# US 2014/0193339 A1 · New family of analogues and nadp+ or nadph, their preparation and their application in therapeutics

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- Number: US 2014/0193339 A1
- Document ID: US20140193339A1
- Status: Published application
- Kind: A1
- Application number: 14/128,161
- Filed: 2012-06-19
- Published: 2014-07-10
- Earliest claimed: 2011-06-21
- Assignees: Universite Paris Descartes
- Inventors: Anny Slama-Schwok; Jean-Luc Boucher; Yun Xu-Li; Eric Deprez; Etienne Henry; Chantal Dessy; Olivier Feron; Bogdan Tarus
- Web page: https://patentgrep.com/patent/US20140193339A1

## CPC

- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- A61K 49/00: Preparations for testing in vivo
- C07H 19/16: Purine radicals
- C07H 19/167: with ribosyl as the saccharide radical
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

A new family of analogues of NADP+ or NADPH, their preparation and their application in therapeutics.

## Claims

### Claim 1

Compounds of formula I:
wherein:
(i) X represents an electron acceptor group, chosen from the group comprising:
—NO2,
—CN,
—CHO,
—COOH,
—CF3,
—F,
—CH═C(CN)2,
—SO3H,
—CONR9R10 or SO2NR9R10, in which R9 and R10 represent each independently of each other an hydrogen, a linear or branched (C1-C3) alkyl group, or an aryl group,
—COR9, in which R9 represents an hydrogen, a linear or branched (C1-C3) alkyl group, or an aryl group, or
a tetrazolyl group,
(ii) Y represents an electron donor group, chosen from the group comprising —NR19—, —OC(R19R14)—, or —SC(R19R14)—, in which:
—R19 is chosen from:
a hydrogen,
a linear (C1-C8) alkyl group, in particular an ethyl, said alkyl group being optionally substituted by one or more group selected from: —OH group, —NH2 group, —COOH group, CONH-arylCOOH group or NHCOarylCOOH group or NHCOarylsulfate group, or NHCOarylsulfonate group, wherein the aryl group is chosen from phenyl, naphtyl or biphenyl, or
a hydrosoluble organic group, in particular PEG,
—R14 represents a hydrogen or a linear or branched (C1-C4) alkyl group, optionally substituted by —OH.
(iii) A represents a bond chosen from the group comprising:
(a) —C≡C—, or
wherein:
M1 and M2 represent independently of each other H, F, Cl, Br or I,
n is an integer chosen from 1, 2, or 3,
(iv) R1, R2, R3, R4, R5, R6, R7 or R8 are each independently selected from the group comprising:
—H,
—F, Cl, Br, I,
a linear or branched (C1-C4) alkyl, optionally substituted by one or more substituants chosen from:
—OH,
—NR11R12, in which R11 and R12 represent each independently of each other an hydrogen or a linear or branched (C1-C3) alkyl group, or
—COOR11, in which R11 represents hydrogen or a linear or branched (C1-C3) alkyl group,
—CONHR13 or NHCOR13, in which R13 represents a linear or branched (C1-C4) alkyl group,
(v) L represents a spacer group selected from the group comprising:
wherein m and q represent each independently of each other an integer chosen from 0 to 5, said groups being optionally substituted by one or more OH,
(vi) B represents the following formula II:
wherein:
T represents an oxygen atom, or a sulphur atom, preferably an oxygen atom;
—R16 and R17 represent each independently of each other OH, H2PO4, HSO4, 0PO3(NH4)2, or any salt of these phosphate or sulphate groups
—R18 represents a purine-base or a pyrimidine-base, in particular adenine, guanine, hypoxanthine, thymine, uracil or cytosine, preferably adenine,
under racemate or isomeric forms, in particular axial or equatorial isomeric forms, and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

Compound according to claim 1, of formula (Ia):
wherein:
—R1, R2, R3, R4, R5, R6, R7, R8, X, A, L, T, R16, R17, R18 R19 are as defined above.

### Claim 3 (depends on 1)

Compounds according to claim 1, of formula (Ib):
wherein:
—R1, R2, R3, R4, R5, R6, R7, R8, X, L, n, R16, R17, R18 are as defined in above.

### Claim 4 (depends on 1)

Compounds according to claim 1, of formula (Ic):
wherein:
—R1, R2, R3, R4, R5, R6, R7, R8, X, n, m, R16, R17, R19 are as defined above.

### Claim 5 (depends on 1)

Compounds according to claim 1, of formula (Id):
wherein:
—R16, R17, X, n, m are as defined above.

### Claim 6 (depends on 1)

Compounds according to claim 1, characterised in that when the bond A is represented by
wherein M1 and M2 represent independently of each other H, F, Cl, Br or I, said compound is in cis form and is photoactivable to active trans form.

### Claim 7 (depends on 1)

Compounds according to claim 1, characterised in that when the bond A is represented by
wherein M1 and M2 represent independently of each other H, F, Cl, Br or I, said compound is in biologically active trans form.

### Claim 8 (depends on 1)

A method for treating cancers, comprising administering to a subject in need thereof an effective amount of the compound according to claim 1 as an anti-angiogenic agent in chemotherapy.

### Claim 9 (depends on 1)

A method of diagnosing cancer comprising administering at least one compound according to claim 1, as an imaging agent in cancer diagnostic.

### Claim 10 (depends on 8)

The method according to claim 8, wherein the cancer is a superficial cancer, in particular chosen from melanomas, upper respiratory tract cancers, and upper aerodigestive tract cancers.

### Claim 11 (depends on 1)

Photoactivable composition comprising a compound according to claim 1, when the bond A is represented by
and is under cis form, or bond A is under both cis and trans form, wherein M1 and M2 represent independently of each other H, F, Cl, Br or I.

### Claim 12 (depends on 11)

A method of treating cancer by chemotherapy, comprising administering to a subject in need there of an effective amount of the composition of claim 11.

### Claim 13 (depends on 12)

A method of alleviating one symptom of superficial cancer, comprising administering to a subject in need thereof an effective amount of the composition according to claim 12.

### Claim 14

Method to inhibit an enzyme chosen from nitric oxide synthase, in particular endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, reductases, in particular P450 reductases, catalases and NADHP oxydases comprising the step of:
(a) mixing a compound of formula (Ia), wherein the bond A is represented by
in cis form or cis-trans mixture with a biological sample containing said enzyme,
(b) light irradiating the sample under appropriate conditions to transform the cis form into active compound said trans form.