Substituted heteropentadieno-pyrrolopyrimidine ribonucleosides for therapeutic use

Patent metadata

Field	Value
Publication number	US-10730905-B2
Application number	US-201716308796-A
Country	US
Kind code	B2
Filing date	Jul 31, 2017
Priority date	Aug 2, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

Substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I, where R is selected from the group comprising furan-2-yl, furan-3-yl, benzofuran-2-yl, methylsulfanyl, methoxy, amino, dimethylamino, methyl or chloro, and pharmaceutically acceptable salt thereof, their optical isomers and mixtures of such optical isomers.

First claim

The invention claimed is:

1. 4-Substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I:

wherein
R is selected from the group consisting of:
C1-C5 alkyl, optionally substituted by at least one substitutent selected from hydroxy, sulfanyl, amino, C1-C5 alkoxy, C1-C5 sulfanyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino;
C2-C6 alkenyl, optionally substituted by at least one substitutent selected from hydroxy, sulfanyl, amino, C1-C5 alkoxy, C1-C5 sulfanyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino;
C6-C12 aryl, optionally substituted by at least one substitutent selected from C1-C5 alkyl, hydroxy, sulfanyl, amino, C1-C5 alkoxy, C1-C5 sulfanyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino;
C4-12 heteroaryl, comprising at least one O atom; optionally substituted by at least one substitutent selected from C1-C5 alkyl, hydroxy, sulfanyl, amino, C1-C5 alkoxy, C1-C5 sulfanyl, C1-C5 alkylamino, di(C1-C5 alkyl)amino;
amino,
C1-C5 alkylamino,
di(C1-C5 alkyl)amino,
C1-C5 alkoxy,
C1-C5 alkylsulfanyl, and
halogen; and

—X— is selected from —O—, —NH— and N(C1-C5 alkyl)-;
or pharmaceutically acceptable salt thereof, their optical isomers, or mixtures or racemic mixtures of such optical isomers.

2. 4-Substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I according to claim 1 , where R is selected from the group consisting of C1-C5 alkyl, phenyl, naphthyl, 2-furyl, 3-furyl, benzofuryl, dibenzofuryl, C1-C5 alkylsulfanyl, amino, C1-C5 alkylamino, di(C1-C5 alkyl)amino, C1-C5 alkoxy and halogen group.

3. 4-Substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I according to claim 1 , where R is selected from the group consisting of furan-2-yl, furan-3-yl, benzofuran-2-yl, methylsulfanyl, methoxy, amino, dimethylamino, methyl and chloro.

4. 4-Substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I according to claim 1 , being selected from the following compounds:
4-methyl-8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-methoxy-8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-(methylsulfanyl)-8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-amine,
4-(furan-2-yl)-8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-(furan-3-yl)-8-(β-D-ribofuranosyl)-8H-furo [2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-(benzofuran-2-yl)-8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
N,N-dimethyl-8-(β-D-ribofuranosyl)-8H-furo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-amine,
4,5-dimethyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-methoxy-5-methyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
5-methyl-4-(methylsulfanyl)-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
5-methyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-amine,
4-(furan-2-yl)-5-methyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-(furan-3-yl)-5-methyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
4-(benzofuran-2-yl)-5-methyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine,
N,N,5-trimethyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidin-4-amine, and
4-chloro-5-methyl-8-(β-D-ribofuranosyl)-5,8-dihydropyrrolo[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine.

5. A method of inhibition of pathological cell proliferation comprising the step of providing 4-substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I according to claim 1 to a subject in need thereof.

6. A method of treatment of tumor diseases selected from the group consisting of lung cancer, leukemia, colon cancer and bone cancer comprising the step of providing 4-substituted heteropentadieno-pyrrolopyrimidine ribonucleosides of general formula I according to claim 1 to a subject in need thereof.

7. A pharmaceutical composition characterised in that it comprises a therapeutically effective amount of at least one compound of general formula I according to claim 1 , and optionally also at least one pharmaceutically acceptable carrier, filles and/or excipient.

8. A pharmaceutical composition according to claim 7 for use in inhibition of pathological cell proliferation of tumor/non-tumor origin and/or for treatment of tumor/non tumor disease associated with cell hyperproliferation.

Assignees

• Ustav Organicke Chemie A Biochemie Av Cr V V I
• Univ Palackeho

Inventors

• Hocek Michal
• Tokarenko Anna
• Smolen Sabina
• Hajduch Marian
• Dzubak Petr

Classifications

• C07H19/24

  Heterocyclic radicals containing oxygen or sulfur as ring hetero atom · CPC title

• C07H19/23 Primary

  Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22 · CPC title

• A61P35/02

  specific for leukemia · CPC title