# US 8,541,607 B2 · Disulfide, sulfide, sulfoxide, and sulfone derivatives of cyclic sugars and uses thereof

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- Number: US 8,541,607 B2
- Document ID: US8541607B2
- Status: Granted
- Kind: B2
- Application number: 12/755,103
- Filed: 2010-04-06
- Published: 2010-08-05
- Granted: 2013-09-24
- Earliest claimed: 2003-10-03
- Assignees: Lacer, S.A.
- Applicants: Jose Repolles Moliner; Eduardo Salas Perez-Rasilla; Francisco Pubill Coy
- Inventors: Jose Repolles Moliner; Eduardo Salas Perez-Rasilla; Francisco Pubill Coy
- Web page: https://patentgrep.com/patent/US8541607B2

## CPC

- C07D 493/04: Ortho-condensed systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 15/10: for impotence
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In the present invention there are disclosed new derivatives of dianhydrohexite mononitrate corresponding to formula (I), tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof: as well as pharmaceutical compositions comprising these compounds and uses thereof.

## Claims

### Claim 1

A method for the treatment of a condition selected from atherosclerosis, endothelial dysfunctions, cardiac allograft vasculopathy, platelet activation, thrombosis, stroke, and/or tissue damage resulting from ischemia or ischemia reperfusion, or symptoms of the above-mentioned conditions, said method comprising administering to a patient a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
n is an integer of 0, 1, or 2,
X represents —S(O)m—, —(C═O)— or a single bond, wherein m is an integer of 0, 1, or 2, with the proviso that when X represents —(C═O)— then n is 0,
R represents hydrogen or is a residue Ra, which residue Ra is selected from the group consisting of:
C1-6 alkyl;
C2-6 alkenyl;
C3-8 cycloalkyl;
C3-8 cycloalkyl, wherein one CH2 group is replaced by O, S, NH or NCH3;
C4-8 cycloalkenyl;
phenyl;
pyridyl;
thiophenyl;
nitrosyl;
S-cysteinyl;
S-glutathionyl; and
wherein R* is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO2 and halogen;
and wherein Ra optionally is substituted by one to three groups independently selected from C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO2 and halogen,
provided that when RXS(O)n — and —ONO2 are trans to each other with respect to the ring plane as depicted in formulae (Ia) and (Ib):
then RXS(O)n— does not represent
wherein Z is an C1-C4 alkyl group, aryl group, or an aralkyl group.

### Claim 2 (depends on 1)

The method according to claim 1 wherein either one or both of m and n is 0.

### Claim 3 (depends on 1)

The method according to claim 1 wherein X represents a single bond or —S—.

### Claim 4 (depends on 1)

The method according to claim 1 wherein R represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, (C1-6 alkyl) C3-8 cycloalkyl, (C1-6 alkyl) C4-8 cycloalkenyl, phenyl or (Cl-6 alkyl) phenyl.

### Claim 5 (depends on 1)

The method according to claim 1 wherein R is C1-6 alkyl.

### Claim 6 (depends on 1)

The method according to claim 1 wherein the compound according to formula (I) is a compound according to formula (Ic) or (Id):

### Claim 7 (depends on 1)

The method according to claim 1 wherein the compound of formula (I) is selected from:
2-thioisosorbide 5-mononitrate,
5, 5′ -dinitrate-2, 2′ -dithiodiisosorbide,
2-methylthioisosorbide 5-mononitrate,
2- [(R) -methylsulfinyl]isosorbide 5-mononitrate,
2- [(S) -methylsulfinyl]isosorbide 5-mononitrate,
2-methylsulfinylisosorbide 5-mononitrate,
2-methylsulfonylisosorbide 5-mononitrate,
S-nitroso-2-thioisosorbide 5-mononitrate,
2- (tetrahydropyran-2-yl-thio) isosorbide 5-mononitrate,
2- (isosorbidyl-2′ -dithio) isosorbide 5-mononitrate, and
2- (5′ -acetyloxyisosorbidyl-2′ -dithio) isosorbide 5-mononitrate.

### Claim 8 (depends on 1)

The method according to claim 1 wherein the compound is 2-acetylthioisosorbide 5-mononitrate, which is represented by the following formula:

### Claim 9 (depends on 1)

The method according to claim 1 which additionally comprises a thrombolytic agent.

### Claim 10 (depends on 9)

The method according to claim 9 wherein the thrombolytic agent is a plasminogen activator.

### Claim 11 (depends on 9)

The method according to claim 9 wherein the thrombolytic agent is urokinase, streptokinase, alteplase or anistreplase.

### Claim 12 (depends on 1)

The method according to claim 1 in which an anticoagulant agent is additionally present.

### Claim 13 (depends on 1)

The method according to claim 1 wherein the anticoagulant agent is heparin, dicoumarol, acenocoumarol, enoxaparine or pentosan polysulfate.

### Claim 14 (depends on 1)

The method according to claim 1 in which an antithrombotic agent is additionally present.

### Claim 15 (depends on 14)

The method according to claim 14 wherein the antithrombotic agents is acetylsalicylic acid, dipyridamole, ticlopidine, clopidrogel, triflusal, pentosan polysulfate or abciximab.

### Claim 16 (depends on 1)

The method according to claim 1 in which an immunoglobulin or a fragment thereof having a specificity for glycoprotein IIb/IIIa is additionally present.

### Claim 17 (depends on 1)

The method according to claim 1 which additionally comprises an hypolipemiant agent.

### Claim 18 (depends on 17)

The method according to claim 17 wherein the hypolipemiant agent is selected from the group consisting of simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, eptastatin, lifibrol, acifran, acitemate, flunicate and rosuvastatin.

### Claim 19 (depends on 1)

The method according to claim 1 in which an antioxidant/free radical scavenger agent is additionally present.

### Claim 20 (depends on 19)

The method according to claim 19 wherein the antioxidant/free radical scavenger agent is selected from the group consisting of nicaraven, ranolazine, emoxipin, glutathione, edaravone, raxofelast, lycopene, N-acetyl-L-cysteine, N-acetyl-D-cysteine, a racemic mixture of N-acetyl-L-cysteine and N-acetyl-D-cysteine, and carvedilol.

### Claim 21 (depends on 1)

The method according to claim 1 wherein the pathological conditions where oxidative stress causes or results in pathogenesis is selected from the group consisting of allergies, stroke, Alzheimer's disease, and ischemic cardiovascular disease.