Combinatorial synthesis of libraries of macrocyclic compounds useful in drug discovery

1. A process for preparing a library of compounds of the formula (1),

where part (A) is a

bivalent radical having its —NH— group linked to the terminal carbonyl group of part (D) shown below

proline or hydroxyproline;

where part (B) is a

bivalent radical having its —NH— group linked to part (A), proline or hydroxyproline, a —(CH 2 ) z — bivalent radical, or a covalent bond;

where part (C) is a

bivalent radical having its —NH— group linked to part (B), proline or hydroxyproline, a —(CH 2 ) t — bivalent radical, or a covalent bond;

where part (T) is selected from the group consisting of

wherein (Q) indicates the site of a covalent bond to part (C) of formula 1 and (N) indicates the site of a covalent bond to N—X of formula 1;

M is selected from the group consisting of —O—, —S— and —NH—;

R 10 and R 11 are independently —H; and

n1, n2, n3, n4, n5, n6 and n7 are independently 1 or 2; and

where X is a monovalent group selected from the group consisting of: —SO 2 —Ar, —SO 2 —CH 3 , —SO 2 —CF 3 , —H, —COH, —CO—CH 3 , —CO—Ar, —CO—R a , —CO—NHR a , —CO—NHAr, —CO—O-tBu, —CO—O—CH 2 —Ar,

the latter hereinafter referred to as part (E);

Ar is an aromatic group, substituted aromatic group or a heteroaromatic group;

a is an integer selected from the group consisting of 0, 1 and 2;

R a is a monovalent group —(CH 2 ) n —CH 3 or —(CH 2 ) n —Ar with n being an integer from 1 to 16;

R 0 , R 1 , R 2 , R 3 and R 4 being independently selected from the group consisting of:

wherein (V) indicates the site of bonding to the attached carbon atom of part (A), part (B), part (C), part (D) or part (E);

R 5 , R 6 1 and R 6 2 each being a monovalent radical independently selected from the group consisting of: —H, —SO 2 —CH 3 , —SO 2 —CF 3 , —COH, —COCH 3 , —CO—Ar, —CO—R a or —CO—NHR a wherein R a is defined as above, —CONHAr, —COO-tBu and —COO—CH 2 —Ar, said radical being or not substituted by at least one monovalent group selected from the group consisting of: —O—CH 3 , —CH 3 , —NO 2 , —NH 2 , —NH—CH 3 , —N(CH 3 ) 2 , —CO—OH, —CO—O—CH 3 , —CO—CH 3 , —CO—NH 2 , OH, F, Cl, Br and I;

R 7 is a monovalent radical selected from the group consisting of:

—H, —COH, —CO—CH 3 , NHOH, NHOR, NHR, —CO—R a wherein R a is defined as above, —CO—Ar and —CO-tBu, said radical being substituted or not by at least one substituent selected from the group consisting of: —O—CH 3 , —CH 3 , —NO 2 , —NH 2 , —NH—CH 3 , —N(CH 3 ) 2 , —CO—OH, —CO—O—CH 3 , —CO—CH 3 , —CO—NH 2 , —OH, —F, —Cl, —Br and —I;

R 8 is a monovalent radical selected from the group consisting of:

—OH, —NH 2 , —OCH 3 , —NHCH 3 , —O-tBu and —O—CH 2 —Ar, said radical being substituted or not by at least one group selected from the group consisting of:

—O—CH 3 , —CH 3 , —NO 2 , —NH—CH 3 , —N(CH 3 ) 2 , —CO—OH, —CO—O—CH 3 , —CO—CH 3 , —CO—NH 2 , —OH, —F, —Cl, —Br and —I;

R 9 is a monovalent radical selected from the group consisting of:

—H, -tBu, —CO—CH 3 , —COAr, —CO—R a wherein R a is defined as above and —COH, said radicals substituted or not by at least one monovalent group selected from the group consisting of:

—O—CH 3 , —CH 3 , —NO 2 , —NH—CH 3 , —N(CH 3 ) 2 , —CO—OH, —CO—O—CH 3 , —CO—CH 3 , —CO—NH 2 , OH, F, Cl, Br and I;

wherein x, y, z and t are integers each independently selected from the group consisting of 0, 1 and 2;

the process comprising the steps of:

a) preparing by coupling a first building block derived from natural or synthetic amino-acids, said first building block being of the formula:

wherein X and R 1 are as defined above, and A, B and C are as defined for part (A), part (B) and part (C) above, respectively;

Sp is

wherein (P) indicates the site of a covalent bond to P, (Q) indicates the site of a covalent bond to C, and P is polystyrene, PEG-polystyrene, polyacrylamide or other solid phase synthesis resin;

b) coupling the first building block prepared in step a) with a second building block hereafter called “tether”, of the formula:

HO-T-PG Z

wherein T refers to part (T) as defined above and PG Z is a protecting group, with the exception that (N) shown above in the definition of part (T) is replaced by (HO) indicating the site of a covalent bond to HO and (Q) shown above in the definition of part (T) is replaced by (PG Z ) indicating the site of a covalent bond to PG Z ; and

c) removing the protection group PG Z from the compound obtained in step b); and

d) carrying out a macrocyclization of the unprotected product obtained in step c) and a cleavage in order to obtain the compound of the formula 1.

2. A process according to claim 1 , wherein part (A), part (B) or part (C) is Arg, the process further comprising the steps of:

a) utilizing a protected ornithine (Orn) residue as a surrogate for Arg,

b) carrying out a selective deprotection of the protecting group on the Orn side chain, and

c) reacting with a protected guanylating reagent to provide the protected Arg element.

3. A process for preparing a library of compounds of formula (8):

comprising the steps of:

a) coupling an amino-acid of the formula (A):

wherein PG α is an amine protecting group, R 3 is defined as in claim 1 and PG 3 is a protecting group, with a compound of the formula:

H-Sp-P

wherein,

Sp is

wherein (P) indicates the site of a covalent bond to P, (H) indicates the site of a covalent bond to H, and P is polystyrene, in order to obtain a compound of the formula (1)

b) removing the amine protection group PGα from the compound of the formula (1) to obtain the corresponding compound of the formula (2):

c) coupling the compound of the formula (2) with another amino-acid of the formula (B):

wherein PGα is defined as above, R 2 is defined as in claim 1 and PG 2 is a protecting group, in order to obtain a compound of the formula (3):

d) removing the amine protection group PGα from the compound of the formula (3) to obtain the corresponding compound of the formula (4):

e) either coupling the compound of the formula (4) with a further amino-acid of the formula (C):

wherein R 1 is defined as in claim 1 , R is CH 3 , Ar, CF 3 or

and PG 1 is a protecting group, in order to obtain a compound of the formula (5):

and coupling said compound of the formula (5) under Mitsunobu conditions with an alcohol of the formula (D):

HO—CH 2 -L-ZPGz  (D)

wherein L is selected from the group consisting of:

and

Z is NH and (Z) indicates the site of a covalent bond to Z of formula (D) and (CH 2 ) indicates the site of a covalent bond to CH 2 of formula (D);

M a is selected from the group consisting of —O—, —S— and —NH—;

R 10a and R 11a are independently —H;

m1, m3, m4, m5, m6 and m7 are independently 1 or 2;

m2 is 0 or 1; and

PG Z is a protecting group, in order to obtain the compound of the formula (6):

or coupling the compound of the formula (4) with a compound of the formula (E):

wherein R, L, R 1 , PG 1 , PG 2 , Z and PG z are defined as above, in order to obtain directly the compound of the formula (6);

f) removing the protecting group PG z from the compound of the formula (6) to obtain the corresponding compound of the formula (7):

and

g) carrying out a macrocyclization of the compound of the formula (7) and a cleavage in order to obtain the compound of the formula (8).

4. A process for preparing a library of compounds of the formula (9), which comprises the process of claim 3 and further comprises removing the protecting group PG 1 , PG 2 and PG 3 of the compound of formula (8) to yield the requested compound of the formula (9):

5. A process for preparing a library of compounds of formula (10):

which comprises the process of claim 3 and further comprises removing the sulfonamide portion of the compound of formula (8) to yield the compound of formula (10).

6. A process for preparing a library of compounds of formula (11):

which comprises the process of claim 5 and further comprises coupling the free amine of the compound of formula (10) with an acid of formula HX, wherein X is as defined in claim 1 , to yield the compound of formula (11).

7. A process for preparing a library of compounds of formula (12):

which comprises the process of claim 6 and further comprises removing the orthogonal protecting groups PG 1 , PG 2 and PG 3 of the compound of formula (11), to yield the compound of formula (12).

8. A process according to any one of claim 1 , 3 , 6 or 7 , wherein each of PG 1 , PG 2 , PG 3 , PG 4 and PG Z have independently the same meanings as the radical R 5 , R 6 1 , R 6 2 , R 7 , R 8 or R 9 as defined in claim 1 .

9. A process according to claim 8 , wherein at least one of PG 1 , PG 2 , PG 3 , PG 4 and PG z is a carbamate or a trityl group.

10. A process according to claim 9 , wherein the carbamate is selected from the group consisting of Boc, Fmoc and Ddz.

11. A process according to claim 9 , wherein the trityl is selected from the group consisting of Trt and Mmt.