US5773571A — Peptide nucleic acids

Claim 1

Independent Claim 565 words

A compound having the formula: ##STR6## wherein: n is at least 2, each of L 1 -L n is independently selected from the group consisting of hydrogen, hydroxy, (C 1 -C 4 )alkanoyl, naturally occurring nucleobases, non-naturally occurring nucleobases, aromatic moieties, DNA intercalators, nucleobase-binding groups, heterocyclic moieties, and reporter ligands, at least one of L 1 -L n being a naturally occurring nucleobase, a non-naturally occurring nucleobase, a DNA intercalator, or a nucleobase-binding group; each of T 1 -T n is (CR 6 R 7 )y where R 6 is hydrogen and R 7 is selected from the group consisting of the side chains of naturally occurring alpha amino acids, or R 6 and R 7 are independently selected from the group consisting of hydrogen, (C 2 -C 6 )alkyl, aryl, aralkyl, heteroaryl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, NR 3 R 4 and SR 5 or R 6 and R 7 taken together complete an alicyclic or heterocyclic system; each R 3 and R 4 is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, hydroxy- or alkoxy- or alkylthio-substituted (C 1 -C 4 )alkyl, hydroxy, alkoxy, alkylthio and amino; R 5 is hydrogen, (C 1 -C 6 )alkyl, hydroxy-, alkoxy-, or alkylthio- substituted (C 1 -C 6 )alkyl; each of D 1 -D n is (CR 6 R 7 ), where R 6 and R 7 are as defined above; each of y and z is zero or an integer from 1 to 10, the sum y+z being greater than 2 but not more than 10; each of G 1 -G n-1 is --NR 3 CO-- in either orientation, where R 3 is as defined above; each of A 1 -A n and J 1 -J n are selected such that: (a) A is a group of formula (IIa), (IIb) or (IIc), and J is N or R 3 N + , provided that at least one A is a group of formula (IIc) wherein S is an interger from 1 to 5; or (b) A is a group of formula (IId) and J is CH; or (c) A is a group of formula (IIa) or (IIb) and J is N or R 3 N + , provided at least one of y or z is not 1 or 2; ##STR7## wherein: X is O, S, Se, NR 3 , CH 2 or C(CH 3 ) 2 where R 3 is as defined above; Y is a single bond, O, S or NR 4 where R 4 is as defined above; each of r and s is zero or an integer from 1 to 5; each R 1 and R 2 is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl which may be hydroxy- or alkoxy- or alkylthio-substituted, hydroxy, alkoxy, alkylthio, amino and halogen; Q is --CO 2 H, --CONR 8 R 9 , --SO 3 H or --SO 2 NR 8 R 9 or an activated derivative of --CO 2 H or --SO 3 H; and Z is --NHR 10 R 11 or --NR 10 C(O)R 11 , where R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, amino protecting groups, reporter ligands, intercalators, chelators, peptides, proteins, carbohydrates, lipids, steroids, oligonucleotides and soluble and non-soluble polymers.

Claim 2

Dependent Claim 565 words

A compound having the formula: ##STR6## wherein: n is at least 2, each of L 1 -L n is independently selected from the group consisting of hydrogen, hydroxy, (C 1 -C 4 )alkanoyl, naturally occurring nucleobases, non-naturally occurring nucleobases, aromatic moieties, DNA intercalators, nucleobase-binding groups, heterocyclic moieties, and reporter ligands, at least one of L 1 -L n being a naturally occurring nucleobase, a non-naturally occurring nucleobase, a DNA intercalator, or a nucleobase-binding group; each of T 1 -T n is (CR 6 R 7 )y where R 6 is hydrogen and R 7 is selected from the group consisting of the side chains of naturally occurring alpha amino acids, or R 6 and R 7 are independently selected from the group consisting of hydrogen, (C 2 -C 6 )alkyl, aryl, aralkyl, heteroaryl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, NR 3 R 4 and SR 5 or R 6 and R 7 taken together complete an alicyclic or heterocyclic system; each R 3 and R 4 is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, hydroxy- or alkoxy- or alkylthio-substituted (C 1 -C 4 )alkyl, hydroxy, alkoxy, alkylthio and amino; R 5 is hydrogen, (C 1 -C 6 )alkyl, hydroxy-, alkoxy-, or alkylthio- substituted (C 1 -C 6 )alkyl; each of D 1 -D n is (CR 6 R 7 ), where R 6 and R 7 are as defined above; each of y and z is zero or an integer from 1 to 10, the sum y+z being greater than 2 but not more than 10; each of G 1 -G n-1 is --NR 3 CO-- in either orientation, where R 3 is as defined above; each of A 1 -A n and J 1 -J n are selected such that: (a) A is a group of formula (IIa), (IIb) or (IIc), and J is N or R 3 N + , provided that at least one A is a group of formula (IIc) wherein S is an interger from 1 to 5; or (b) A is a group of formula (IId) and J is CH; or (c) A is a group of formula (IIa) or (IIb) and J is N or R 3 N + , provided at least one of y or z is not 1 or 2; ##STR7## wherein: X is O, S, Se, NR 3 , CH 2 or C(CH 3 ) 2 where R 3 is as defined above; Y is a single bond, O, S or NR 4 where R 4 is as defined above; each of r and s is zero or an integer from 1 to 5; each R 1 and R 2 is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl which may be hydroxy- or alkoxy- or alkylthio-substituted, hydroxy, alkoxy, alkylthio, amino and halogen; Q is --CO 2 H, --CONR 8 R 9 , --SO 3 H or --SO 2 NR 8 R 9 or an activated derivative of --CO 2 H or --SO 3 H; and Z is --NHR 10 R 11 or --NR 10 C(O)R 11 , where R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, amino protecting groups, reporter ligands, intercalators, chelators, peptides, proteins, carbohydrates, lipids, steroids, oligonucleotides and soluble and non-soluble polymers.

Claim 3

Dependent Claim 26 words

A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically effective carrier, binder, thickener, diluent, buffer, preservative, or surface active agent.

Claim 4

Dependent Claim 517 words

A process for preparing a compound according to claim 28, comprising the steps of: A) providing a polymer substrate, said polymer being functionalized with a chemical group capable of forming an anchoring linkage with an amino acid; B) coupling said polymer with a first amino acid through said anchoring linkage, said first amino acid having formula (IV): ##STR8## wherein: L is selected from the group consisting of naturally occurring nucleobases, non-naturally occurring nucleobases, aromatic moieties, DNA intercalators, nucleobase-binding groups, heterocyclic moieties, and reporter ligands, wherein amino groups are, optionally, protected by amino protecting groups; each T is (CR 6 R 7 )y where R 6 is hydrogen and R 7 is selected from the group consisting of the side chains of naturally occurring alpha amino acids, or R 6 and R 7 are independently selected from the group consisting of hydrogen, (C 2 -C 6 )alkyl, aryl, aralkyl, heteroaryl, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, NR 3 R 4 and SR 5 or R 6 and R 7 taken together complete an alicyclic or heterocyclic system; each R 3 and R 4 is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, hydroxy- or alkoxy- or alkylthio-substituted (C 1 -C 4 )alkyl, hydroxy, alkoxy, alkylthio and amino; R 5 is hydrogen, (C 1 -C 6 )alkyl, hydroxy-, alkoxy-, or alkylthio-substituted (C 1 -C 6 )alkyl; each D is (CR 6 R 7 ) z where R 6 and R 7 are as defined above; each of y and z is zero or an integer from 1 to 10, the sum y+z being greater than 2 but not more than 10; A and J are selected such that: (a) A is a group of formula (IIc) and J is N or R 3 N + ; or (b) A is a group of formula (IId) and J is CH; or (c) A is a group of formula (IIa) or (IIb) and J is N or R 3 N + , provided at least one of y or z is not 1 or 2; ##STR9## wherein: X is O, S, Se, NR 3 , CH 2 or C(CH 3 ) 2 where R 3 is as defined above; Y is a single bond, O, S or NR 4 where R 4 is as defined above; each of r and s is zero or an integer from 1 to 5; each R 1 and R 2 is independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl which may be hydroxy- or alkoxy- or alkylthio-substituted, hydroxy, alkoxy, alkylthio, amino and halogen; and each E is COOH or an activated or protected derivative thereof; and each M is NHR 3 or NR 3 R 12 , where R 3 is as defined above, and R 12 is an amino protecting group; C) removing said amino protecting group from said coupled first amino acid to generate a free amino group; and D) reacting said free amino group with a second amino acid having formula (IV) to form a peptide chain.

Claim 5

Dependent Claim 56 words

The process of claim 3 further comprising the steps of: E) removing said amino protecting group from said second amino acid to generate a terminal free amino group on said peptide chain; and F) reacting said free amino group on said peptide chain with a further amino acid having formula (IV) to lengthen said peptide chain.

Claim 6

Dependent Claim 16 words

The process of claim 4 wherein steps E and F are performed a plurality of times.

Claim 7

Dependent Claim 23 words

The process of claim 3 further comprising removing at least one protecting group remaining on the amino acid moieties of the peptide chain.

Claim 8

Dependent Claim 17 words

The process of claim 3 further comprising cleaving said anchoring linkage without substantially degrading said peptide chain.

Claim 9

Dependent Claim 21 words

The process of claim 3 wherein the polymer substrate contains polystyrene, polyacrylamide, silica, a composite material, cotton, or a derivative thereof.

Claim 10

Dependent Claim 51 words

The process of claim 4 wherein the chemical group capable of forming said anchoring linkage is chloro-, bromo- and iodo-substituted alkyl, amino-substituted alkyl, amino and aryl-substituted alkyl, amino- and alkylaryl-substituted alkyl, hydroxy-substituted alkyl, or a derivative thereof having a spacer group that can be cleaved substantially without degradation of said polypeptide.

Claim 11

Dependent Claim 39 words

The process of claim 9 wherein chloro-substituted alkyl is chloromethyl, amino-substituted alkyl is aminomethyl, amino- and alkyl-substituted aryl is α-aminobenzyl, amino- and alkylaryl-substituted alkyl is selected from the group consisting of a-amino-3- and α-amino-4-methylbenzyl, and hydroxy-substituted alkyl is hydroxymethyl.

Claim 12

Dependent Claim 58 words

The process of claim 9 wherein: the chemical group is derived from an amino-containing moiety selected from amino-substituted alkyl, amino- and aryl substituted alkyl, and amino- and alkylaryl-substituted alkyl; and the chemical group includes a spacer group derived from the group consisting of 4-(haloalkyl)aryl-lower alkanoic acids, Boc-aminoacyl-4-(oxymethyl)aryl-lower alkanoic acids, N-Boc-p-acylbenzhydrylamines, N-Boc-4'-(lower alkyl)-p-acylbenzhydrylamines, N-Boc-4'-(lower alkoxy)-p-acylbenzhydrylamines, and 4-hydroxymethylphenoxy-lower alkanoic acids.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2001-06-29	2001-12-29	2002-06-30	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2005-06-29	2005-12-29	2006-06-30	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2009-06-29	2009-12-29	2010-06-30	$7700.00	Window Closed / Lapsed

Peptide nucleic acids

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