Methods for synthesis of amino-tetrahydroisoquinoline ring...

Details Methods for synthesis of amino-tetrahydroisoquinoline ring... Methods for synthesis of amino-tetrahydroisoquinoline ring...

2001-12-21

2003-08-19

Davis, Zinna Northington (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S559000, C546S062000, C546S081000, C546S084000

Reexamination Certificate

active

06608193

ABSTRACT:

FIELD OF INVENTION
The present invention relates to methods of preparing amino-tetrahydroisoquinoline ring compounds. More particularly, the invention relates to the synthesis of amino-substituted-carboxylic acid ring compounds using a solid support. The invention also relates to methods of preparing combinatorial libraries of amino-substituted-carboxylic acid ring compounds.
BACKGROUND ART
The amino-substituted-tetrahydroisoquinoline-carboxylic acids (amino-substituted-TIQ-carboxylic acid) are useful in numerous pharmaceutical applications. Such compounds have been useful in treatment of degenerative joint disorders, disorders of the connective tissue, ulcerations, atherosclerosis, stenosis, inflammation, carcinomatosis, anorexia, and septic shock. Thus, it is desirable to generate derivatives of amino-substituted-TIQ-carboxylic acid such as ring-containing tetrahydroisoquinoline compounds, referred to as amino-substituted-tetrahydroisoquinoline ring compounds (amino-substituted-TIQ-ring compounds), for testing as potential drug candidates. The acceleration of drug discovery has generated growing demands for efficient synthetic methods to produce therapeutic candidates. Preferably the methods are suitable for use in generating combinatorial libraries.
Loevezijn et al.,
Tetrahedron Letters,
39:4737-4740 (1998), teach the synthesis of indolyl diketopiperzine alkaloids using a hydroxyethyl functionalized polystyrene resin. Loevezijn et al. disclose loading the resin with L-tryptophan, followed by condensation with an aldehyde or ketone. Loevezijn et al. further disclose that the resulting secondary amine is coupled with a protected amino acid, deprotected and simultaneously cyclized and cleaved. Fantauzzi et al.,
Tetrahedron Letters,
39:1291-1294 (1998), teach the synthesis of tetrahydro-&bgr;-carboline-3-carboxamides and tetrahydro-&bgr;-carboline-2,3-bis-lactams using a 4-hydroxythiolphenol-linked resin. Fantauzzi et al. disclose acylation of the resin with protected-tryptophan followed by deprotection and cyclization with aldehydes provided tetrahydro-&bgr;-carbolines. Fantauzzi et al. further disclose cleavage with primary amines provided the amides, while acylation at the carboline 2-positions with protected amino acids followed by deprotection and neutralization resulted in intramolecular cyclization and cleavage to provide bis-lactams.
Szardenings et al., U.S. Pat. No. 5,817,751, teach methods for the synthesis of diketopiperazine and diketomorpholine derivatives. Szardenings et al. disclose that the methods include providing a first amino acid derivative on a solid support, and combining an aldehyde or ketone, an isocyanide, and a free protected amino acid or an &agr;-hydroxy acid with the first amino acid derivative. The resulting precursor is the cyclized. Schudok, U.S. Pat. No. 5,962,471, teaches substituted 6- and 7-amino-tetrahydroisoquinoline-carboxylic acids suitable for therapy of disorders involving increased activity of matrix-degrading metalloproteinases. Schudok teaches that methods of synthesizing such compounds include the nitration of tetrahydroisoquinoline; acylation with carbonyl or sulfonyl chloride, carboxylic or sulfonic imidazolides, chloroformic acid esters, active esters or anhydrides; treatment with an amino acid, carboxylic acid, aldehyde or substituted guanidine; or alkylation.
There is a need for facile and efficient methods for the synthesis of amino-substituted-TIQ-ring compounds. It is desirable that the methods conveniently produce combinatorial libraries of compounds.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide novel methods of preparing amino-tetrahydroisoquinoline ring compounds, particularly amino-substituted-tetrahydroisoquinoline ring compounds such as amino-substituted-tetrahydroisoquinoline-diketopiperazines (amino-substituted-TIQ-DKPs) and amino-substituted-tetrahydroisoquinoline-benzodiazepines (amino-substituted-TIQ-BDAs). It is also an object of the invention to provide novel methods of preparing combinatorial libraries of amino-substituted-tetrahydroisoquinoline ring compounds.
In accordance with one aspect of the invention, there are provided methods of preparing an amino-substituted-tetrahydroisoquinoline ring compound comprising the steps of providing a support-bound amino-substituted-tetrahydroisoquinoline-carboxylic acid in the form of a carboxylate having the structure:
wherein W represents a solid support and R
1
is alkyl, aryl, heterocyclic moiety, amide, sulfonamide, urea, thiourea, or alcohol; forming a support-bound intermediate by reacting the support-bound amino-substituted-tetrahydroisoquinoline-carboxylate with a reagent; and cyclizatively cleaving the support-bound intermediate to form the amino-substituted-tetrahydroisoquinoline ring compound. The reagent is selected from the group consisting of (i) isocyanates having the structure R
3
NCO wherein R
3
is an alkyl or aryl, (ii) thioisocyanates having the structure R4NCS wherein R
4
is an alkyl or aryl, (iii) protected non-cyclic amino acids having the structure:
wherein P is a protecting group, n is from 0 to 1, and R
5
is the side chain of an amino acid, (iv) protected cyclic amino acids having the structure:
represents a heterocycle, P is a protecting group, and Y is NO
2
, NHP, OP, or SP, and (v) protected cyclic amino acids having the structure:
represents a heterocycle, aryl, or hydrocarbocycle, P is a protecting group, and Y is NO
2
, NHP, OP, or SP.
In accordance with another aspect of the invention there are provided methods of preparing an amino-substituted-tetrahydroisoquinoline-diketopiperazine by reacting the support-bound amino-substituted-tetrahydroisoquinoline-carboxylate with the protected cyclic amino acid (iv).
In accordance with yet another aspect of the invention there are provided methods of preparing an amino-substituted-tetrahydroisoquinoline-diketopiperazine by forming a support-bound intermediate having a nitro group and a protecting group by reacting the support-bound amino-substituted-tetrahydroisoquinoline-carboxylate with an amino-protected nitro-substituted-tetrahydroisoquinoline carboxylic acid; reducing the nitro group of the support-bound intermediate; reacting the support-bound intermediate with an aldehyde; removing the protecting group; and cyclizatively cleaving the support-bound intermediate to form amino-substituted-tetrahydroisoquinoline-diketopiperazine.
In accordance with one aspect of the invention there are provided methods of preparing an amino-substituted-tetrahydroisoquinoline-benzodiazepine by reacting the support-bound amino-substituted-tetrahydroisoquinoline-carboxylate with the protected cyclic amino acid (v).
In accordance with yet another aspect of the invention there are provided methods of preparing an amino-substituted-tetrahydroisoquinoline-benzodiazepine by forming a support-bound intermediate having a nitro group and a protecting group by reacting the support-bound amino-substituted-tetrahydroisoquinoline carboxylate with an amino-protected nitro-anthranilic acid; reducing the nitro group of the intermediate; reacting the intermediate with an aldehyde; removing the protecting group; and cyclizatively cleaving the support-bound intermediate to form the amino-substituted-tetrahydroisoquinoline-benzodiazepine.
The present invention provides convenient means for preparing amino-substituted-tetrahydroisoquinoline ring compounds and combinatorial libraries thereof. The present invention also provides convenient means for preparing 7-amino-tetrahydroisoquinoline ring compounds and combinational libraries thereof. These and additional objects and advantages will be more fully apparent in view of the following description.
DETAILED DESCRIPTION
As used herein “amino-substituted-tetrahydroisoquinoline ring compounds” refer to compounds which comprise an isoquinoline moiety having a amino-substituted group and at least one additional ring moiety. Preferably the additional ring moiety is fused to the isoquinoline moiety. The amino-substituted-tetrahydroisoquinoline ring

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