# US 11,028,087 B2 · 2,6-disubstituted-9-cyclopentyl-9H-purines, use thereof as medicaments, and pharmaceutical compositions

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- Number: US 11,028,087 B2
- Document ID: US11028087B2
- Status: Granted
- Kind: B2
- Application number: 16/494,650
- Filed: 2018-03-19
- Published: 2020-03-19
- Granted: 2021-06-08
- Earliest claimed: 2017-03-20
- Assignees: Univerzita Palackeho V Olomouci
- Applicants: Univerzita Palackeho V Olomouci
- Inventors: Tomas Gucky; Eva Reznickova; Radek Jorda; Vladimir Krystof; Miroslav Strnad; Tereza Radosova Muchova; Vladimir Divoky
- Web page: https://patentgrep.com/patent/US11028087B2

## CPC

- C07D 473/34: attached in position 6, e.g. adenine
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61P 35/00: Antineoplastic agents
- C07D 487/10: Spiro-condensed systems
- C07D 491/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel 2,6-disubstituted-9-cyclopentyl-9H-purines of general formula I, capable of inhibiting the activity of kinases such as FLT3, CDKs and PDGFRs in cancer and other related proliferative diseases. The invention further includes pharmaceutical compositions containing the 2,6-disubstituted-9-cyclopentyl-9H-purines. Compounds of the present invention can be used as active ingredients of a pharmaceutical compositions for treating acute myeloid leukemia (AML).

## Claims

### Claim 1

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I
wherein R1 is selected from the group consisting of:
and
Q is ═CH— or ═N—;
X is CH2, NH or C═O;
m is 1 or 2 or 3;
n is 1 or 2 or 3;
A is selected from the group consisting of O, N, CH, and C; with the proviso that:
if A is O, then o=p=0 and R2, B and R3 are not present,
if A is N or CH, then R2 is selected from II, CH3, and CH2CH3, and o=p=0 and B and R1 are not present,
if A is C, then R2 is not present, o is 1 or 2 or 3, p is 1 or 2 or 3, and B and R3 are as defined below;
B is selected from O and N, with the proviso that:
if B is O, then R3 is not present,
if B is N, then R3 is selected from H, CH3, and CH2CH3; and
pharmaceutically acceptable salts thereof.

### Claim 2

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I,
wherein R1 is selected from the group consisting of:
and
Q is ═CH— or ═N—;
X is CH2, NH or C═O;
m is 1 or 2 or 3;
n is 1 or 2 or 3;
A is selected from the group consisting of O, N, CH, and C; with the proviso that:
if A is O, then o=p=0 and R2, B and R3 are not present,
if A is N or CH, then R2 is selected from H, CH3, and CH2CH3, and o=p=0 and B and R3 are not present,
if A is C, then R2 is not present, o is 1 or 2 or 3, p is 1 or 2 or 3, and B and R3 are as defined below;
B is selected from O and N, with the proviso that:
if B is O then R1 is not present,
if B is N, then R3 is selected from H, CH3, and CH2CH3; and
pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I according to claim 1, wherein A is O.

### Claim 4 (depends on 1)

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I according to claim 1, wherein X is CH2.

### Claim 5 (depends on 1)

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I according to claim 1, wherein m and/or n and/or o and/or p are 1 or 2, wherein m and n are both identical and/or o and p are both identical.

### Claim 6 (depends on 1)

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I according to claim 1, wherein A is C; m, n, o and p are 1; and B is O or N.

### Claim 7 (depends on 1)

2,6-disubstituted-9-cyclopentyl-9H-purines of the general formula I according to claim 1, wherein the entity of the general formula (II)
is selected from the following substituents:
4-morpholin-4-ylmethyl-phenylamino, 4-piperazin-1-ylmethyl-phenylamino, 4-(4-methyl-piperazin-1-ylmethyl)-phenylamino, 4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino, 4-(2-oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-phenylamino, 4-(2,6-diaza-spiro[3.3]hept-2-ylmethyl)-phenylamino, 4-(6-methyl-2,6-diaza-spiro[3.3]hept-2-ylmethyl)-phenylamino, 4-(6-ethyl-2,6-diaza-spiro[3.3]hept-2-ylmethyl)-phenylamino, 4-morpholin-4-ylcarbonyl-phenylamino, 4-piperazin-1-ylcarbonyl-phenylamino, 4-(4-methyl-piperazin-1-ylcarbonyl)-phenylamino, 4-(4-ethyl-piperazin-1-ylcarbonyl)-phenylamino, 4-(2-oxa-6-aza-spiro[3.3]hept-6-ylcarbonyl)-phenylamino, 4-(2,6-diaza-spiro[3.3]hept-2-ylcarbonyl)-phenylamino, 4-(6-methyl-2,6-diaza-spiro[3.3]hept-2-ylcarbonyl)-phenylamino, 4-(6-ethyl-2,6-diaza-spiro[3.3]hept-2-ylcarbonyl)-phenylimino, 6-morpholin-4-ylmethyl-pyridin-3-ylamino, 6-piperazin-1-ylmethyl-pyridin-3-ylamino, 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamino, 6-(4-ethyl-piperazin-1-ylmethyl)-pyridin-3-ylamino, 6-(2-oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-pyridin-3-ylamino, 6-(2,6-diaza-spiro[3.3]hept-2-ylmethyl)-pyridin-3-ylamino, 6-(6-methyl-2,6-diaza-spiro[3.3]hept-2-ylmethyl)-pyridin-3-ylamino, 6-(6-ethyl-2,6-diaza-spiro[3.3]hept-2-ylmethyl)-pyridin-3-ylamino, 6-morpholin-4-ylcarbonyl-pyridin-2-ylamino, 6-piperazin-1-ylcarbonyl-pyridin-2-ylamino, 6-(4-methyl-piperazin-1-ylcarbonyl)-pyridin-2-ylamino, 6-(4-ethyl-piperazin-1-ylcarbonyl)-pyridin-2-ylamino, 6-(2-oxa-6-aza-spiro[3.3]hept-6-ylcarbonyl)-pyridin-2-ylamino, 6-(2,6-diaza-spiro[3.3]hept-2-ylcarbonyl)-pyridin-2-ylamino, 6-(6-methyl-2,6-diaza-spiro[3.3]hept-2-ylcarbonyl)-pyridin-2-ylamino, and 6-(6-ethyl-2,6-diaza-spiro[3.3]hept-2-ylcarbonyl)-pyridin-2-ylamino.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising at least one 2,6-disubstituted-9-cyclopentyl-9H-purine according to claim 1, optionally in combination with at least one antitumor agent selected from the group consisting of cytosine arabinoside, daunorubicin, doxorubicin, cyclophosphamide, etoposide, carboplatin, fludarabine, mitoxantrone, dexamethasone, rituximab, midostaurin, GCS factor, decitabine, azacitidine, paclitaxel, gemcitabine, motesanib and panitumumab, and further comprising at least one pharmaceutically acceptable carrier.