Novel analogs of valproic acid and methods of treatment therewith

Abstract

The present invention relates to compounds of formula I, wherein R1 is either H or D, and D is deuterium, or a pharma- ceutically acceptable salt thereof. The present invention also relates to methods of treating abnormal conditions associated with excess fibrin deposition, thrombus formation, migraine headaches, bipolar disorder, epilepsy, and related conditions in which inhibition of histone deacetylase (HDAC) provides a therapeutic benefit. [Formula 1] TIFF2025500459000018.tif28128

Description

[Technical field]

[0001] The present invention relates to novel compounds useful for treating abnormal conditions associated with excessive thrombosis, fibrin deposition, epilepsy, bipolar disorder and / or histone deacetylation. [Background technology]

[0002] Valproic acid, commonly abbreviated as VPA, is a well-known compound that was first used as an anticonvulsant to treat seizures, and is also used to treat mania in patients with bipolar disorder and to prevent migraines. In addition, VPA is an inhibitor of histone deacetylases (HDACs) and can therefore alter gene expression. As such, VPA has recently been investigated as a potential anticancer therapeutic. However, it is unclear whether VPA's ability to act as an HDAC inhibitor is related to its ability to treat seizures, bipolar disorder, and prevent migraines.

[0003] Although administration of VPA can provide therapeutic benefit, there is significant toxicity associated with VPA. Indeed, VPA administration can be associated with significant liver toxicity, including acute liver failure. In particular, there is growing evidence that 4-ene-VPA (shown below), a common metabolite of VPA, is at least partially responsible for VPA-associated toxicity.

[0004] [ka]

[0005] As with any active pharmaceutical ingredient, the risks associated with administering VPA may outweigh the benefits of administering this compound for any type of specific treatment.Therefore, the problem that plagues the art is that VPA, while beneficial, may bring too great a toxicity risk to patients to be useful for use in treating certain patients.Therefore, there is a need for new compounds and / or pharmaceutical compositions that allow the treatment of at least some of the above medical indications while minimizing side effects such as liver toxicity. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2010 / 0143507 [Patent Document 2] US Patent Application Publication No. 2012 / 0071554 [Non-patent literature]

[0007] [Non-Patent Document 1] Rettie, A., et al., J. Biol. Chem, 263(27):13733-13738(1988) [Non-Patent Document 2] Corrado E.,et al.An update on the role of markers of inflammation in atherosclerosis,Journal of Atherosclerosis and Thrombosis,2010;17:1-11 [Non-Patent Document 3] Koenig W., Fibrin(ogen)in cardiovascular disease:a update, Thrombosis Haemostasis 2003;89:601-9 [Non-Patent Document 4] Langer, Science 249:1527-1533(1990) [Non-Patent Document 5] Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989) [Non-Patent Document 6] Sefton,1987,CRC Crit.Ref.Biomed.Eng.14:201 [Non-Patent Document 7] Buchwald et al.,1980,Surgery 88:507 [Non-Patent Document 8] Saudek et al.,1989,N.Engl.J.Med.321:574 [Non-Patent Document 9] Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974) [Non-Patent Document 10] Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984) [Non-Patent Document 11] Ranger and Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61 [Non-Patent Document 12] Levy et al.,1985,Science 228:190;During et al.,1989,Ann.Neurol.25:351.Howard et al.,1989,J.Neurosurg.71:105) Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present disclosure to overcome or at least mitigate one or more of the above-mentioned disadvantages. Further, it is an object of the present disclosure to provide advantages and aspects not offered by the heretofore known art. [Means for solving the problem]

[0009] Thus, the present disclosure provides at least one compound of formula I

[0010] [ka] wherein R1 is either H or D, and D is deuterium, or a pharma- ceutically acceptable salt thereof. The present invention also relates to methods of treating abnormal conditions associated with excess fibrin deposition, thrombus formation, fibrosis, epilepsy, migraine, bipolar disorder, and related conditions in which inhibition of histone deacetylase (HDAC) provides a therapeutic benefit. [Brief description of the drawings]

[0011] [Figure 1] Figure 1 shows the effect of bleeding time in mice treated with the compounds of the present invention. Tail bleeding time was evaluated in mice treated with saline or 100 mg / kg VPA, Compound Ia, Compound Ib, Rettie, A., et al., J. Biol. Chem, 263(27):13733-13738 (1988) 4, '507 Publication "D10" compound, or '507 Publication "D11" compound and control. N=10 for control, VPA, Compound Ia, Compound Ib, D10 and D11. N=4 for Rettie, A., et al., J. Biol. Chem, 263(27):13733-13738 (1988) 4 compounds. [Diagram 2] 1 shows platelet accumulation in the cremaster laser-induced thrombosis assay (30 mg / kg). [Diagram 3] Fibrin formation in cremaster laser-induced thrombosis assay (30 mg / kg). [Figure 4]Platelet accumulation in the cremaster laser-induced thrombosis assay (100 mg / kg) is shown. [Diagram 5] Figure 2 shows the formation of 4-ene-VPA metabolite in VPA, compound Ia (Cmpd Ia) and compound Ib (Cmpd Ib). Values ​​were normalized by setting the formation of 4-ene-VPA metabolite in VPA to 1.0. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The disclosed invention relates to at least one compound of formula I

[0013] [ka] wherein R1 is either H or D, and D is deuterium, or a pharma- ceutically acceptable salt thereof. As used herein, the phrase "a compound of the invention" refers to any one or more of the specific compounds of formula I.

[0014] In certain embodiments, compounds of formula (I) are provided, wherein R 1 represents H.

[0015] In a further embodiment, there is provided a compound of formula (I) wherein R 1 represents D.

[0016] Particular compounds of the present invention include compounds Ia and / or Ib, and pharma- ceutically acceptable salts thereof.

[0017] [ka]

[0018] Compound Ia may also be referred to herein as 2-(propyl-2,2,3,3-d4 pentane-4,4,5,5-d4 acid, 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4) pentanoic acid or 4,4,5,5-tetradeutero-2-(2,2,3,3-tetradeuteropropyl) valeric acid (compound 1a), and compound Ib may also be referred to herein as 2-(propyl-2,2,3,3-d4) pentane-2,4,4,5,5-d5 acid or 2,4,4,5,5-pentadeutero-2-(2,2,3,3-tetradeuteropropyl) valeric acid (compound 1b). The compounds of the present invention may be prepared by converting certain hydrogen atoms to deuterium isotopes ( 2 The present inventors have unexpectedly discovered that valproic acid having the particular deuteration pattern of formula I has a surprising metabolic profile that reduces the levels of known toxic metabolites of VPA, as well as a high safety profile that both treats conditions associated with excessive fibrin deposition and / or thrombus formation, and reduces the excessive blood loss often seen with drugs that target these conditions.

[0019] The terms "compounds of the invention" and "compounds described herein" are used interchangeably and can be used to refer to compounds of Formula I, Compound Ia, and Compound Ib.

[0020] Pharmacologically active compounds in which hydrogen is replaced by deuterium generally exhibit the same pharmacodynamic effects as their non-deuterated counterparts. However, deuteration can alter the metabolism of the parent compound in unpredictable ways. For example, Rettie, A., et al., J. Biol. Chem, 263(27):13733-13738 (1988) ("Rettie") reported that deuteration of VPA at specific positions in VPA reduces and increases the formation of 4-ene-VPA metabolites. Specifically, Rettie noted that deuteration at the 4 and 4' positions of VPA (4,4,4',4'-D4VPA) results in the formation of significantly less 4-ene metabolites compared to VPA. On the other hand, Rettie reported that VPA fully deuterated at the 5 and 5' positions (5,5,5,5',5',5D6VPA) formed increased amounts of 4-ene-VPA metabolites compared to VPA. These results suggest that deuteration at the 4 and / or 4' positions of VPA may reduce the formation of 4-ene metabolites and therefore possibly reduce the toxicity associated with VPA administration. However, these results also suggest that deuteration at the 5 and 5' positions of VPA increases the production of 4-ene-VPA metabolites and therefore increases the toxicity associated with VPA administration. Thus, Rettie suggests that deuteration at the 5 and / or 5' positions of VPA should be avoided.

[0021] The general concept of deuterated VPA is not new. For example, as mentioned above, Rettie has produced deuterated VPA compounds. In particular, Rettie has produced four deuterated compounds: (4,4'-D2VPA), (4,4,4',4'-D4VPA), (5,5,5-D3VPA) and (5,5,5,5',5',5'D6VPA). Interestingly, compounds deuterated at the 4 and 4' positions produced less 4-ene-VPA than VPA in metabolic studies, and compounds deuterated at the 5 and 5' positions produced more 4-ene-VPA than VPA in metabolic studies. Again, these data suggest avoiding deuteration at the 5 and / or 5' positions in VPA to reduce toxicity.

[0022] U.S. Patent Application Publication No. 2010 / 0143507, which was abandoned without a continuation application filed, also discloses a large genus of deuterated VPA compounds. However, the '507 publication does not disclose or suggest specific deuterated molecules having the specific pattern of deuteration of the compounds of the present invention. Furthermore, the '507 publication does not provide any guidance or suggestion as to which specific compounds will produce less 4-ene-VPA when metabolized, or which specific compounds may provide any therapeutic benefit. In fact, the '507 publication does not contain any activity or metabolic data of any kind. Of the few specific molecules that the '507 publication discloses, the 5 and 5' positions are either fully deuterated, i.e., the compounds contain six (6) aryl groups at these two positions. 2 H isotopes or is fully hydrogenated, i.e., the compound has zero (0) isotopes at these two positions. 2 H isotope.

[0023] U.S. Patent Application Publication No. 2012 / 0071554 (WO 2010 / 062656), which was abandoned without a continuation filed, also discloses deuterated VPA compounds. However, the '554 publication does not disclose or suggest specific deuterated molecules having the specific pattern of deuteration of the compounds of the present invention. Furthermore, the '554 publication does not provide any guidance or suggestion as to which specific compounds will produce less 4-ene-VPA when metabolized or which specific compounds may provide any therapeutic benefit. In fact, the '554 publication does not contain any activity, stability or metabolic data of any kind. Of the few specific molecules that the '554 publication discloses, the 5 and 5' positions are either fully hydrogenated, i.e., the compounds have zero (0) hydrogen atoms at these two positions. 2 H isotope or only one of these positions is deuterated, i.e. the compound has three (3) H isotopes at only one of these two positions. 2H isotope or is deuterated only once at each of these positions, i.e., the compound has one (1) H isotope at each of these two positions. 2 H isotope.

[0024] Thus, while the general concept of deuterated VPA may not be new, there is no guidance in the art that suggests deuterizing two hydrogens at each of the 5 and 5' positions of VPA. Indeed, the data in Rettie, A., et al., J. Biol. Chem., 263(27):13733-13738 (1988) teaches to completely avoid deuterization of the 5 and / or 5' positions of VPA. However, the inventors have demonstrated that compounds that are quadruple deuterated at the 5 and 5' positions, i.e., that the compound has two (2) hydrogens at each of these two positions, are deuterated at the 5 and 5' positions. 2 We have found that the compounds of the present invention with H isotope have a dramatic reduction in metabolism to toxic 4-ene-VPA metabolites. Specifically, the formation of 4-ene-VPA metabolites is reduced by about 97% for compound Ia and about 89% for compound Ib when compared to VPA, as provided in Example 4 and Figure 5. This dramatic reduction in the formation of toxic metabolites from the compounds of the present invention was not expected. Thus, the present invention provides a novel and safer compound for treating conditions in which deuterated VPA is or can be used as a monotherapy or part of a combination therapy. As described below, the compounds of the present invention also have unexpected therapeutic advantages over VPA.

[0025] Surprisingly, the compounds described herein, which are novel derivatives of VPA with specific deuteration patterns, not only reduce the formation of toxic 4-ene-VPA metabolites, but may also provide unexpectedly superior performance in reducing excessive bleeding when administered compared to VPA. Furthermore, these compounds provide advantageous results in terms of platelet activation and fibrin formation over VPA, indicating that these compounds are useful in treating conditions associated with excessive thrombus formation and / or fibrin deposition.

[0026] Therefore, the present invention also provides a method of using the compounds of the present invention to treat abnormal conditions associated with thrombus formation, excessive fibrin deposition, and / or fibrosis. In other words, the present invention provides a method of treating abnormal conditions associated with thrombus formation, excessive fibrin deposition, and / or fibrosis in a subject in need of treatment. The method of treating abnormal conditions associated with thrombus formation, excessive fibrin deposition, and / or fibrosis comprises administering to a subject in need of treatment a therapeutically effective amount of one or more of the compounds of the present invention.

[0027] Also provided is a compound as described herein, i.e., a compound of the present invention, or a pharmaceutical composition as described herein, for use in treating and / or preventing abnormal conditions associated with thrombus formation, excessive fibrin deposition, and / or fibrosis. Administering a pharmaceutical composition as described herein may reduce excess blood loss in the subject being treated. Thus, the methods for treating or preventing conditions characterized by or associated with thrombus formation, excessive fibrin deposition, and / or fibrosis as described herein (and compounds for use in such methods) may also involve reducing excess blood loss in the subject being treated.

[0028] There is also provided the use of a compound as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of an abnormal condition associated with thrombus formation, excessive fibrin deposition and / or fibrosis.

[0029] Thus, according to a further aspect of the invention there is provided a compound of the invention for use as a medicament.

[0030] Examples of conditions characterized by or associated with thrombus formation and / or excessive fibrin deposition that can be treated and / or prevented in a subject using one or more of the compounds of the invention include, but are not limited to, atherosclerosis, myocardial infarction, ischemic stroke, deep vein thrombosis, superficial vein thrombosis, thrombophlebitis, pulmonary embolism, disseminated intravascular coagulation, renal vascular disease, and intermittent claudication. In one embodiment, the condition is selected from the group consisting of myocardial infarction, ischemic stroke, deep vein thrombosis, and pulmonary embolism. Particular pathological conditions associated with fibrosis which the compounds of the invention may be useful in treating and / or preventing include, but are not limited to, cardiac fibrosis such as myocardial fibrosis, atrial fibrosis, fibrosis associated with cardiac hypertrophy and remodeling, fibrosis associated with myocardial infarction, atrial fibrillation and heart failure, right and left heart failure with reduced and preserved ejection fraction, cardiac fibrosis associated with pulmonary disease, fibrosis associated with pulmonary arterial hypertension, thromboembolic associated fibrosis, fibrosis associated with NASH, liver cirrhosis and portal hypertension, renal fibrosis with and without systemic hypertension, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), peritoneal fibrosis, i.e. progressive fibrotic thickening of the peritoneum, conjunctival fibrosis, i.e. overproduction of type I collagen in the membrane on the inner surface of the eyelid and at the front of the eyeball, and / or renal fibrosis associated with chronic kidney disease.

[0031] Methods using the compounds of the present invention to treat abnormal conditions associated with thrombus formation, excessive fibrin deposition, and / or fibrosis may reduce excess blood loss in a subject.

[0032] As described herein, several conditions and risk factors are associated with predisposition to thrombotic events (i.e., thrombus formation). These include atherosclerosis, hypertension, abdominal obesity, smoking, a sedentary lifestyle, and low-grade inflammation. Thus, in certain embodiments of the invention, treatment or prevention is in patients with one or more such conditions / risk factors.

[0033] In a more particular embodiment, a patient at high risk of developing a pathological condition associated with excessive fibrin deposition and / or thrombus formation is (i) suffering from one or more medical conditions associated with an increased risk of thrombosis, such as metabolic syndrome (e.g., type II diabetes), neoplastic disease, heart failure, renal failure and / or sepsis; (ii) has previously experienced one or more occurrences of a pathological condition associated with excessive fibrin deposition and / or thrombus formation, e.g., one or more occurrences of myocardial infarction, ischemic stroke, and pulmonary embolism (e.g., one or more occurrences of ischemic stroke, such as a major ischemic stroke, a minor ischemic stroke, or a TIA); and / or (iii) Patients with one or more lifestyle and / or environmental factors that increase risk, such as being a smoker, being obese, and / or having reduced mobility (e.g., patients who are bedridden, such as those in a healthcare facility or elderly care facility).

[0034] In certain embodiments of the invention, pathological conditions that may be treated or prevented according to the invention are those caused in whole or at least in part by increased fibrin deposition and / or decreased fibrinolytic capacity due to local or systemic inflammation, including, but not limited to, myocardial infarction, stable angina, unstable angina, intermittent claudication, ischemic stroke, transient ischemic attack, deep vein thrombosis and pulmonary embolism.

[0035] Specific biomarkers that can identify local or systemic inflammation include high sensitive C-reactive protein (hs-CRP) (greater than 2.0 mg / l serum) and fibrinogen (greater than 3 g / l serum) (Corrado E., et al. An update on the role of markers of inflammation in atherosclerosis, Journal of Atherosclerosis and Thrombosis, 2010;17:1-11, Koenig W., Fibrin(ogen) in cardiovascular disease: a update, Thrombosis Haemostasis 2003;89:601-9).

[0036] In one embodiment, the treatment or prevention includes reversal and prevention of fibrosis. In a more specific embodiment, the treatment or prevention includes reversal and prevention of either or both of primary or secondary fibrosis, remodeling and repair, and effects on fibrosis associated with cardiovascular disease, inflammatory diseases, fibrosis associated with activation of the renin-angiotensin-system, mineralocorticoid receptors and PAI-1, and other systemic diseases.

[0037] In another embodiment, the fibrosis is selected from the group consisting of cardiac fibrosis, arterial fibrosis, pulmonary fibrosis, pulmonary arterial hypertension associated fibrosis, thromboembolic associated fibrosis, NASH associated fibrosis, renal fibrosis, ocular fibrosis, skin fibrosis, hepatic fibrosis, pancreatic fibrosis and other GI tract fibrosis.

[0038] In one embodiment, one or more compounds of the present invention may be used to treat and / or prevent diseases associated with elevated pulmonary or systemic blood pressure.

[0039] In one embodiment, one or more compounds of the present invention may be used to treat and / or prevent pulmonary arterial hypertension (PAH) and / or chronic thromboembolic pulmonary hypertension (CTEPH).

[0040] In one embodiment, one or more compounds of the present invention may be used to treat and / or prevent thrombus formation associated with increased pulmonary arterial pressure, including, but not limited to, pulmonary arterial hypertension (PAH) and / or chronic pulmonary thromboembolic hypertension (CTEPH).

[0041] The present invention also provides the method of using the compound of the present invention to inhibit histone deacetylase.In other words, the present invention provides the method of inhibiting histone deacetylase in a subject who needs to inhibit histone deacetylase.The method of inhibiting histone deacetylase comprises administering one or more therapeutically effective amounts of the compound of the present invention to the subject who needs to inhibit histone deacetylase.

[0042] There is also provided the use of a compound described herein, or a pharmaceutical composition described herein, for the manufacture of a medicament for the inhibition of histone deacetylase.

[0043] Also provided is a compound described herein, or a pharmaceutical composition described herein, for use in inhibiting histone deacetylase.

[0044] Also provided is the use of a compound described herein or a pharmaceutical composition described herein in the inhibition of histone deacetylase, in certain embodiments, such uses may be described as non-therapeutic and / or ex vivo.

[0045] The present invention also provides a method of using the compound of the present invention to treat a subject diagnosed with bipolar disorder.In other words, the present invention provides a method of treating bipolar disorder in a subject who needs bipolar disorder treatment.The method of treating bipolar disorder comprises administering a therapeutically effective amount of one or more compounds of the present invention to a subject who needs treatment.

[0046] Also provided is a compound as described herein and / or a pharmaceutical composition as described herein for use in the treatment and / or prevention of bipolar disorder.

[0047] There is also provided the use of a compound described herein and / or a pharmaceutical composition described herein for the manufacture of a medicament for use in the treatment and / or prevention of bipolar disorder.

[0048] The present invention also provides a method of using the compounds of the present invention to treat a subject diagnosed with epilepsy.In other words, the present invention provides a method of treating epilepsy in a subject in need of treatment.The method of treating epilepsy comprises administering a therapeutically effective amount of one or more compounds of the present invention to a subject in need of treatment.

[0049] Also provided is a compound as described herein and / or a pharmaceutical composition as described herein for use in the treatment and / or prevention of epilepsy.

[0050] There is also provided the use of a compound as described herein and / or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment and / or prevention of epilepsy.

[0051] For the avoidance of doubt, the method of treating epilepsy comprises administering to a subject in need of such treatment a therapeutically effective amount of one or more compounds of the present invention.

[0052] The present invention also provides a method of using the compounds of the present invention to prevent migraine headaches in a subject. In other words, the present invention provides a method of reducing the likelihood of migraine headaches or reducing the frequency of migraine headaches in a subject in need of such treatment. The method of treating migraine headaches includes administering a therapeutically effective amount of one or more compounds of the present invention to a subject in need of such treatment.

[0053] Also provided is a compound as described herein and / or a pharmaceutical composition as described herein for use in the treatment and / or prevention of migraine.

[0054] There is also provided a compound as described herein and / or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment and / or prevention of migraine.

[0055] Methods of treatment and methods of using the compounds of the invention include administering one or more of the compounds of the invention to a subject in need of such treatment. Suitable dose ranges for the compounds of the invention are generally from about 0.0001 milligrams per kilogram of body weight per dose to about 2000 milligrams per kilogram of body weight per day. In certain embodiments of the invention, the dose is from about 0.001 milligrams per kilogram to about 4000 milligrams per kilogram of body weight, or from about 0.01 milligrams per kilogram to about 3000 milligrams per kilogram of body weight, or from about 0.1 milligrams per kilogram to about 2000 milligrams per kilogram of body weight, or from about 0.1 milligrams per kilogram to about 1500 milligrams per kilogram of body weight, or from about 0.1 milligrams per kilogram to about 1000 milligrams per kilogram of body weight, or from about 1 milligrams per kilogram to about 500 milligrams per kilogram of body weight, or from about 1 milligrams per kilogram to about 100 milligrams per kilogram of body weight, or from about 1 milligrams per kilogram to about 90 milligrams per kilogram of body weight. or about 1 milligram to about 80 milligrams per kilogram of body weight, or about 1 milligram to about 70 milligrams per kilogram of body weight, or about 1 milligram to about 60 milligrams per kilogram of body weight, or about 1 milligram to about 50 milligrams per kilogram of body weight, or about 1 milligram to about 40 milligrams per kilogram of body weight, or about 1 milligram to about 30 milligrams per kilogram of body weight, or about 1 milligram to about 20 milligrams per kilogram of body weight, or about 1 milligram to about 10 milligrams per kilogram of body weight, or about 1 milligram to about 5 milligrams per kilogram of body weight. In other embodiments, one or more compounds of the present invention are administered at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 7 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg or 100 mg / kg.In other specific embodiments, the daily dose is in the range of about 1 to 4000 mg per patient (e.g., 1 to 3000 mg or 1 to 2000 mg per patient), administered in a single dose or multiple doses. In other more specific embodiments, one or more of the compounds of the invention are administered in a daily dose of about 10 mg to about 2000 mg, about 50 mg to about 1300 mg, e.g., about 100 mg to about 1200 mg, or about 50 mg to about 1000 mg, e.g., about 100 mg to about 800 mg, about 100 mg to about 600 mg, or about 200 mg to about 600 mg. The daily dose may be administered as a single bolus dose, or the total dose may be divided into multiple doses, e.g., 2, 3, 4, 5, 6, 7, or 8 doses per day.

[0056] The compounds of the present invention include pharma- ceutically acceptable salts of the compounds of formula I. The phrase "pharmaceutically acceptable salts" as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts (i.e., salts containing pharmacologically acceptable anions), including sulfuric acid, citric acid, maleic acid, acetic acid, oxalic acid, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tartrate ... The salts of the present invention include, but are not limited to, citric acid, pantothenic acid, bitartrate, ascorbate, succinate, maleate, gentisic acid, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)). Compounds included in the present compositions that contain an amino moiety may form pharma- ceutically acceptable salts with various amino acids in addition to the acids listed above. The compounds described herein are acidic in nature and can form salts, for example, with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Particular examples of pharma- ceutically acceptable addition salts include those derived from metals, such as, for example, calcium, magnesium, potassium, or, preferably, sodium. In certain embodiments, such salts may exist as "hemisalts" (i.e., a 2:1 ratio of compound counterion). The compounds described herein may also form complexes with various amines.Examples of amines include alkylamines, amino alcohols (eg, 2-(dimethylamino)ethanol), basic amino acids (eg, lysine), and quaternary amines (eg, choline).

[0057] As used herein, unless otherwise indicated, the phrase "therapeutically effective amount" of the composition is measured by the therapeutic effectiveness of a compound of the invention in ameliorating or alleviating at least one adverse effect of a disorder.

[0058] The term "prevent" or "prevention" is intended to include reducing the frequency or likelihood that a subject will experience (e.g., reducing the risk of) undesirable physiological activity or symptoms associated with an abnormal condition or disorder. The term "prevent" or "prevention" as used herein does not require absolute prevention of the abnormal condition. In one embodiment, "treatment" or "treating" refers to reducing or ameliorating a disease, disorder, abnormal condition, or at least one identifiable symptom thereof. In another embodiment, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter, not necessarily identifiable by the patient. In yet another embodiment, "treatment" or "treating" refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of an identifiable symptom, physiologically, e.g., stabilization of a physical parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset of a disease, disorder, or abnormal condition.

[0059] As used herein, those skilled in the art will understand that a reference to "Prevent" a particular condition or the "Prevention" of a particular condition may also be referred to as the "Prophylaxis" of that condition, and vice versa. Thus, each reference herein to "Preventing" a condition can be replaced with a reference to the "Prophylaxis" of that condition.

[0060] In certain embodiments, the composition is administered to a patient, such as a human. In this specification, the terms subject and patient are used interchangeably. The subject can also be a non-human mammal, such as for companion pets or for veterinary use for agricultural or livestock animals. Examples of non-human subjects include, but are not limited to, non-human primates, dogs, cats, cows, pigs, bulls, horses, etc.

[0061] The compounds of the present invention may be administered by any convenient or conventional route, for example, orally, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa), etc., or may be administered together with another biologically active pharmaceutical agent. Administration may be systemic or local. Various delivery systems, such as encapsulation in liposomes, microparticles, microcapsules, capsules, etc., are known and can be used to administer the compounds or compositions of the present invention. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, intrarectal, or topical (e.g., to the ear, nose, eye, or skin). In certain embodiments, the compounds of the present invention are administered orally.

[0062] In certain embodiments, it may be desirable to administer one or more compounds of the present invention locally to the area that needs treatment.This can be achieved, for example, but not limited to, by local injection during surgery, by local application, for example, in conjunction with wound dressing after surgery, by injection, by using a catheter, by using a suppository, or by using an implant, which is a porous, non-porous, or gelatinous material, including membranes or fibers, such as sialastic membranes.In one embodiment, administration can be by direct injection into the site (or former site) of atherosclerotic plaque tissue.

[0063] In another embodiment, the compounds of the present invention can be delivered in a vesicle, such as a liposome. See Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0064] In yet another embodiment, the compounds of the present invention can be delivered in a controlled release system. In one embodiment, a pump can be used. See Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N. Engl. J. Med. 321:574. In another embodiment, a polymeric material can be used. See Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61. See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25: 351. Howard et al., 1989, J. Neurosurg. 71: 105).

[0065] All formulations known in the art and described for valproic acid and its pharmaceutically acceptable salts can be used when administering the compounds of the present invention.For example, in known pharmaceutical formulations that contain valproic acid mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, the present compositions and methods contemplate replacing VPA in these known formulations with one or more compounds of the present invention.

[0066] In certain embodiments, the compositions contain a therapeutically effective amount of a compound of the invention, together with a suitable amount of pharma- ceutically acceptable vehicle so as to provide the form for proper administration to the patient.

[0067] The term "pharmaceutical acceptable" as used herein means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier with which the compound of the present invention is administered. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used. Water can be a vehicle when the compound of the present invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. Other examples of suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by AR Gennaro. The present composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

[0068] The compositions may take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing a liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use.

[0069] In another embodiment, the compounds of the present invention are formulated according to the usual procedures as pharmaceutical compositions adapted for intravenous administration to humans. Typically, the compounds of the present invention for intravenous administration are in a solution in a sterile isotonic aqueous buffer. If necessary, the composition may include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic, such as lignocaine, to ease pain at the injection site. Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example, as a lyophilized powder or water-free concentrate in a sealed container, such as an ampoule or sachette indicating the quantity of active agent. When the compounds of the present invention are administered by injection, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. When the compounds of the present invention are administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0070] Formulations for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more optional pharmaceutical agents, such as sweeteners, such as fructose, aspartame, or saccharin, flavorings, such as peppermint, wintergreen oil, or cherry, coloring agents, and preservatives to provide a pharma- ceutically palatable preparation. Furthermore, when in tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding the osmotically active driving compound are also suitable for orally administered compounds of the invention. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells and displaces the pharmaceutical agent or pharmaceutical composition through an opening. These delivery platforms can provide an essentially zero order delivery profile, as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate can also be used.Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.

[0071] Those skilled in the art will appreciate that compounds of formula (I), including compounds of formula (Ia) and (Ib), may be prepared using techniques known to those skilled in the art.

[0072] In certain embodiments, a compound of formula (Ia) or a compound of formula (Ib):

[0073] [ka] or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula (II)

[0074] [ka] There are processes that include a step of decarboxylation under conditions known to those skilled in the art (such as by heating at a suitable temperature for a suitable period of time, e.g., heating at 160° C. overnight), optionally in the presence of DO; Reaction in the absence of DO results in the preparation of a compound of formula (Ia), and reaction in the presence of DO (e.g. in the presence of excess DO, such as when DO is used as a solvent) results in the preparation of a compound of formula (Ib), The compound of formula (Ia) or (Ib) may be in the form of a pharma- ceutically acceptable salt, optionally comprising the further step of reacting with a suitable salt counterion (i.e., reacting with a suitable compound to form a salt, such as a suitable base, e.g., an appropriate amount of sodium hydroxide where the salt is a sodium or hemi-sodium salt).

[0075] Those skilled in the art will also appreciate that the starting materials used in the preparation of the compounds of Formula I may be prepared using techniques known to those skilled in the art.

[0076] In certain embodiments, the compound of formula (III) is

[0077] [ka] Processes for the preparation of compounds of formula (II) are provided which include a step of hydrolysis under conditions known to those skilled in the art (such as by hydrolysis in the presence of a suitable base, for example aqueous base such as aqueous sodium hydroxide).

[0078] In certain embodiments, the compound of formula (IV) is

[0079] [ka] A process for the preparation of a compound of formula (III) is provided which comprises a hydrogenation step under conditions known to those skilled in the art (such as in the presence of a suitable catalyst, e.g., a rhodium catalyst) and in the presence of a suitable deuterium source (e.g., deuterium gas).

[0080] In certain embodiments, a process for preparing a compound of formula (IV) comprising:

[0081] [ka] The process includes a step of alkylation of a compound of formula (V) under conditions known to those skilled in the art, such as by reaction with a suitable base metal (e.g. a metal hydride such as sodium hydride) followed by reaction with a suitable alkylating agent (e.g. a suitable alkyl halide such as propargyl bromide).

[0082] In certain embodiments, a process for preparing a compound of formula (I) (i.e., a compound of formula (Ia) or Ib)) comprises the steps of: A process for preparing a compound of formula (IV) as described herein, Subsequently, a process for preparing a compound of formula (III) as described herein, Subsequently, a process for preparing a compound of formula (II) as described herein, Subsequently, processes are provided, including processes for preparing the compounds of formula (I) described herein.

[0083] Those skilled in the art will appreciate that the compounds of formula (II), (III), (IV) and (V) may be novel. Accordingly, compounds of formula (II), (III), (IV) and / or (V), and pharma- ceutically acceptable salts thereof, are also provided.

[0084] Compounds of formula (V) are either commercially available and / or may be synthesized using techniques known to those skilled in the art.

[0085] Such compounds can be isolated from their reaction mixtures and, if necessary, purified using conventional techniques known to those skilled in the art. Thus, the process for preparing the compounds of the invention described herein may comprise, as a final step, the isolation and optional purification of the compounds of the invention (e.g., the isolation and optional purification of the compound of formula I). EXAMPLES

[0086] The present invention is further illustrated by reference to the following examples, which are not intended to limit the scope of the invention.

[0087] In case of discrepancy between the nomenclature and any compound depicted in the figures, the latter takes precedence (unless it conflicts with any of the experimental details that may be provided or is clear from the context).

[0088] Example 1 - Synthetic Route Synthesis of Compound Ia and Compound Ib Step 1.

[0089] [ka] Dimethyl 2-(2,2,3,3-tetradeuteriopropyl)propanedioate

[0090] Dimethylpropargylmalonate (10.0 g, 58.8 mmol) and tris(triphenylphosphine)rhodium(I) chloride (1.6 g, 1.8 mmol, 3%) were mixed in 100 ml toluene. The reaction flask was evacuated and repeatedly flushed with nitrogen. The reaction flask was connected to a hydrogenation manifold and the reaction flask was evacuated and flushed with deuterium. The mixture was stirred under deuterium. After complete reduction, the reaction mixture was filtered through Celite and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by Kugelrohr distillation (10 mbar @ 130 °C). A clear, colorless oil was obtained (7.2 g, 69%). 1 H NMR (400 MHz, chloroform-d) δ 3.73 (s, 6H), 3.37 (t, J = 7.6 Hz, 1H), 1.87 (d, J = 7.6 Hz, 2H), 0.88 (s, 1H).

[0091] Step 2.

[0092] [ka] Dimethyl 2-prop-2-ynyl-2-(2,2,3,3-tetradeuteriopropyl)propanedioate

[0093] Sodium hydride (60% in mineral oil, 5.55 g, 139 mmol) was slurried in 200 ml of THF cooled on ice under nitrogen. Dimethyl 2-(2,2,3,3-tetradeuteriopropyl)propanedioate (16.5 g, 92.6 mmol) in 50 ml of THF was added dropwise. After 30 min, propargyl bromide (14.3 g, 120 mmol) in 50 ml of THF was added dropwise. The reaction mixture was stirred at 0° C. for 2 h and quenched by adding saturated NH4Cl (100 ml). Heptane (200 ml) was added and the phases were separated. The organic phase was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated. A light brown oil was obtained (18 g). The crude contained mineral oil and was used as is. 1 H NMR (400 MHz, chloroform-d) δ 3.74 (s, 6H), 2.82 (d, J = 2.7 Hz, 2H), 2.05-1.96 (m, 3H), 0.89 (s, 1H).

[0094] Step 3.

[0095] [ka] Dimethyl 2,2-bis(2,2,3,3-tetradeuteriopropyl)propanedioate

[0096] Dimethyl 2-prop-2-ynyl-2-(2,2,3,3-tetradeuteriopropyl)propanedioate (18 g, 83 mmol) and tris(triphenylphosphine)rhodium(I) chloride (1.54 g, 1.66 mmol, 2%) were mixed in 300 ml of toluene. The reaction flask was evacuated and repeatedly flushed with nitrogen. The reaction flask was connected to a hydrogenation manifold and the reaction flask was evacuated and flushed with deuterium.

[0097] The mixture was stirred under deuterium. After 1, 2 and 3 days, 0.5 g more rhodium catalyst was added and the reaction was restarted. After complete reduction, the solvent was removed under reduced pressure. Heptane (200 ml) was added. After stirring for 30 min, the precipitate was removed by filtration through Celite. The mother liquor was concentrated and the residue was purified by Kugelrohr distillation (30 mbar @ 160°C). A clear colorless oil was obtained (13 g, 70%). 1 H NMR (400 MHz, chloroform-d) δ 3.70 (s, 6H), 1.83 (s, 4H), 0.86 (s, 2H).

[0098] Step 4.

[0099] [ka] 2,2-bis(2,2,3,3-tetradeuteriopropyl)propanedioic acid

[0100] Sodium hydroxide (13.9 g, 348 mmol) was dissolved in 100 ml of water. Dimethyl 2,2-bis(2,2,3,3-tetradeuteriopropyl)propanedioate (13 g, 58 mmol) in 50 ml of methanol was added. The reaction mixture was stirred at reflux for 5 h and at room temperature overnight. The reaction mixture was washed with 2×50 ml of DCM. The aqueous phase was concentrated under vacuum to remove traces of DCM. The solution was cooled on ice and 80 ml of 5 M HCl was added. A white precipitate was formed. The mixture was stirred on ice for 1 h and the precipitate was collected by filtration and washed with a small amount of water. A white solid (11 g, 97%), 1 H NMR (500 MHz, chloroform-d) δ 1.92 (s, 4H), 0.88 (s, 2H).

[0101] Step 5.

[0102] [ka] "Compound Ia", 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoic acid.

[0103] 2,2-Bis(2,2,3,3-tetradeuteriopropyl)propanedioic acid (11 g, 56 mmol) was mixed with 100 ml of water in a glass insert into a steel bomb. The bomb was heated to 160° C. overnight. After cooling to room temperature, the water / oil mixture was transferred to a separatory flask with heptane. The aqueous phase was extracted three times with heptane. The combined organic phase was washed with brine, dried over (Na2SO4), filtered, and concentrated to give a light brown oil (8.0 g, 94%) containing traces of heptane. 1 H NMR (400MHz, chloroform-d) δ2.42-2.30(m,1H), 1.60(dd,J=13.4,8.9Hz,2H),1.43(dd,J=13.4,5.3Hz,2H),0.86(s,2H).

[0104] Step 6.

[0105] [ka] "Compound Ia, sodium hemi-salt", 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoic acid and sodium 2-[(2,2,3,3-2H4)propyl](4,4,5,5-2H4)pentanoate

[0106] Compound Ia (8.00 g, 52.5 mmol) and finely ground sodium hydroxide (1.05 g, 26.3 mmol) were mixed in 20 ml of MTBE. The mixture was stirred at 50° C. for 30 min. A clear light brown solution was obtained. After cooling on ice, 80 ml of acetonitrile was added. A large amount of precipitate was formed. After stirring on an ice bath for 1 h, the precipitate was collected by filtration and washed with acetonitrile. The solid was dried under vacuum overnight. A white solid (6.79 g, 79%, presumed hemi-salt), 1H NMR(400MHz,DMSO-d6)δ2.06(ddd,J=14.1,9.0,5.2Hz,1H),1.41(dd,J=12.9,9.0Hz,2H ),1.19(dd,J=13.0,5.2Hz,2H),0.77(s,2H),LCMS(ESI-):m / z[MH]-Calculated value: 151, Actual value: 151.

[0107] Compound Ib was prepared as above, with the addition of carrying out the final decarboxylation in D2O.

[0108] Example 2 - Excessive Bleeding Assay To determine the risk of excessive bleeding associated with the compounds of the present invention, the last 5 mm of the mouse tail was removed to determine the time required for the blood vessel to clot properly and prevent excessive blood loss. Briefly, mice were administered Compound Ia (Formula Ia), Compound Ib (Formula Ib), or " 2 H4-VPA (the "Reference 4" compound), the compound of claim 11 from U.S. Patent Application Publication No. 2010 / 0143507 ("D11"), the compound of claim 12 from U.S. Patent Application Publication No. 2010 / 0143507 ("D10"), VPA or a vehicle control (sodium chloride saline) were administered and bleeding time assays were performed.

[0109] C57BL / 6 wild-type mice aged 10-12 weeks were purchased from Jackson Laboratories for these experiments. Various compounds were administered to the mice by IP injection once daily at a dose of 100 mg / kg compound for 5 days prior to resection.

[0110] Mice were sedated with 250 μL of ketamine solution (ketamine (100 μL) / xylazine (50 μL) in 850 μL of saline). Mice were then placed face down on a heat pad on top of a bead bath so that the tail could be drawn into a saline-filled tube. A 5 mm tail was cut with a scalpel, the tail placed in a saline-filled tube, and a timer was started. The timer was stopped when bleeding had stopped, but possible rebleeding was observed starting 10 min after the initial bleeding had stopped. If the mouse bled continuously for 10 min, the experiment was stopped and the mouse was euthanized. One-way ANOVA with Dunnett's correction for multiple comparisons was performed to determine the statistical significance of bleeding times.

[0111] As shown in FIG. 1, the bleeding time of control mice was about 100 seconds. Interestingly, 100 mg / kg VPA and reference D10 caused a significant increase in bleeding time compared to control. Treatment with all compounds except compound Ia caused an increase in bleeding time compared to control time. Of note, reference 4 compound from Rettie, A., et al., J.Biol.Chem., 263(27):13733-13738 (1988) showed a significantly higher bleeding time than compound Ia. Taken together, this data indicates that compound Ia has the best safety profile in terms of risk of excessive bleeding of all compounds tested.

[0112] Example 3 - Thrombosis evaluation of compounds of the present invention The effects of the compounds of the invention and VPA on the ability and timing of clot formation were determined by measuring platelet accumulation and fibrin formation in the cremaster artery during the formation of non-occlusive clots following laser-induced injury to blood vessels in 10-12 week old mice (C57BL / 6 wild type mice purchased from Jackson Laboratories).

[0113] Valproic acid (VPA) was purchased as a powder from Sigma-Aldrich and resuspended in 0.9% sodium chloride (saline) to prepare a final stock solution of each compound. VPA and other compounds (compound Ia and compound Ib) were administered to mice by IP injection at final concentrations of 30 mg / kg and 100 mg / kg.

[0114] A Zeiss Axio Examiner Z1 fluorescent multichannel intravital microscope was used to assess platelet accumulation and fibrin formation. The microscope was equipped with (1) a solid-state laser delivery system (LaserStack; Ablate! Photoablation system, Intelligent Imaging Innovations), (2) a high-speed sCMOS camera, and (3) a laser ablation system (Intelligent Imaging Innovations, Denver, CO, USA). SlideBook 6.0 digital microscope software for image recording and analysis was also used. Antiplatelet and antifibrin antibodies, both commercially available, were used for imaging purposes.

[0115] The dynamic accumulation of platelets and fibrin within thrombi at the site of injury in vivo was assessed under intravital microscopy in cremaster arterioles in response to laser-induced injury. Adult male mice (10-12 weeks old) were treated with 30 mg / kg and 100 mg / kg for 5 days prior to injury, anesthetized by intraperitoneal injection of ketamine / xylazine (100 and 10 mg / kg, respectively), and cannulated in the jugular vein. A tracheal tube was inserted to facilitate respiration. Cremaster arterioles were surgically prepared and perfused with pre-warmed bicarbonate saline buffer throughout the experiment.

[0116] DyLight 488-conjugated rat anti-mouse platelet GP1bβ antibody (0.1 μg / g; EMFRET Analytics) and Alexa Fluor 647-conjugated anti-fibrin (0.3 μg / g) were administered intravenously via the jugular vein cannula before vascular injury. Microcirculation was monitored and recorded under a multichannel intravital microscope.

[0117] Multiple independent thrombi (6–8 thrombi in each mouse) were induced in arterioles (diameter 30–50 μm) of each mouse by a laser ablation system. Images of thrombus formation at the site of the injured arteriole were acquired in real time under a 63x water immersion objective using a Zeiss Axio Examiner Z1 fluorescence microscope equipped with a solid-state laser firing system (LaserStack; Intelligent Imaging Innovations) and a high-speed sCMOS camera. After subtracting the fluorescent background using the Slidebook program, all captured images were analyzed for changes in fluorescence intensity over the course of thrombus formation. To assess statistical significance, one-way ANOVA with Dunnett's test for multiple comparisons was performed.

[0118] As shown in Figures 2 and 3, Compound Ia at a dose of 30 mg / kg caused a consistent reduction in both platelet accumulation and fibrin formation over VPA in this thrombosis assay, indicating that Compound Ia is beneficial in treating or preventing conditions associated with excessive fibrin deposition when compared to VPA and Compound Ib. In addition, Compound Ia and Compound Ib administered at a dose of 100 mg / kg caused a consistent reduction in platelet accumulation over VPA in this thrombosis assay (Figure 4).

[0119] Example 4 - Formation of 2-propyl-4-pentenoic acid (4-ene metabolite). Formation of 2-propyl-4-pentenoic acid (4-ene metabolite) in Cyp 2C9 in vitro experiments with VPA and compounds of the invention. VPA, compound Ia and compound Ib (all compounds at 1 mM) were incubated with human CYP2C9 0.2 pmol / μl bactosomes (Cypex, UK) in 100 mM potassium phosphate buffer pH 7.4 containing 5 mM magnesium chloride and 2 mM NADPH. Samples were collected before (time 0) and at different time points after (30, 60 and 180 min) addition of NADPH. Samples were added to an equal volume of ice-cold acetonitrile, vortexed, centrifuged at 10000×g and stored at +4° C. until analysis. To increase analytical sensitivity, sample supernatants were diluted with N-(3-dimethylaminopropyl)-N ’ The products were derivatized with 3-ethylcarbodiimide and 3-nitrophenylhydrazine hydrochloride. The products obtained were analyzed using LC-MS / MS (UHPLC Agilent 6495, XSelect HSS T3 XP column). The calculation of the area under the curve of the formed 4-ene metabolite was based on the trapezoid rule, and the formation was % 4-ene. * The amount of 4-ene metabolite formed for compounds Ia and Ib was compared to the amount of 4-ene metabolite formed for VPA. For compound Ia, the reduction in the amount of 4-ene metabolite formed was 967% when compared to VPA. For compound Ib, the reduction in the amount of 4-ene metabolite formed was 888% when compared to VPA (see FIG. 5).

Claims

1. A compound of formula I, 【Chemistry 1】 R １ is either H or D, where D is deuterium; or a pharmaceutically acceptable salt thereof.

2. In the formula, R １ The compound of claim 1 , wherein is H.

3. R １ The compound of claim 1 , wherein

4. The compound of any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is a sodium salt.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and at least one pharmaceutical vehicle.

6. A compound according to any one of claims 1 to 3 for use in the treatment and / or prevention of abnormal conditions associated with thrombus formation, excessive fibrin deposition and / or fibrosis.

7. A compound according to any one of claims 1 to 3 for use in the treatment of bipolar disorder.

8. A compound according to any one of claims 1 to 3 for use in the treatment of migraine.

9. A compound according to any one of claims 1 to 3 for use in the treatment of epilepsy.

10. A pharmaceutical for treating an abnormal condition associated with thrombus formation, excessive fibrin deposition and / or fibrosis in a subject in need thereof, comprising a therapeutically effective amount of the pharmaceutical composition of claim 5.

11. 7. The compound for use according to claim 6, wherein the abnormal condition associated with thrombus formation and / or excessive fibrin deposition is selected from the group consisting of atherosclerosis, myocardial infarction, ischemic stroke, deep vein thrombosis, superficial vein thrombosis, thrombophlebitis, pulmonary embolism, disseminated intravascular coagulation, renal vascular disease and intermittent claudication, and the abnormal condition associated with fibrosis is selected from the group consisting of cardiac fibrosis, arterial fibrosis, pulmonary fibrosis, fibrosis associated with pulmonary arterial hypertension, fibrosis associated with thromboembolism, fibrosis associated with NASH, renal fibrosis, ocular fibrosis, dermal fibrosis, hepatic fibrosis, pancreatic fibrosis and other GI tract fibrosis.

12. 7. The compound for use according to claim 6, wherein the compound or pharmaceutical composition for use is administered to the subject via a route of administration selected from the group consisting of oral, intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, transdermal, rectal and topical.

13. 6. A pharmaceutical composition according to claim 5 for use in the treatment and / or prevention of abnormal conditions associated with thrombus formation, excessive fibrin deposition and / or fibrosis.

14. 14. The pharmaceutical composition for use according to claim 13, wherein the abnormal condition associated with thrombus formation and / or excessive fibrin deposition is selected from the group consisting of atherosclerosis, myocardial infarction, ischemic stroke, deep vein thrombosis, superficial vein thrombosis, thrombophlebitis, pulmonary embolism, disseminated intravascular coagulation, renovascular disease and intermittent claudication, and the abnormal condition associated with fibrosis is selected from the group consisting of cardiac fibrosis, arterial fibrosis, pulmonary fibrosis, fibrosis associated with pulmonary arterial hypertension, fibrosis associated with thromboembolism, fibrosis associated with NASH, renal fibrosis, ocular fibrosis, dermal fibrosis, hepatic fibrosis, pancreatic fibrosis and other GI tract fibrosis.

15. 14. The pharmaceutical composition for use according to claim 13, wherein the pharmaceutical composition is administered via a route of administration selected from the group consisting of oral, intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, transdermal, rectal and topical.

16. A pharmaceutical product for treating bipolar disorder in a subject in need thereof, comprising a therapeutically effective amount of the pharmaceutical composition of claim 5.

17. 8. The compound for use according to claim 7, wherein the compound or pharmaceutical composition for use is administered to the subject via a route of administration selected from the group consisting of oral, intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, transdermal, rectal and topical.

18. 10. A medicament for reducing migraine frequency in a subject in need thereof, comprising a therapeutically effective amount of the pharmaceutical composition of claim 5.

19. 9. The compound for use according to claim 8, wherein the compound or pharmaceutical composition for use is administered to the subject via a route of administration selected from the group consisting of oral, intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, transdermal, rectal and topical.

20. A pharmaceutical for treating epilepsy in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 5.

21. 10. The compound for use according to claim 9, wherein the pharmaceutical composition is administered to the subject via a route of administration selected from the group consisting of oral, intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, transdermal, rectal and topical.

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