Synthesis and composition of rapafucin libraries

Abstract

A Rapafucin library containing compounds of the general structure, (A) and (E), and a synthesis of these compounds are provided. ##STR00001##

Claims

1. A compound of Formula I: ##STR00019## or a pharmaceutically acceptable salt thereof, wherein: R is ##STR00020## R.sup.1, R.sup.4, and R.sup.5 are each hydrogen, R.sup.2 and R.sup.3 are each methoxy; m=0: X.sub.1 is O or NR.sup.6; Y is ##STR00021## X.sub.2 is O or NR.sup.6C(O); R.sup.6 is hydrogen or alkyl; Z is ##STR00022## L.sub.1 is CH.sub.2C(O) or (CH.sub.2).sub.2C(O); L.sub.2 is OCOCHCH(CH.sub.2).sub.2N(Me)-; L.sub.3 is CH.sub.2CH.sub.2; and the effector domain has the structure of formula (VIII)
-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-(VIII) wherein AA.sub.1, AA.sub.2, AA.sub.3 and AA.sub.4 are each independently selected from ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##

2. The compound of claim 1, wherein X.sub.2 is O and L.sub.1 is CH.sub.2C(O).

3. The compound of claim 1, wherein X.sub.2 is NR.sup.6C(O) and L.sub.1 is (CH.sub.2).sub.2C(O).

4. The compound according to claim 1, with the following formula ##STR00028## wherein the Effector domain -AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4- (VIII) is selected from the group consisting of TABLE-US-00002 Compound Name -AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4- Sequence A15-39-1 Gly-dmPhe-Pro-mVal A15-39-2 Ala-dmPhe-Pro-mVal A15-39-4 Nva-dmPhe-Pro-mVal A15-39-6 Leu-dmPhe-Pro-mVal A15-39-8 Phe-dmPhe-Pro-mVal A15-39-15 Phg-dmPhe-Pro-mVal A15-40-2 Ala-dmPhe-Pro-mlle A15-40-4 Nva-dmPhe-Pro-mlle A15-40-15 Phg-dmPhe-Pro-mlle A15-34-2 Ala-dmPhe-Pro-mLeu.

5. The compound according to claim 1, with the following formula ##STR00029## wherein the Effector domain -AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4- (VIII) is selected from the group consisting of TABLE-US-00003 Compound Name -AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4- Sequence E15-39-1 Gly-dmPhe-Pro-mVal E15-39-2 Ala-dmPhe-Pro-mVal E15-39-5 HoSMe-dmPhe-Pro-mVal E15-40-2 Ala-dmPhe-Pro-mlle E15-40-4 Nva-dmPhe-Pro-mlle E15-32-2 Ala-dmPhe-Pro-mAla E15-33-1 Gly-dmPhe-Pro-mNIe E15-33-2 Ala-dmPhe-Pro-mNIe E15-34-1 Gly-dmPhe-Pro-mLeu E15-34-2 Ala-dmPhe-Pro-mLeu E15-S-19 Gly-dmPhe-Pro-mNva E15-S-21 Gly-dmPhe-Pro-dmAla E15-S-22 Gly-dmPhe-Pro-Ach.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1. Number of compounds in library.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(2) ##STR00007## ##STR00008##

(3) R.sub.1 and R.sub.3 in Scheme 1 are amino acids selected from the following group of amino acids:

(4) ##STR00009## ##STR00010##

(5) R.sub.2 and R.sub.4 in Scheme 1 are amino acids selected from the following group of amino acids:

(6) ##STR00011##

(7) The synthesis of the amide mFKBD in Scheme 1 is as follows:

(8) ##STR00012## ##STR00013## ##STR00014##

(9) The synthesis of the ether mFKBD in Scheme 1 is as follows:

(10) ##STR00015## ##STR00016##

(11) The general formula for a Rapafucin with an amide mFKBD is represented by A.

(12) ##STR00017##

(13) The general formula for a Rapafucin with an ether mFKBD is represented by E.

(14) ##STR00018##

(15) Specific Examples of A and E as well as their properties are listed in Table 1.

(16) TABLE-US-00001 TABLE 1 Name Sequence Hillslope IC50(nM) Name Sequence Hillslope IC50(nM) A15-39-1 Gly-dmPhe- 0.9753 27.95 E15-40-2 Ala-dmPhe- 1.212 34.15 Pro-mVal Pro-mlle A15-39-2 Ala-dmPhe- 1.164 23.73 E15-40-4 Nva-dmPhe- 1.195 173.1 Pro-mVal Pro-mlle A15-39-4 Nva-dmPhe- 1.112 18 E15-32-2 Ala-dmPhe- 1.134 66.71 Pro-mVal Pro-mAla A15-39-6 Leu-dmPhe- 1.105 54.14 E15-33-1 Gly-dmPhe- 1.007 13.91 Pro-mVal Pro-mNIe A15-39-8 Phe-dmPhe- 1.191 54.99 E15-33-2 Ala-dmPhe- 1.017 9.76 Pro-mVal Pro-mNIe A15-39-15 Phg-dmPhe- 0.8952 16.51 E15-34-1 Gly-dmPhe- 1.494 28.54 Pro-mVal Pro-mLeu E15-39-1 Gly-dmPhe- 1.024 48.88 E15-34-2 Ala-dmPhe- 0.741 10.53 Pro-mVal Pro-mLeu E15-39-2 Ala-dmPhe- 1.125 33.54 A15-34-2 ** Ala-dmPhe- 0.3876 31.45 Pro-mVal Pro-mLeu E15-39-5 HoSMe- 0.8614 59.46 E15-S-19 Gly-dmPhe- 1.363 42.27 dmPhe-Pro- Pro-mNva mVal A15-40-2 Ala-dmPhe- 0.6276 34.4 E15-S-21 Gly-dmPhe- 1.314 154.9 Pro-mlle Pro-dmAla A15-40-4 Nva-dmPhe- 0.87 12.19 E15-S-22 Gly-dmPhe- 1.236 261.9 Pro-mlle Pro-Ach A15-40-15 Phg-dmPhe- 0.9138 100.1 Pro-mlle

(17) Approximately, 45,000 compounds were obtained as part of the Rapafucin library (FIG. 1).

(18) Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

REFERENCES

(19) The following reference is relied upon and incorporated herein in its entirety. 1. US 2014/0073581.