Salicylic Acid Derivatives

• US 20080293781A1
• Filed: 11/14/2006
• Published: 11/27/2008
• Est. Priority Date: 11/23/2005
• Status: Abandoned Application

• Current Assignee: Nicox SA
• Original Assignee: Nicox SA
• Inventors: Fruttero, Roberta, Donnola, Monica, Gasco, Alberto, Lazzarato, Loretta
• Application Number:
  US12/094,655
• Publication Number:
  US 20080293781A1
• Time in Patent Office: Days
• US Class Current: 514/361
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 203/00 Esters of nitric or nitrous acid
• CPC Class Codes: C07D 271/08 1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles

Abstract

The present invention refers to O-acyl salicylic acid derivatives (I) bearing a NO donor moiety, a process for their preparation and pharmaceutical compositions containing them. (I) wherein: D is ONO₂ or (A).

Claims

1. A compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof:

wherein;

D is —

ONO₂ or wherein V is —

CH₂—

, —

O—

, —

S—

or —

NH—

;

U is C₁-C₁₀ alkyl, optionally substituted with —

OH or —

NH₂, aryl, C₁-C₁₀ alkoxy, aryloxy, C₁-C₁₀ thioalkyl, thioaryl, halogen, di-C₁-C₁₀ (alkylamino), diarylamino, arylC₁-C₁₀ (alkylamino), C₁-C₁₀ (alkylsulphoxy), arylsulphoxy, C₁-C₁₀ (alkylsulphone), arylsulphone, —

CN, —

NO₂, —

NHCOR₀,

—

COR₀, —

COOR₀, —

CON(R₀)(R₁), wherein R₀ and R₁ are the same or different, and are H, alkyl or aryl;

X is a bivalent radical having the following meanings;

a) straight or branched C₁-C₂₀ alkylene, optionally substituted with one or more of the substituents selected from the group consisting of halogen atom, —

OH, —

COOH, —

ONO₂ or T, wherein T is —

OC(O)(C₁-C₁₀ alkyl)-ONO₂ or —

O(C₁-C₁₀ alkyl)-ONO₂;

b) a C₅-C₇ cycloalkylene group optionally substituted with linear or branched C₁-C₁₀ alkyl group;

c)

wherein;

Y is straight or branched C₁-C₂₀ alkylene, or —

CH═

CH—

(CH₂)n²- wherein n is an integer from 0 to 10;

R is H, C1-C₅ alkyl, —

COOH, or —

OR′

wherein R is H or a C₁-C₃ alkyl group;

Z is O, —

C(O)O—

or —

OC(O)—

;

n is 0 or 1;

n¹ is 0 or 1;

X₁ is a straight or branched C₁-C₂₀ alkylene, optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms,

—

OH, —

COOH, —

ONO₂ or X₁ is a group of formula (III)

wherein;

n³ is an integer from 0 to 5;

n⁴ is an integer from 1 to 5;

wherein, the group D of formula (I) is bound to the X₁ group of formula (II), and to the —

(CH₂)n⁴- group of formula (III);

d)

wherein n⁵ is an integer from 1 to 20;

Z₁ is —

C(O)O—

or —

OC(O)—

;

n⁶ is an integer from 0 to 20;

n⁷ is an integer from 1 to 20;

wherein the group D of formula I) is bound to —

(CH2)n⁷- group;

e)

wherein

Q is O or S;

n⁸ is an integer from 1 to 6;

n⁹ is an integer from 1 to 10;

n¹⁰ is an integer from 1 to 10;

f)

n¹¹ is an integer from 0 to 10;

n¹² is an integer from 1 to 10;

R¹, R², R³, R⁴ are the same or different, and they are H or straight or branched C₁-C₄ alkyl;

wherein the D group of formula (I) is linked to

W is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from

2. A compound of formula (I) according to claim 1,

wherein:

X is;

a) straight or branched C₁-C₁₀ alkylene, optionally substituted with one or more of the substituents selected from the group consisting of halogen atom, —

OH, —

COOH, —

ONO₂ or T, wherein T is —

OC(O)(C₁-C₁₀ alkyl)-ONO₂ or —

O(C₁-C₁₀ alkyl)-ONO₂;

c)

wherein;

Y is straight or branched C₁-C₆ alkylene, or —

CH═

CH—

(CH₂)n²- wherein n² is 0 or 1;

R is H, —

CH₃, —

COOH, or —

OR′

wherein R′

is H or —

CH₃;

Z is O, —

OC(O)—

;

n is 0 or 1

n¹ is 0 or 1;

X₁ is a straight or branched C₁-C₁₀ alkylene, optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, —

OH, —

COOH, —

ONO₂ or X₁ is a group of formula (III);

wherein;

n³ is 0 or 1;

n⁴ is 1;

wherein, the group D of formula (I) is bound to the X₁ group of formula (II), and to the —

(CH₂)n⁴- group of formula (III);

d)

wherein n⁵ is an integer from 1 to 10;

Z₁ is —

C(O)O—

or —

OC(O)—

;

n⁶ is an integer from 0 to 10;

n⁷ is an integer from 1 to 10;

wherein the group D of formula I) is bound to —

(CH₂)n⁷- group;

e)

wherein

Q is —

O—

or —

S—

;

n⁸ is an integer from 1 to 4;

n⁹ is an integer from 1 to 6;

n¹⁰ is an integer from 1 to 6;

wherein;

n¹¹ is an integer from 0 to 4;

n¹² is an integer from 1 to 4;

R¹, R², R³, R⁴ are H;

wherein the D group of formula (I) is linked to

W is an heterocyclic ring selected from;

3. A compound of formula (I) according to claim 1,

wherein:

X is;

a) a straight or branched C₁-C₁₀ alkylene, optionally substituted with one or more —

ONO₂ groups;

c)

wherein;

Y is straight or branched C₁-C₆ alkylene, or —

CH═

CH—

(CH₂)n₂- wherein n² is 0 or 1;

R is H or —

OR′

wherein R′

is CH₃;

Z is O or —

OC(O)—

;

n is 0 or 1;

n¹ is 0 or 1;

X₁ is a straight or branched C₁-C₆ alkylene, optionally substituted with one or more —

ONO₂ groups or X₁ is a group of formula (III);

wherein;

n³ is 0 or 1;

n⁴ is 1;

wherein, the group D of formula (I) is bound to the X₁ group of formula (II), and to the —

(CH₂)_n⁴—

group of formula (III);

d)

wherein n⁵ is an integer from 1 to 5;

Z₁ is —

C(O)O—

or —

OC(O)—

;

n⁶ is an integer from 0 to 5;

n 7 is an integer from 1 to 5;

wherein the group D of formula I) is bound to —

(CH2)n⁷- group;

e)

wherein

Q is O;

n⁸ is 1 or 2;

n⁹ is an integer from 1 to 4;

n¹⁰ is an integer from 1 to 2.

4. A compound of formula (I) according to claim 1 selected from the group:

5. A process for preparing a compound of formula (I) according to claim 1, comprising the oxidation of a compound of formula (VIII):

wherein X and D are as defined in claim 1.

6. A compound of general formula (I) according to claim 1 for use as a medicament.

7. Use of a compound according to claim 1 for the preparation of an medicament having anti-inflammatory, antithrombotic and antiplatelet activity.

8. Use of a compound according to claim 1 for the preparation of an medicament for treating inflammation, pain, fever and cardiovascular diseases.

9. Use of a compound according to claim 1 for the preparation of an medicament for preventing or treating cancer diseases.

10. Use of a compound according to claim 9 for the preparation of an medicament for treating colon cancer, bladder cancer, prostate cancer.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) and/or a salt or stereoisomer thereof as defined in claim 1.