TRANYLCYPROMINE DERIVATIVES AS INHIBITORS OF HISTONE DEMETHYLASES LSD1 AND/OR LSD2

• US 20130035377A1
• Filed: 04/15/2011
• Published: 02/07/2013
• Est. Priority Date: 04/20/2010
• Status: Active Grant

• Current Assignee: Fondazione Ieo, Universita' Degli Studi Di Milano (Repubblica Italiana)
• Original Assignee: Fondazione Ieo, Universita' Degli Studi Di Milano (Repubblica Italiana), Universita' Degli Studi Di Pavia (Repubblica Italiana), Universita' Degli Studi Di Roma La Sapienza (Repubblica Italiana)
• Inventors: Minucci, Saverio, Mai, Antonello, Mattevi, Andrea
• Granted Patent: US 8,765,820 B2
• Time in Patent Office: Days
• US Class Current: 514/443
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07C 233/44 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/80 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/26 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07D 333/60 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Tranylcypromine derivatives useful as therapeutic agents, particularly for the prevention and/or treatment of diseases and conditions associated with the activity of histone demethylases LSD1 and LSD2, such as the diseases characterized by deregulation of gene transcription, cell differentiation and proliferation, e.g. tumors, viral infections, are herein described. These compounds belong to the structural formula (I) wherein A and R₃ are as defined in the specification. The invention also relates to the preparation of these compounds, as well as to compositions containing them and to therapeutic use thereof.

Claims

1. A compound of the general formula (I)

2. The compound as claimed in claim 1, wherein:

A is R; and

R₃ is H.

3. The compound as claimed in claim 2, wherein:

R is alkyl, aryl, arylalkyloxy, arylalkyl, or any of which may be optionally substituted.

4. The compound as claimed in claim 1, wherein:

A is CH(R₁)—

NH—

CO—

R₂; and

R₃ is H.

5. The compound as claimed in claim 1, wherein:

A is CH(R₁)—

NH—

CO—

R₂; and

R₃ is —

CH₃.

6. The compound as claimed in claim 4, wherein, independently or in any combination:

R₁ is alkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or any of which may be optionally substituted; and

R₂ is arylalkyloxy, heteroarylalkyloxy, arylalkylamino, or any of which may be optionally substituted.

7. The compound of claim 1, belonging to the following group:

trans benzyl 4-(2-aminocyclopropyl)phenylcarbamate;

trans N-(4-(2-aminocyclopropyl)phenyl)benzamide;

trans N-(4-(2-aminocyclopropyl)phenyl)-1-naphthamide;

trans N-(4-(2-aminocyclopropyl)phenyl)-2-naphthamide;

trans N-(4-(2-aminocyclopropyl)phenyl)biphenyl-4-carboxamide;

trans N-(4-(2-aminocyclopropyl)phenyl)-2-phenylacetamide;

trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-1-yl)acetamide;

trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-2-yl)acetamide;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-methyl-1-oxobutan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-methyl-1-oxopentan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate;

trans benzyl 2-(4-(2-aminocyclopropyl)phenylamino)-2-oxo-1-phenylethylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(4-bromophenyl)-1-oxopropan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(4-methoxyphenyl)-1-oxopropan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-4-phenylbutan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3,3-diphenylpropan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(naphthalen-1-yl)-1-oxopropan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-(1H-indol-3-yl)-1-oxobutan-2-ylcarbamate;

trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-(benzo[b]thiophen-3-yl)-1-oxobutan-2-ylcarbamate;

trans 4-bromobenzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate;

cis benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate;

trans N¹-(4-(2-aminocyclopropyl)phenyl)-N⁸-hydroxyoctanediamide;

trans benzyl 1-((4-(2-aminocyclopropyl)phenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate;

trans N-(4-(2-aminocyclopropyl)phenyl)-2-(3-benzylureido)-3-phenylpropanamide;

or a isomer, tautomer, racemic form, enantiomer, diastereomer, epimer, polymorph, solvate, mixtures thereof, prodrug, or pharmaceutically acceptable salts thereof.

8. Process for the preparation of a compound of general formula (I) as defined in claim 1, wherein A is R, the process comprising:

(a) reacting a compound of formula (II) with an acylating agent to give a compound of formula (III)

9. Process for the preparation of a compound of general formula (I), as claimed in claim 1, wherein A is CH(R₁)—

NH—

CO—

R₂, the process comprising;

(a) reacting a compound of formula (II) with an acylating agent to give a compound of formula (IV)

10. The compound according to claim 1 being an inhibitor of LSD1 and/or LSD2 histone demethylase.

18. A method for preventing and/or treating diseases and conditions associated with the activity of histone demethylase LSD1 and/or LSD2, in particular tumors or viral infections, by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of general formula (I) as defined in claim 1.

19. The method of claim 18 wherein the diseases are selected from the group consisting of neuroblastoma, prostate cancer, breast cancer, bladder cancer, lung cancer, colorectal cancer, acute myeloid leukemia, T-lineage acute lymphoblastic leukemia and Herpes Simplex Virus infection.

20. A pharmaceutical composition comprising an effective amount of one or more compounds of general formula (I), according to claim 1, alone or in combination with other active compounds, and at least one pharmaceutically acceptable excipient.

21. The pharmaceutical composition of claim 20 being formulated in unit dosage form.

11-17. -17. (canceled)