring system includes two bridgehead atoms. Bridgehead atoms are bonded to one or more bridges that interconnect one or more ring systems thereby forming a large cyclic structure. Located in each bridge are two or more nitrogenous moieties that are derivatized with chemical functional groups. The ring systems can include further nitrogenous moieties, either as ring atoms or on pendant groups attached to the ring. These can also be derivatized with chemical functional groups. The totality of the chemical functional groups imparts certain conformational and other properties to the macrocyclic compounds. In accordance with certain embodiments of the invention, libraries of such macrocyclic compounds are prepared utilizing permutations and combinations of the chemical functional groups and the nitrogenous moieties to build complexity into the library.

Claims

1. A compound having one of the structures:

##STR3## wherein;

Z is H, hydroxyl, amino, thiol, acyl, protected hydroxyl, protected amino, protected thiol, protected acyl or --N(T--L)₂ ;

r is from 0 to about 8;

J is N, O, S, or a heterocyclic ring system;

t is 0 or 1;

each T is independently a single bond, a methylene group or a group having the structure;

space="preserve" listing-type="equation">--{[CR.sup.1 R.sup.2 ].sub.m --(R.sup.5)--[CR.sup.1 R.sup.2 ].sub.n --[C(R.sup.6)].sub.p --(E)--}.sub.q --

where

R⁶ is ═

O, S, ═

NR² ;

R⁵ and E, independently, are a single bond, CH═

CH, C.tbd.C, O, S, NR³, SO₂, or C₆ -C₁₄ aryl;

each R¹, R² and R³ is, independently, H, alkyl or haloalkyl having 1 to about 10 carbon atoms;

alkenyl having 2 to about 10 carbon atoms;

alkynyl having 2 to about 10 carbon atoms;

or aryl having 6 to about 14 carbon atoms;

m and n, independently, are zero to 5;

p is zero or 1;

q is 1 to about 10; and

each L is independently, H, C₂ -C₁₀ alkyl or substituted alkyl, C₂ -C₁₀ alkenyl or substituted alkenyl, C₂ -C₁₀ alkynyl or substituted alkynyl, C₄ -C₇ carbocyclic alkyl or substituted C₄ -C₇ carbocyclic alkyl, alkenyl or alkynyl carbocyclic, substituted alkenyl or alkynyl carbocyclic, or C₆ -C₁₄ aryl or substituted aryl where the substituent groups are selected from hydroxyl, amino, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, or alkynyl groups;

an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms;

a nitrogen, sulfur or oxygen containing heterocycle;

a metal coordination group;

a conjugate group;

halogen;

hydroxyl (OH);

thiol (SH);

keto (C═

O);

carboxyl (COOH);

amide (CONR¹);

amidine (C(═

NH)NR¹ R²);

guanidine (NHC(═

NH)NR¹ R²);

glutamyl R³ OOCCH(NR¹ R²)(CH₂)² C(═

O)--);

nitrate (ONO₂) nitro (NO₂);

nitrile (CN);

trifluoromethyl (CF₃);

trifluoromethoxy (OCF₃);

O-alkyl;

S-alkyl;

NH-alkyl;

N-dialkyl;

O-aralkyl;

S-aralkyl;

NH-aralkyl;

amino (NH₂);

azido (N₃);

hydrazino (NHNH₂);

hydroxylamino (ONH₂);

sulfoxide (SO);

sulfone (SO₂);

sulfide (S--);

disulfide (S--S);

silyl;

a nucleosidic base;

an amino acid side chain;

a carbohydrate;

a drug;

or a group capable of hydrogen bonding; and

with the proviso that not more than three of said --T--L groups are p-toluenesulfonyl or H, and

with the proviso that at least two of said --T--L groups are different.

2. The compound of claim 1 wherein t is 0, r is 0 and Z is H.

3. The compound of claim 1 wherein t is 1 and J is a heterocyclic ring system.

4. The compound of claim 3 wherein said heterocyclic ring system contains at least two nitrogen atoms.

5. The compound of claim 4 wherein said heterocyclic ring system is piperazine.

6. The compound of claim 1 wherein each of said --T--L groups is different from the other of said --T--L groups.