IP Library › Granted Patent US 8,822,442
Granted Patent B2
US 8,822,442 · App. 11/262,403 · Granted Sep 2, 2014

Somatostatin-dopamine chimeric analogs

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Quick Facts
Patent No.
US 8,822,442
App. No.
11/262,403
Granted
Sep 2, 2014
Kind
B2
Abstract

The invention features somatostatin-dopamine chimeric analogs and methods relating to their therapeutic use for the treatment of neoplasia, acromegaly, and other conditions.

Claims (285)

1. A chimeric analog comprising formula (I),

wherein:

X is H, Cl, Br, I, F, —CN, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, or substituted C 2-10 alkynyl;

R1 is H, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, substituted C 2-10 alkynyl, or —CN;

R2 and R3, each is, independently, H or absent, provided that when R2 and R3 are absent a double bond is present between the carbon atoms to which they are attached;

R4 is H, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, or substituted C 2-10 alkynyl;

Y is —O—, —C(O)—, —S—, —S—(CH 2 ) s —C(O)—, —S(O)—, —S(O) 2 —, —SC(O)—, —OC(O)—, —N(R5)-C(O)—, or —N(R6)-;

L is —(CH 2 ) p —C(O)—, when Y is —S—, —S(O)—, —S(O) 2 —, —O— or —N(R6)-; or L is —C(O)—(CR7R8) q -C(O)—, when Y is —N(R6)-, —O—, or —S—; or L is (amino acid) t , when Y is —C(O)—, SC(O)—, —OC(O)—, —S—(CH 2 ) s —C(O)—, or —N(R5)-C(O)—;

W is —CR9, R10-

R5 and R6 each is, independently, H, C 1-10 alkyl, substituted C 1-10 alkyl; C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, aryl, alkylaryl, or substituted alkylaryl;

R7, R8, R9, and R10 each is, independently, H, F, Cl, Br, I, C 1-10 alkyl, substituted C 1-10 alkyl; C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, aryl, alkylaryl, or substituted alkylaryl; or R7 and R8 can, optionally, join together to form a ring system; or R9 and R10 can, optionally, join together to form a ring system;

i is 2-10;

m is 0 or 1;

n is 0-10;

p is 1-10;

q is 1-5;

s is 1-10;

t is 1-10;

Z is a somatostatin analog selected from the group consisting of:

DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ;

DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ;

cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ;

DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ; and

DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

or a pharmaceutically acceptable salt thereof; and

wherein each moiety depicted between the brackets is, independently for each occurrence, attached to an N-terminal or an internal amine group, carboxylic acid group, or hydroxyl group of Z.

2. A chimeric analog comprising formula (II),

wherein:

X is H, Cl, Br, I, F, —CN, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, or substituted C 2-10 alkynyl;

R1 is H, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, substituted C 2-10 alkynyl, or —CN;

R2 and R3, each is, independently, H or absent, provided that when R2 and R3 are absent a double bond is present between the carbon atoms to which they are attached;

R4 is H, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, or substituted C 2-10 alkynyl;

R5 is H, C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl, substituted C 1-10 alkyl, substituted C 1-10 heteroalkyl, substituted C 2-10 alkenyl, substituted C 2-10 alkynyl, or a group of the formula of —(CH 2 ) r N(R11,R12);

Y is —O—, —C(O)—, —S—, —SC(O)—, —OC(O)—, —N(R6)-C(O)—, —N(R7)-, or —N(R8)-(CH 2 ) s —C(O)—;

L is —(CH 2 ) p —C(O)—, when Y is —S—, —O— or —N(R7)-; or L is —C(O)—(CR9R10) q -C(O)—, when Y is —N(R7)-, —O—, or —S—; or L is (amino acid) t , when Y is —C(O)—, SC(O)—, —OC(O)—, —N(R8)-(CH 2 ) s —C(O)—, or —N(R6)-C(O)—;

W is —CR9, R10-;

R6, R7, and R8 each is, independently, H, C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, aryl, alkylaryl, or substituted alkylaryl;

R9, and R10 each is, independently, H, Cl, Br, I, F, C 1-10 alkyl, substituted C 1-10 alkyl; C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, aryl, alkylaryl, or substituted alkylaryl; or R9 and R10 can, optionally, join together to form a ring system;

R11, and R12 each is, independently, H, C 1-10 alkyl, substituted C 1-10 alkyl; C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, aryl, alkylaryl, or substituted alkylaryl;

i is 2-10;

m is 0 or 1;

n is 2-10;

p is 1-10;

q is 1-5;

r is 1-8;

s is 1-10;

t is 1-10;

v is 2-4;

Z is a somatostatin analog selected from the group consisting of:

DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ;

DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ;

cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ;

DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ; and

DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

or a pharmaceutically acceptable salt thereof; and

wherein each moiety depicted between the brackets is, independently for each occurrence, attached to an N-terminal or an internal amine group, carboxylic acid or hydroxyl group of Z.

3. The chimeric analog of claim 1 or claim 2 , wherein said chimeric analog comprises a compound according to the formula of:

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Aepa-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Aepa-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-DLys(Dop3)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-DLys(Dop3)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-DLys(Dop3)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-DLys(Dop3)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop3-DLys(Dop3)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-Lys(Dop4)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-Lys(Dop4)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-Lys(Dop4)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-Lys(Dop4)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-Lys(Dop4)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-DLys(Dop4)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-DLys(Dop4)-Aepa-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-DLys(Dop4)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-DLys(Dop4)-Lys-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop4-DLys(Dop4)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DPhe-cyclo[Cys-3ITyr(Dop1)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop1-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop1)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop1-DLys(Dop1)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop1-Lys(Dop1)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Aepa-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2

Dop2-Lys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Aepa-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Lys-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-DLys(Dop2)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop4-Lys(Dop4)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop3-Lys(Dop3)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 , or

Dop4-Lys(Dop4)-Aepa-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

or a pharmaceutically acceptable salt thereof.

4. A method of eliciting a dopamine receptor agonist effect in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a chimeric analogue, wherein said chimeric analogue comprises a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof; and wherein said effective amount is the amount effective to elicit a dopamine receptor agonist effect in said subject.

5. The method of claim 4 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 , or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ; or

a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2

or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ; or

a pharmaceutically acceptable salt thereof.

8. A method of eliciting a somatostatin receptor agonist effect in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a chimeric analogue, wherein said chimeric analogue comprises a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof; and wherein said effective amount is the amount effective to elicit a somatostatin receptor agonist effect in said subject.

9. The method of claim 8 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 , or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2

or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ;

a pharmaceutically acceptable salt thereof.

12. A method of eliciting both a dopamine receptor agonist effect and a somatostatin receptor agonist effect in a subject in need thereof, wherein said method comprises administering to said subject an effective amount of a chimeric analogue, wherein said chimeric analogue comprises a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof; and wherein said effective amount is the amount effective to elicit a dopamine receptor agonist effect and a somatostatin receptor effect in said subject.

13. The method of claim 12 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-Dtyr-Dtyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 , or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ; or

a pharmaceutically acceptable salt thereof.

14. The method of claim 13 , wherein said chimeric analogue comprises a compound according to the formula of

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein said chimeric analogue comprises a compound according to the formula of

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2;

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof; and

in a pharmaceutically acceptable carrier, wherein said effective amount is the amount effective to elicit a dopamine receptor agonist effect or a somatostatin receptor agonist effect or both in a subject in need thereof.

17. The pharmaceutical composition of claim 16 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 , or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH 2 ;

or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 17 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2

or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 18 , wherein said chimeric analogue comprises a compound according to the formula of:

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH 2 ;

a pharmaceutically acceptable salt thereof.

20. A method of treating a neuroendocrine tumor in a subject, said method comprising administering to said subject a therapeutically effect amount of a chimeric analog, wherein said chimeric analog comprises a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2, or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof;

wherein said therapeutically effective amount is the amount effective to treat said neuroendocrine tumor in said subject.

21. The method of claim 20 , wherein said neuroendocrine tumor is a neuroendocrine tumor of the pituitary.

22. The method of claim 21 , wherein said neuroendocrine tumor of the pituitary is a growth hormone producing tumor.

23. The method of claim 22 , wherein the condition of said growth hormone producing tumor is acromegaly.

24. The method of claim 21 , wherein said neuroendocrine tumor of the pituitary is a prolactin-producing tumor.

25. The method of claim 21 , wherein the condition of said neuroendocrine tumor of the pituitary is a prolactinoma.

26. The method of claim 24 , wherein the condition of said prolactin-producing tumor or prolactinoma is hyperprolactinemia.

27. A method of treating acromegaly in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effect amount of a chimeric analog, wherein said chimeric analog comprises a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2, or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof; and wherein said therapeutically effective amount is the amount effective to treat acromegaly in said subject.

28. A method of treating hyperprolactinemia in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effect amount of a chimeric analog, wherein said chimeric analog comprises a compound according to the formula of:

a compound according to claim 1 or claim 2 ;

or a pharmaceutically acceptable salt thereof; or

Dop2-DPhe-Doc-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,

Dop2-DPhe-cyclo[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DTyr-DTyr-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,

Dop2-Lys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2, or

Dop2-DLys(Dop2)-DPhe-cyclo[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,

or a pharmaceutically acceptable salt thereof; or an organic or inorganic salt thereof; and wherein said therapeutically effective amount is the amount effective to treat said hyperprolactinemia in said subject.

Assignments (3)
CHANGE OF NAME Recorded Feb 11, 2009
From: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
To: IPSEN PHARMA S.A.S.
Reel/Frame 022240/0332 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 17, 2006
From: BIOMEASURE, INCORPORATED
To: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
Reel/Frame 017782/0249 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 5, 2006
From: DONG, ZHENG XIN; CULLER, MICHAEL DEWITT; SHEN, YEELANA
To: BIOMEASURE, INCORPORATED
Reel/Frame 017760/0101 →