3H-phenoxazine derivatives suitable as near-infrared imaging agents, preparation an use thereof

• US 20070031336A1
• Filed: 08/17/2004
• Published: 02/08/2007
• Est. Priority Date: 08/18/2003
• Status: Abandoned Application

• Current Assignee: Hans-Ulrich Gremlich, Martin Hintersteiner, Rainer Kneuer, Willy Kinzy
• Original Assignee: Hans-Ulrich Gremlich, Martin Hintersteiner, Rainer Kneuer, Willy Kinzy, Yves Auberson
• Inventors: Auberson, Yves, Hintersteiner, Martin, Kneuer, Rainer, Kinzy, Willy, Gremlich, Hans-Ulrich
• Application Number:
  US10/568,841
• Publication Number:
  US 20070031336A1
• Time in Patent Office: Days
• US Class Current: 424/9.600
• CPC Class Codes: C07D 513/14 Ortho-condensed systems

Abstract

The present invention provides compounds of formula (I) wherein X and Y represent CH, CH₂ or a divalent or trivalent heteroatom under the proviso that X and Y are not simultaneously CH or CH₂; m and o represent independently of each other 0 or 1, with the proviso that if m is 0 then the dotted line between Y and the neighboring C atom represents a bond and Y is CH or a trivalent heteroatom, if m is 1 then the dotted line between Y and the neighboring C atom is absent and Y is CH₂ or a divalent heteroatom, if o is 0 then the dotted line between X and the neighboring C atom represents a bond and X is CH or a trivalent heteroatom, if o is 1 then the dotted line between X and the neighboring C atom is absent and X is CH₂ or a divalent heteroatom; A represents (CH₃CR₄)_p and Q represents (CR₉R₁₀)_n; n and p represent independently of each other 0 or 1; R₆, R₇, R₁₃ and R₁₄ denote independently of each other hydrogen, halogen, (C_1-4)alkyl, (C_1-4)alkylSO₂, SO₃H, carboxy, (C_1-4)alkoxy carbonyl, (C_1-4)alkoxy, OH or NR₁₅R₁₆; R₁, R₂, R₃, R₄, R₉, R₁₀, R₁₁ and R₁₂ denote independently of each other hydrogen, (C_1-4)alkyl, carboxy, (C_1-4)alkoxy carbonyl or (C_1-4)alkoxy, or, when X is CH or CH₂ then R₁ and R₂ can also be OH or NR₁₅R₁₆, or when Y is CH or CH₂ then R₁₁, R₁₂ can also be OH or NR₁₅R₁₆; R₅, R₈, R₁₅ and R₁₆ are independently of each other hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, R₁₇O—C(O)—(C_1-4)alkyl or (reactive group)-(C_1-4)alkyl; and R₁₇ represents hydrogen or (C_1-4)alkyl; compositions comprising such compounds, a process for the production of such compounds of formula (I), a method of labeling target structures, especially amyloid plaques, in the brain, a method for identifying Alzheimer'"'"'s disease, use of a compound of formula I as a near-infrared imaging agent and a conjugate comprising a compound of formula (I) covalently linked to a biomolecule through a reactive group.

Claims

1. Compounds of formula I

wherein

X and Y represent CH, CH₂ or a divalent or trivalent heteroatom under the proviso that X and Y are not simultaneously CH or CH₂;

m and o represent independently of each other 0 or 1, with the proviso that

if m is 0 then the dotted line between Y and the neighboring C atom represents a bond and Y is CH or a trivalent heteroatom,

if m is 1 then the dotted line between Y and the neighboring C atom is absent and Y is CH₂ or a divalent heteroatom,

if o is 0 then the dotted line between X and the neighboring C atom represents a bond and X is CH or a trivalent heteroatom,

if o is 1 then the dotted line between X and the neighboring C atom is absent and X is CH₂ or a divalent heteroatom;

A represents (CR₃R₄)_p and Q represents (CR₉R₁₀)_n;

n and p represent independently of each other 0 or 1;

R₆, R₇, R₁₃, and R₁₄ denote independently of each other hydrogen, halogen, (C_1-4)alkyl, (C_1-4)alkylSO₂, SO₃H, carboxy, (C_1-4)alkoxy carbonyl, (C_1-4)alkoxy, OH or NR₁₅R₁₆;

R₁, R₂, R₃, R₄, R₉, R₁₀, R₁₁ and R₁₂ denote independently of each other hydrogen, (C_1-4)alkyl, carboxy, (C_1-4)alkoxy carbonyl or (C_1-4)alkoxy, or, when X is CH or CH₂ then R₁ and R₂ can also be OH or NR₁₅R₁₆, or when Y is CH or CH₂ then R₁₁, R₁₂ can also be OH or NR₁₅R₁₆;

R₅, R₈, R₁₅ and R₁₆ are independently of each other hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, R₁₇OC(O)—

(C_1-4)alkyl or (reactive group)-(C_1-4)alkyl; and

R₁₇ represents hydrogen or (C_1-4)alkyl;

in free base or acid addition salt form.

2. A compound of formula I according to claim 1 in free base or acid addition salt form wherein X is O, S or CH₂ and Y is O, S or CH₂ with the proviso that X and Y are not both simultaneously CH₂.

3. A compound of formula I according to claim 1 wherein said compound is selected from

4,8-dimethyl-2,3,4,9,10,11-hexahydro-1,6-dioxa-4,13-diaza-8-azonia-pentacen chloride;

8-ethyl-4-methyl-2,3,4,9,10,11-hexahydro-1,6-dioxa4,13-diaza-8-azonia-pentacen chloride;

4,8-dimethyl-3,8,9,10-tetrahydro-2H-1,6,11-trioxa-8,13-diaza-4-azonia-pentacen tetrafluoroborate;

4,8-dimethyl-2,3,9,10-tetrahydro-4H-1,6-dioxa-11-thia-4,13-diaza-8-azonia-pentacen chloride; and

8-(3-ethoxycarbonyl-propyl)-4-methyl-3,8,9,10-tetrahydro-2H-1,6,11-trioxa-8,13-diaza-4-azonia-pentacen chloride.

4. A composition comprising a compound according to of claim 1 and a pharmaceutically acceptable excipient or diluent.

5. A process for the production of a compound of formula I or a salt thereof, comprising the steps of reacting a phenol derivative of formula III

wherein the radicals and symbols A, X, R₁, R₂, R₅, R₆, R₁₄ and o have the meanings as defined in claim 1 for a compound of formula I, with a nitroso or diazo compound of formula IV

wherein the radicals and symbols Q, Y, R₇, R₈, R₁₁, R₁₂, R₁₃ and m have the meanings as defined in claim 1 for a compound of formula I, R₁₈ represents oxo or p-nitrophenyl-N═

and R₁₉ represents hydroxy;

and recovering the resulting compound of formula I in free base form or in form of an acid addition salt.

10. Use of a compound of formula I according to claim 1 in free base or acid addition salt form as a near-infrared imaging agent.

12. Use according to claims 10 as a near-infrared imaging agent to image amyloid plaques.

13. A conjugate comprising a compound of formula I according to claim 1 covalently linked to a biomolecule through a reactive group.

14. A conjugate according to claim 13 wherein the biomolecule is selected from the group consisting of nucleoside, nucleotide, oligonucleotide, nucleic acid, protein, peptide, amino acid, polysaccharide, oligosaccharide, monosaccharide, drug or a small molecule having a molecular weight of less than 500.

15. A conjugate according to claim 13 capable of being detected using near-infrared radiation.

6. A method of labeling target structures in the brain comprising:

(i) applying a composition comprising a compound of formula I

wherein

X and Y represent CH, CH₂ or a divalent or trivalent heteroatom under the proviso that X and Y are not simultaneously CH or CH₂;

m and o represent independently of each other 0 or 1, with the proviso that

if m is 0 then the dotted line between Y and the neighboring C atom represents a bond and Y is CH or a trivalent heteroatom,

if m is 1 then the dotted line between Y and the neighboring C atom is absent and Y is CH₂ or a divalent heteroatom,

if o is 0 then the dotted line between X and the neighboring C atom represents a bond and X is CH or a trivalent heteroatom,

if o is 1 then the dotted line between X and the neighboring C atom is absent and X is CH₂ or a divalent heteroatom;

A represents (CR₃R₄)_p and Q represents (CR₉R₁₀)_n;

n and p represent independently of each other 0 or 1;

R₆, R₇, R₁₃, and R₁₄ denote independently of each other hydrogen, halogen, (C_1-4)alkyl, (C_1-4)alkylSO₂, SO₃H, carboxy, (C_1-4)alkoxy carbonyl, (C_1-4)alkoxy, OH or NR₁₅R₁₆;

R₁, R₂, R₃, R₄, R₉, R₁₀, R₁₁ and R₁₂ denote independently of each other hydrogen, (C_1-4)alkyl, carboxy, (C_1-4)alkoxy carbonyl or (C_1-4)alkoxy, or, when X is CH or CH₂ then R₁ and R₂ can also be OH or NR₁₅R₁₆, or when Y is CH or CH₂ then R₁₁, R₁₂ can also be OH or NR₁₅R₁₆;

R₅, R₈, R₁₅ and R₁₆ are independently of each other hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, R₁₇OC(O)—

(C_1-4)alkyl or (reactive group)-(C_1-4)alkyl; and

R₁₇ represents hydrogen or (C_1-4)alkyl;

in free base or acid addition salt form,

or of formula II

wherein

R₆, R₇, R₁₃, and R₁₄ denote independently of each other hydrogen, halogen, (C_1-4)alkyl, (C_1-4)alkylSO₂, SO₃H, carboxy, (C_1-4)alkoxy carbonyl, (C_1-4)alkoxy, OH or NR₁₅R₁₆, and

R₂₁ and R₂₂ are hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, phenyl, phenylalkyl, carboxy or halogen;

R₁₄ and R₂₂ together with the carbon atoms to which they are attached can also form a saturated or unsaturated ring;

R₂₁ and R₁₃ together with the carbon atoms to which they are attached can also form a saturated or unsaturated ring;

R₅, R₈, R₂₀ and R₂₃ are hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, polyoxyhydrocarbyl, phenyl, phenylalkyl;

R₈ and R₂₀ together with the nitrogen atom to which they are attached can form a saturated or unsaturated ring,

R₂₃ and R₅ together with the nitrogen atom to which they are attached can form a saturated or unsaturated ring,

R₂₂ and R₂₃ together with the atoms to which they are attached can form a saturated or unsaturated ring,

R₅ together with R₆ together with the atoms to which they are attached can form a saturated or unsaturated ring,

R₇ together with R₈ together with the atoms to which they are attached can form a saturated or unsaturated ring,

R₂₀ together with R₂₁ together with the atoms to which they are attached can form a saturated or unsaturated ring,

(ii) allowing sufficient time for said compound to be chemically associated with the target structure in the brain, and

(iii) detecting said compound using near-infrared radiation.

7. The method according to claim 6 wherein said target structures are amyloid plaques.

8. The method according to claim 7 for identifying diseases related to amyloid plaque generation and/or aggregation.

9. The method according to claim 7 for identifying Alzheimer'"'"'s disease.

11. Use of a compound of formula II as defined in claim 6 as a near-infrared imaging agent.