WO2019089618A1

WO2019089618A1 - Lipoic acid derivatives containing thiosulphates and methods of treating sepsis and sepsis related conditions using the same

Info

Publication number: WO2019089618A1
Application number: PCT/US2018/058244
Authority: WO
Inventors: Nagesh R. Palepu; Philip C. Buxton; Jay Pravda
Original assignee: Theranomic Biopharma Llc
Priority date: 2017-11-01
Filing date: 2018-10-30
Publication date: 2019-05-09

Abstract

Lipoic acid derivative compounds containing thiosulphates, methods of preparing the same as well methods of treating conditions associated with oxidative stress such as sepsis and related conditions and/or ulcerative colitis using the same are disclosed.

Description

LIPOIC ACID DERIVATIVES CONTAINING THIOSULPHATES AND METHODS OF TREATING SEPSIS AND SEPSIS RELATED CONDITIONS USING THE SAME

Field of the Invention

The present invention related to lipoic acid derivatives containing thiosulphates, synthesis of such compounds, and methods of treating conditions associated with oxidative stress such as sepsis, sepsis related conditions or ulcerative colitis using the compounds.

Background of the Invention

Septic shock is a frequent common cause of mortality for hospitalized patients. According to published PCT application WO2014/008273, the contents of which are incorporated herein by reference, fatality rates can be as high as 80% for those developing multiple organ failure.

Overall, a third of all patients developing septic shock die despite receiving antibiotics and supportive care. Even patients who survive sepsis associated conditions for the first month, have a 2.7 times higher mortality rate the first year and a 2.3 times higher mortality rate the next three years compared to persons of similar age, sex and co-morbidity.

Efforts have been made over the years to improve patient outcomes with new treatments, however there is still a need for improved compounds which can be administered to patients suffering from sepsis and related conditions.

There is also a continuing desire to improve treatments for diseases or conditions associated with oxidative stress such as inflammatory bowel diseases including ulcerative colitis. See, for example Pravda, J. Radical Induction Theory of Ulcerative Colitis World J. Gastroenterol. 2005 Apr. 28; 11(16): 2371-2384, the contents of which are incorporated herein by reference.

The present invention addresses these needs. Summary of the Invention

In one aspect of the invention there are provided compounds of the formula:

wherein:

R'₁ is H, C_1-12 alkyl, CO H2, CO₂R' ₃ wherein R'₃ is H, C_1-12 alkyl, or an alkali metal; R'₂ is

or

wherein each R'₄ is independently an alkali metal or H;

and m and n are independently selected integers from 1 to 24.

The compounds are useful for example in the treatment of sepsis and sepsis-related conditions and can neutralize hydrogen peroxide both in vivo and in vitro. Some compounds corresponding to Formula (I) include

and

Further aspects of the invention include methods of synthesizing the compounds according to formula (I) and methods of treatment including the compounds of formula (I).

Brief Description of the Drawings

Figure 1 provides two reaction schemes for preparing compounds in accordance with the invention.

Description of the Invention

Generally, in accordance with a first aspect of the invention there are provided compounds of formula (I)

wherein:

R'₁ is H, C_1-12 alkyl, CO H2, CO₂R'₃ wherein R'₃ is H, C_1-12 alkyl, or an alkali metal;

R'₂ is

or

wherein each R'₄ is independently an alkali metal or H;

and m and n are independently selected integers from 1 to 24. For purposes of the present invention, the term "alkyl" shall be understood to include straight, branched, substituted C_1-12 alkyls, C_3-8 cycloalkyls or substituted cycloalkyls, etc.

In some embodiments of the invention, R'₁ is CO2H. In other embodiments, R'₁ is CO₂CH₂CH₃ or H2. In further aspects of the invention, m is an integer from 1 to 4, or alternatively m is 1; n is an integer from 1-6 or alternatively n is 3.

For purposes of the invention, when R'₄ is an alkali metal, it is preferable that it is Na or K, and more preferably Na.

In many aspects of the invention, R'2 is

wherein R'₄ is as previously defined, i.e. preferably Na, K or H.

Some preferred compounds in accordance with the invention include

As can be seen from the above, many of the preferred compounds described herein are derivatives of lipoic acid.

In a further aspect of the invention there are provided methods of preparing the compounds of the invention. Accordingly, in one embodiment, the methods include reacting a compound of formula (II)

wherein:

R1 is H, C_1-12 alkyl, CO H₂, CO₂R₃ wherein R₃ is H, C_1-12 alkyl, or an alkali metal; R₂ is

wherein R₄ is CI, Br, I or tosyl; and

m is an integer from 1 to 24; with a compound of

formula (III) (R₅)HSO₃ or formula (IV) (R₅)S₂O₃,

wherein R5 is an alkali metal salt, in a mixture of water and an alcohol such as ethanol or, preferably methanol. The amount of water and alcohol used in the reactions will be in a ratio sufficient to dissolve all the reactants and allow the reaction to substantially go to completion.

The reaction is preferably carried out under reflux conditions for several hours, such as overnight. The desired products can be obtained using techniques well known to those of ordinary skill thereafter via filtration and concentration by vacuum or other techniques apparent to the artisan of ordinary skill.

Turning now to Figure 1, illustrative chemical syntheses are provided. In accordance therewith, in some preferred aspects of the inventive process, the compound of formula (I) is

the compound of formula (II) is

and the compound of formula (III) is NaHSO₃.

Within the scope of the invention and depending upon the reaction conditions, the synthetic reaction will also yield compounds of

It will be understood and appreciated by those of ordinary skill that the amount of each reactant will be sufficient to facilitate the substantially complete or completion of the desired reaction.

As shown in the second reaction scheme of Fig. 1, an alternative aspect of the invention is provided wherein the compound of formula (I) is:

the com ound of formula (II) is

and the compound of formula (IV) is Na₂S₂O₃. The invention also includes methods of treating conditions associated with oxidative stress such as sepsis or sepsis associated states or ulcerative colitis and related conditions in a subject such as a human by administering an effective amount of a compound of formula (I) to a subject in need thereof. In other embodiments, the subject is any non-human animal, such as a domestic pet, e.g. a cat, a dog, a horse, or a zoo animal. The methods also include neutralization of hydrogen peroxide by contacting the hydrogen peroxide with a compound of the invention either in vivo or in vitro.

For purposes of the present invention, the term "sepsis associated state", as used herein, refers to any one condition in the sepsis continuum, as defined by the American College of Chest

Physicians and the Society of Critical Care Medicine (Bone et al. (1992) Chest, 101(6): 1644-55, the entire contents of which are hereby incorporated herein by reference). In some embodiments, the term "sepsis associated state" can refer to any one of Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis and Septic Shock. Conditions associated with sepsis called "Sepsis 3" are also capable of being treated with the compounds of the present invention. See https://www.sccm.org/SiteCollectionDocuments/Quality-Sepsis-Definitions-SCCM-ESICM- Joint-Session-Critical-Care-Congress.pdf, the contents of which are incorporated herein by reference. Systemic Inflammatory Response Syndrome (SIRS) is defined by the presence of two or more of the following: a) hypothermia or fever; b) increased heart rate (> 90 beats per minute); c) tachypnea or hypocapnia due to hyperventilation; and d) leukopenia, leukocytosis, or bandemia.

Sepsis is defined as SIRS in response to a confirmed infectious process.

Infection can be suspected or proven (e.g., by culture, stain, or polymerase chain reaction), or a clinical syndrome pathognomonic for infection. Specific evidence for infection includes white blood cells (WBCs) in normally sterile fluid (such as urine or cerebrospinal fluid); evidence of a perforated viscus (free air on abdominal x-ray or CT scan; signs of acute peritonitis); abnormal chest x-ray (CXR) consistent with pneumonia (with focal opacification); or petechiae, purpura, or purpura fulminans. Severe Sepsis is defined as sepsis with organ dysfunction, hypoperfusion, or hypotension.

Septic Shock is defined as sepsis with refractory arterial hypotension or hypoperfusion abnormalities in spite of adequate fluid resuscitation. Signs of systemic hypoperfusion may be either end-organ dysfunction or increased serum lactate (> 4 mmol/L). Other signs include oliguria and altered mental status. Patients are defined as having septic shock if they have sepsis plus hypotension after aggressive fluid resuscitation (typically upwards of 6 liters or 40 ml/kg of crystalloid solution).

In some embodiments, the definitions of sepsis associated states, e.g., Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis and Septic Shock, as defined by the American College of Chest Physicians and the Society of Critical Care Medicine also encompass modifications for pediatric population, e.g. , as described in Goldstein et al. (2005) Pediatr. Crit. Care Med., 6(l):2-8, the entire contents of which are hereby incorporated herein by reference.

Regardless of the condition associated with oxidative stress being treated with the compounds of the invention, the amount of the compound administered is described as an effective amount. This will also be the case where the desired result is neutralization of hydrogen peroxide. The amount is an amount sufficient to cause neutralization when a compound of the invention is contacting the hydrogen peroxide either in vivo or in vitro.

Such amount will be apparent to those of ordinary skill without undue experimentation and will be dependent upon clinical presentation of the subject. Generally, it is contemplated that amounts of from about 0.1 to about 10 mg/kg per day will be effective when administered in one dose or more than one divided doses. The term "effective amount" shall also be understood as being a quantity sufficient to maintain a desired blood level in the subject. It is contemplated that the compounds of the invention can be administered by any pharmaceutically acceptable manner with the oral, rectal and parenteral routes being preferred when incorporated into

pharmaceutically acceptable dosage forms/ parenterally acceptable formulations. The compositions may be co-administered with other pharmacologically effective compounds useful in the treatment of the condition associated with oxidative stress, i.e. sepsis, related conditions, ulcerative colitis, etc.

EXAMPLES

1. Synthesis from lipoic acid and sodium bisulphite

To a solution of 51.9g of sodium bisulphite (0.5 moles) in 300ml of water stirred at room temperature is added 5.2 g of alpha lipoic acid 0.025 moles). After 30 minutes the addition of 3% hydrogen peroxide solution (14.5g, 0.013 moles) is carried out over a period of 10 minutes. Stirring is continued for 30 minutes followed by addition of a further 14.5g of 3% hydrogen peroxide solution over a period of 20 minutes. Stirring is continued for a further 30 minutes after which the reaction mixture is allowed to stand overnight at room

temperature. Water is removed by rotary evaporation to give a semi-solid residue which is extracted with lOOmL of methanol. This extract is concentrated to allow the di-thiosulfate of lipoic acid to crystallize.

2. Synthesis from Di-chloro-octanoic acid and Sodium thiosulfate

A mixture of well-powdered sodium thiosulfate (60 mmol, 15 g) and 6, 8-dichloro-octanoic acid (30 mmol, 6.5 g) in 50% v/v aqueous ethanol (50ml) is stirred magnetically at 60 - 70°C for 6 hr. The solvents are removed by rotary evaporation to leave a residue which is extracted with methanol. The methanol extract is filtered, concentrated by rotary evaporation and allowed to crystallize to form the di-thiosulfate of lipoic acid.

3. Reaction of Lipoic acid with NaHSO₃ in Methanol/Water

In a flask equipped with a condenser were placed lipoic acid (2.5 g, 12.05 mmol), NaHSO₃ (5 g, 48.3 mmol), water (4 mL), and methanol (60.3 mL). The reaction mixture was heated to reflux overnight. The resulting suspension was cooled to room temperature and it was filtered.

Afterward, the filtrate was concentrated and dried under high vacuum overnight. To the resulting solid was added anhydrous methanol (80 mL), and heated to reflux for 30 min, cooled to room temperature, and filtered. The filtrate was concentrated. To the resulting solid was added anhydrous methanol (20 mL), heated to reflux, cooled to room temperature, and filtered. The filtrated was concentrated and dried under high vacuum to afford the desired product (3.46 g) in 66% yield.

4. Synthesis of Octane-1,3-Dithiosulfate Sodium or Octane-l,3-di-Bunte Salt 1,3-dichloro-octane (3 g, 12.4 mmol), sodium thiosulfate (7.2 g, 29 mmol), water (6 mL), methanol (18.6 mL) were placed in a flask and heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (10 mL). The filtrate was concentrated to dryness. Anhydrous methanol (20 mL) was added and heated to 50 °C. The reaction mixture was allowed to cool to room temperature and filtered. After concentration, 2.7 g of the crude product was obtained. It was left under the high vacuum overnight. The dried crude product was calculated to be 1.6 g. To the dried crude product was added MTBE (20 mL), heated to reflux, and filtered. The filter cake was dried under the high vacuum to afford the product 4●2Na+(1.3 g).

Claims

WHAT IS CLAIMED IS:

1 A compound of the formula:

wherein:

R'₁ is H, C_1-12 alkyl, CO H₂, CO₂R'₃ wherein R'₃ is H, C_1-12 alkyl, or an alkali metal; R'₂ is

or

wherein each R'₄ is independently an alkali metal or H;

and m and n are independently selected integers from 1 to 24.

2. The compound of claim 1, wherein R'₁ is CO₂H.

3. The compound of claim 1, wherein R'₁ is CO₂CH₂CH₃ or H₂.

4. The compound of claim 1, wherein n is 3.

5. The compound of claim 1, wherein R'₄ is Na, K or H.

6. The compound of claim 5, wherein R'₄ is Na.

7. The compound of claim 1, wherein R'₂ is

8. A compound of claim 1 having the structure:

9. A compound of claim 1 selected from the group consisting of:

10. A method of preparing the compound of claim 1, compri

reacting a compound of formula (II)

R₁ is H, C_1-12 alkyl, CONH2, CO2R3 wherein R₃ is H, C_1-12 alkyl, or an alkali metal; R₂ is

or

wherein R₄ is CI, Br, I or tosyl; and

m is an integer from 1 to 24; with a compound of formula (III) (R₅)HSO₃ or

formula (IV) (R₅)S₂O₃,

wherein R₅ is an alkali metal salt, in a mixture of water and an alcohol.

11. The method of claim 10, wherein the compound of formula (I)

the compound of formula (II) is

and the compound of formula (III) is NaHSO₃.

12. The method of claim 10, wherein the compound of formula (I)

the compound of formula (II) is

and the compound of formula (IV) is Na₂S₂O₃.

13. The method of claim 10, wherein the alcohol is methanol or ethanol.

14. The method of claim 10, wherein the reaction is carried out under reflux conditions.

15. A method of treating a condition associated with oxidative stress sepsis associated state in a subject, comprising administering an effective amount of the compound of claim 1 to a subject in need thereof.

16. The method of claim 15, wherein the compound is

17. The method of claim 15, wherein the compound is selected from the group consisting of:

18. The method of claim 15, wherein the effective amount is administered to the subject orally, rectally, or parenterally.

19. The method of claim 15, wherein the subject is a human.