NZ616467B2 - Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease - Google Patents

Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease Download PDF

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NZ616467B2
NZ616467B2 NZ616467A NZ61646712A NZ616467B2 NZ 616467 B2 NZ616467 B2 NZ 616467B2 NZ 616467 A NZ616467 A NZ 616467A NZ 61646712 A NZ61646712 A NZ 61646712A NZ 616467 B2 NZ616467 B2 NZ 616467B2
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ethyl
carboxy
dimethylpropanaminium
salt
dioxo
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NZ616467A
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NZ616467A (en
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Maija Dambrova
Solveiga Grinberga
Ivars Kalvins
Janis Kuka
Edgars Liepins
Daina Lola
Einars Loza
Osvalds Pugovics
Ilmars Stonans
Reinis Vilskersts
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Grindeks A Joint Stock Company
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Priority claimed from PCT/EP2012/057806 external-priority patent/WO2012146736A1/en
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Publication of NZ616467B2 publication Critical patent/NZ616467B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid

Abstract

The disclosure relates to salts of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium, specifically the (2E)-3-carboxyacrylate, 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate and dihydrogenphosphate salt. The disclosure also relates to the process for preparing said salts and the use of these salts in the treatment of cardiovascular diseases, such as ischemic heart diseases like myocardial infarction. s in the treatment of cardiovascular diseases, such as ischemic heart diseases like myocardial infarction.

Description

Description Use of oxy-N-ethyl-MN—dimethylpropanaminium salts in the treatment of cardiovascular disease Technical Field The present ion relates to new compound oxy-N—ethyI-N,N- dimethylpropan-i-aminium salts, and to a method of preparation thereof (compound of formula 4) I + R1 —N\/\,COOH AcO COOH I HNiNH H p0 Mo JCOOH R, = 2 4 , j ’ '00C ’ rooc ’ , 00C *00C The t invention relates also to use of 3-carboxy-N—ethyl-N,N- dimethylpropan-i-aminium salts in the treatment of cardiovascular disease.
Background Art Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vesels.
An ted 16.7 million — or 29.2% of total global deaths - result from the various forms of cardiovascular disease (CVD).
Myocardial infarction (heart attack) is a serious result of coronary artery disease.
Myocardial infarction (MI) is the irreversible necrosis of heart muscle secondary to prolonged ischemia. A heart attack or myocardial infarction is a medical emergency in which the supply of blood to the heart is suddenly and severely reduced or cut off, causing the muscle to die from lack of . More than 1.1 million people experience a heart attack (myocardial infarction) each year, and for many of them, the heart attack is their first symptom of coronary artery disease. A heart attack may be severe enough to cause death or it may be silent. As many as one out of every five people have only mild symptoms or none at all, and the heart attack may only be discovered by routine electrocardiography done some time later.
A heart attack (myocardial infarction) is usually caused by a blood clot that blocks an artery ofthe heart. The artery has often already been narrowed by fatty ts on its walls. These deposits can tear or break open, reducing the flow of blood and releasing substances that make the platelets ofthe blood sticky and more likely to form clots. Sometimes a clot forms inside the heart itself, then breaks away and gets stuck in an artery that feeds the heart. A spasm in one of these es causes the blood flow to stop. y—Butyrobetaine, from which the mammalian organism synthesises carnitine, was primarily characterised as a toxic substance which accelerates respiration, causes salivation and lacrimation, pupil on, vasoconstriction and heart stop in diastole LINNEWEH, W. Gamma- Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Sey/ers Ze/fschn'fl fUrphys/o/og/lsche Chem/e. 1929, vol.181, p.42-53. At the same time, in later papers other s ascertained that y-butyrobetaine is extremely low toxic (LD50>7000 mg/kg, s.c.) ROTZSCH, W. lber die Toxizitat des Carnitins und einiger verwandter Stoffe. Acfa b/'0/. med. germ. 1959, vol.3, 6.
In the literature data on nonsubstututed y-butyrobetaine cardiovascular effects are missed, thought it was reported HOSEIN, E.A. Pharmacological actions of y- butyrobetaine. Nature. 1959, 3, p.328-329. that y—butyrobetaine is a substance similar to acetyl e with a prolonged action. However, later the same authors reported that by an error the experiments involved, d of y- butyrobetaine, its methyl esther which in fact possesses cholinergic properties.
Contrary to the former y—butyrobetaine was characterised as a pharmacologically inert substance HOSEIN, E.A. ion and probable functions of betaine esters in brain lism. Nature. 1960, vol.187, p.321-322.
As structurally d compounds to 3-carboxy-N-ethyl-N,N-dimethylpropan aminium salts are disclosed in: 0 GB 1238868 A 14.07.1971 were disclosed betaines, such as 4— trimethylammoniobutanoate, used for polymers. Howerver no pharmacological propeties of these betaines weren’t ted; 0 US 5973026 A (XEROX CORP) 26.10.1999 were sed 4- trimethylammoniobutanoate and 3-[diethyl(methyl)ammonio]propionate 3O for using for ink compositions; o LLOYD ANDREW, et al. A comparison ofglycine, sarcosine, N,N- dimethylglycine, glycinebetaine and N-modified betaines as liposome cryoprotectants. l ofpharmacy andpharmacology. 1992, vol.44, no.6, p.507—511 disclosed 2—[ethyl(dimethyl)ammonio]acetate used as cryoprotectants for liposomes; W0 2012/146736 3 0 DAVID B. and s , THOMAS, et al. sis, Characterization, on Behavior of Electrolyte- and pH—Responsive Carboxybetaine- ning Cyclocopolymers. Macromolecules. 2003, vol.36, no.26, p.9710—9715 disclose 4—[dia||yl(methy|)ammonio]butanoate and its synthesis ng from N,N-diallyl-N—methylaminiom and ethyl 4- bromobutanoate. The free acis is obtained from the ester in a second step using Amberlite ion exchange resin. The product is used as intermediate to synthesise polymers; 0 Prelog M 1930, vol.2, p.712-722 disclosed the synthesis of 4- trimethylammoniobutanoate starting from 4-dimethylammoniobutanoate and methyliodide; o ethylammoniobutanoate and its synthesis starting from trimethylamine and ethyl 4-bromobutanoate was described JP 6766 A (KONAN GAKUEN) 07.05.2009. The free acid is obtained from the ester in a second step using Amberlite ion exchange resin; 0 A (KALVINSH IVARS; CHERNOBROVIJS ALEKSANDRS; VARACHEVA LARISA; PUGOVICHS OSVALDS) .05.2008 was described 4-trimethylammoniobutanoate and synthesis, which started from the correspondin ester and using KOH—solution; 0 CA 2508094 A (VIVIER CANADA INC) 20.11.2006 was disclosed betaines, such as 4-trimethylammoniobutanoate, for use as medicament for rating collagen synthesis; 0 US 5965615 A (TAIHO PHARMACEUTICAL CO LTD; VALSTS ZINATNISKA IESTADE BEZP ) 12.10.1999 was disclosed 4- trimethylammoniobutanoate as a medicament for the treatment of myocardial metabolic disorder, the same compound was disclosed in US 2007191381 A (CONCERT PHARMACEUTICALS INC) 16.08.2007 for treatment of myocardial tion. 3- (2,2,2-Trimethylhydrazinium) nate dihydrate is known as compound with protective properties (this substance being known under its International Nonproprietary Name of Meldonium). 3— (2,2,2-Trimethylhydrazinium) propionate is disclosed in US 4481218 (INST ORGANICHESKOGO SINTEZA) 06.11.1984 as well in US 4451485 A (INSTITU ORCH SINTEZA AKADEMII) 29.05.1984.
It is well known that 3- (2, 2,2-trimethylhydrazinium) propionate as dihydrate is widely used for lling carnitine and gamma-butyrobetaine concentration ratio and consequently the speed of fatty acid beta-oxidation in the body DAMBROVA M., LIEPINSH E., KALVINSH I. I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends in Cardiovascular Medicine,. 2002, vol.12, no.6, 279.
Due to these ties, Meldonium is extensively applied in medicine as an chemic , stress-protective and cardioprotective drug in treating various vascular diseases and other pathologies involving tissue ischernia KARPOV R.S., SKAYA O.A., VRUBLEVSKY A.V., SOKOLOV A.A., TEPLYAKOV A.T., SKARDA I., DZERVE V., KLINTSARE D., VITOLS A., KALNINS U., KALVINSH I., MATVEYA L., URBANE D. Clinical Efficacy and Safety of Mildronate in Patients With lschemic Heart Disease and Chronic Heart Failure.
Kardiologiya. 2000, no.6, p.69-74. In the treatment of cardiovascular diseases the mechanism of action of 3(2,2,2-trimethylhydrazinium)propionate based on tion of ine biosynthesis rate and related long-chain fatty acid transport limitation through mitochondria membranes SIMKHOVICH B.Z., SHUTENKO Z.V., MEIRENA D.V., KHAGI K.B., MEZHAPUKE R.J., MOLODCHINA T.N., KALVINS I.J., LUKEVICS E. 3-(2,2,2,-Trimethylhydrazinium)propionate (THP) - a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties.
Biochemical Pharmacology. 1988, vol 37, p.195-202., KIRIMOTO T., ASAKA N., NAKANO M., TAJIMA K., MIYAKE H., MATSUURA N. Beneficial effects of MET- 88, a y-butyrobetaine hydroxylase tor in rats with heart failure following myocardial infarction. European Journal of Pharmacology. 2000, vol.395, no.3, p.217-224.
A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was known or that the information it contains was part of the common general dge as at the priority date of any of the claims. y of invention As it was known what Meldonium dehydrate has cardioprotective effect; however there are no data that γ-butyrobetaine itself has pronounced cardioprotective effect. In the patent EP 0845986 B (KALVINSH IVARS, VEVERIS MARIS) 02.04.2003 is disclosed pharmaceutical composition of Meldonium dihydrate and γ -butyrobetaine for use in the treatment of cardiovascular diseases.
It would be desirable to provide a compound, which has pronounced cardioprotective .
According to a first embodiment of the invention, there is provided 3-carboxy-N- ethyl-N,N-dimethylpropanaminium (2E)carboxyacrylate COOH - OOC N COOH According to a second embodiment of the ion, there is ed 3-carboxy- N-ethyl-N,N-dimethylpropanaminium 2,6-dioxo-1,2,3,6-tetrahydropyrimidine carboxylate HN NH COO- O N COOH According to a third embodiment of the invention, there is provided 3-carboxy-N- ethyl-N,N-dimethylpropanaminium dihydrogen phosphate H PO - 2 4 N COOH According to a fourth embodiment of the ion, there is provided a process for preparing 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salt sing: a. adding N,N-dimethylethylamine to ethyl 4-bromobutanoate in appropriate solvent to obtain 4-ethoxy-N-ethyl-N,N-dimethyloxobutanaminium bromide; b. passing 4-ethoxy-N-ethyl-N,N-dimethyloxobutanaminium bromide through ion exchange resin column to obtain 4-[ethyl(dimethyl)ammonio] butanoate; c. adding acid ed from the group, consisting of fumaric acid, orotic acid and phosphoric acid in appropriate solvent to obtain the corresponding 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salt.
According to a fifth embodiment of the invention, there is provided a 3-carboxy-N- ethyl-N,N-dimethylpropanaminium salt, selected from the group consisting of 3- carboxy-N-ethyl-N,N-dimethylpropanaminium (2E)carboxyacrylate, 2,6- dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate and dihydrogenphosphate for use as a medicament.
According to a sixth embodiment of the invention, there is ed a 3-carboxy-N- ethyl-N,N-dimethylpropanaminium salt, selected from the group consisting of 3- carboxy-N-ethyl-N,N-dimethylpropanaminium, (2E)carboxyacrylate and 2,6- dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate and dihydrogenphosphate for use in treatment of cardiovascular es.
There are provided new compounds 3-carboxy-N-ethyl-N,N-dimethylpropan aminium salts (compound of formula 4), which have a similar structure to Meldonium or γ-butyrobetaine.
To our surprise oxy-N-ethyl-N,N-dimethylpropanaminium salts possess pronounced cardioprotective effect and are more effective as Meldonium dihydrate in vivo dial infarction models, due to this property 3-carboxy-N-ethyl-N-N- dimethylpropanaminium salts may be used in ne. 3-Carboxy-N-ethyl-N,N- dimethylpropanaminium salts can be use as a solution for injection.
The ing is a method of preparation of said compound of formula 4.
There is disclosed a process, which can be used in purpose to prepare target compound 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salts of formula 4, see scheme bellow.
Process for preparing 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salt of formula 4 involves the following process steps: a) adding N,N-dimethylethylamine to ethyl 4-bromobutanoate (1) in appropriate solvent to obtain 4-ethoxy-N-ethyl-N,N-dimethyloxo butanaminium bromide (2); b) passing 4-ethoxy-N-ethyl-N,N-dimethyloxobutanaminium e (2) through ion exchange resin column to obtain 4- [ethyl(dimethyl)ammonio] butanoate (3); c) adding acid which is selected from 2-(acetyloxy)benzoic acid (4 a) or (E)- butenedioic acid (4 b) or ic acid (4 c) or 2,6-dioxo-1,2,3,6- W0 2012/146736 6 tetrahydropyrimidinecarboxylic acid monohydrate (4 d) or phosphoric acid (4 e) to y|(dimethyl)ammonio] butanoate (3) in appropriate solvent to obtain oxy-N-ethyI-N,N-dimethylpropan- 1-aminium salt (4).
Description of embodiments The present invention will be described in more detail by referring to the following non—limiting examples.
Preparation of 4-ethoxy-N-ethyl-N,N-dimethyIoxobutanaminium bromide (2) ure A To a solution of ethyl 4-bromobutanoate (1) (20.0 g, 102.5 mmol) in acetonitrile (70 ml) N,N-dimethylethylamine (15 ml, 139 mmol) was added and stirred at ambient temperature for 3 days. The reaction e was evaporated, the residue was triturated with acetone (50 ml), filtered, washed with ether, and dried to afford 26.051 g (94.8%) of the 4—ethoxy—N-ethyI-N,N—dimethyI—4—oxobutanaminium bromide. LCMS (ES|+, m/Z): [M-Br-]+ 188, purity 98.9%. 1H NMR (CDCIs, HMDSO) 8: 1.26 (t, J=7.2 Hz, 3H); 1.44 (t, J=7.4 Hz, 3H); 2.00-2.11 (m, 2H); 2.52 (t, J=6.6 Hz, 2H); 3.40 (s, 6H); 3.64-3.73 (m, 2H); 3.69 (q, J=7.4 Hz, 2H); 4.14 (q, J=7.2 Hz, 2H).
Procedure B To a on of ethyl 4-bromobutanoate (1) (19.5 g, 100 mmol) in acetone (70 ml) N,N-dimethylethylamine (15 ml, 139 mmol) was added and stirred at ambient temperature for 3 days. The reaction mixture was ed; the solid material was washed with an acetone, ether, and dried to afford 24.19 g (90.2%) of the title compound 2. The filtrate was evaporated; the residue (2.147 g) was ated with ether and dried to give an extra batch (0.962 g, 3.6%) ofthe product 2 ofthe same quality as the main portion. The evaporation of the ether washings allowed recovering 0.956 g (4.9 mmol, 4.9%) of the starting material 1. 4-ethoxy-N-ethyl- N,N-dimethyloxo-1—butanaminium bromide: LCMS (ESI+, m/Z): [M-Br-]+ 188, purity 98.4%. 1H NMR (CDCI3, HMDSO) 8: 1.26 (t, J=7.2 Hz, 3H); 1.44 (t, J=7.4 Hz, 3H); 2.00- 2.11 (m, 2H); 2.52 (t, J=6.6 Hz, 2H); 3.40 (s, 6H); 3.64—3.73 (m, 2H); 3.69 (q, J=7.4 Hz, 2H); 4.14 (q, J=7.2 Hz, 2H).
W0 2012/146736 7 Preparation of 4-[ethyl(dimethyl)ammonio]butanoate (3) A solution of 4-ethoxy-N-ethyl-N,N-dimethyloxo—1-butanaminium bromide (2) (12.00 g, 44.7 mmol) in water (10 ml) was passed through Amberlite ® IRA-410 (OH) ion exchange resin column (250 ml) eluting slowly (ca. 10 drops/min) with ethanol (TLC control). The eluate was evaporated and the residue (12 g) was dissolved in water (50 ml). To this solution DOWEX® 50WX8 ion exchange resin (5 g) was added and stirred at ambient temperature for 0.5 h. The reaction mixture was ed through celite (1 cm) and the eluate was evaporated. The e was azeotropically dried with isopropanol, itrile, and acetone. The obtained solid was triturated with acetone (10 ml) and the mixture was kept at 0°C for 2 h. The precipitate was filtered and dried in vacuo over P205 to give 4.65 g (65%) of the 4- [ethyl(dimethyl)ammonio]butanoate (3).
(DMSO-de, HMDSO) 8: 1.24 (t, J=7.3 Hz, 3H); .76 (m, 2H); 1.81 (t, J=6.4 Hz, 2H); 2.95 (s, 6H); 3.16-3.23 (m, 2H); 3.29 (q, J=7.3 Hz, 2H). LCMS (ESI+, m/Z): 160 [M+H]+.
Anal. Calc. for 02- 1.55 H20: C 51.34; H 10.82; N 7.48.
Found: C 51.36, H 11.40, N 7.34.
Preparation of 3—carboxy-N—ethyl—N,N-dimethylpropanaminium 2- (acetyloxy)benzoate (4 a) 3—Carboxy—N—ethyl—N,N-dimethylpropanaminium 2-(acetyloxy)benzoate was ed in a form of a water mixture. Thus, ca. 90% 4-[ethyl- (dimethyl)ammonio]butanoate (3) (2.20 g, 12.44 mmol) and 2-(acetyloxy)—benzoic acid (2.266 g, 12.57 mmol) were placed in a volumetric flask and diluted with water up to 100 ml. The t of the mixture dissolves by heating and precipitates by lowering of the temperature. According to 1H-NMR, the precipitated solid material consists of almost pure 2-(acetyloxy)—benzoic acid.
Preparation of 3—carboxy-N—ethyl—N,N—dimethylpropanaminium (2E) carboxyacrylate (4 b) To a on of 4-[ethyl(dimethyl)ammonio]butanoate (3) (2.0 g, 12.56 mmol) in anh. ethanol (10 ml) a hot (60°C) solution of (E)-butenedioic acid (1.46 g, 12.56 mmol) in ethanol (50 ml) was added. The reaction mixture was allowed to stand at ambient temperature for 2 h, the precipitated crystals were filtered and dried over WO 46736 8 P205 to give 2.98 g (85%) of the 3-carboxy-N—ethyl-N,N—dimethylpropanaminium (2E)carboxyacrylate. M.p. 122-123°C. 1H-NMR (D20, D88) 6: 1.36 (tt, J=1.9, 7.3 Hz, 3H); 2.06 (m, 2H); 2.49 (t, J=7.1 Hz, 2H); 3.06 (s, 6H); 3.31 (m, 2H); 3.40 (q, J=7.3 Hz, 2H); 6.75 (s, 1.9H, CH=CH).
LCMS ESI+ (m/Z): 160 [M+H]+. Titration assays: water content r) 0.13%, betaine content (HCIO4) 93.0%, (E)-butenedioic acid content 46.1%.
Anal. Calc. for CBH17NOZ' 1.2 C4H4O4 ): C 51.50, H 7.36, N 4.69.
Found: C 51.52, H 7.35, N 4.61.
Preparation of 3—carboxy-N—ethyl—N,N—dimethylpropanaminium 3- carboxypropanoate (4 c) 3-Carboxy—N—ethyl-N,N—dimethylpropanaminium 3-carboxypropanoate was prepared in a form of a water on. Thus, ca. 90% 4-[ethyl- (dimethyl)ammonio]butanoate (3) (2.20 g, 12.44 mmol) and succinic acid (1.49 g, 12.62 mmol) were placed in a volumetric flask and ved and diluted with water up to 100 ml.
Preparation of 3-carboxy-N-ethyl-N,N—dimethylpropanaminium 2,6-dioxo— 1,2,3,6-tetrahydropyrimidinecarboxylate (4 d) To a solution of 4-[ethyl(dimethyl)ammonio]butanoate (3) (2.0 g, 12.56 mmol) in isopropanol (100 ml) 2,6-dioxo-1,2,3,6-tetrahydropyrimidinecarboxylic acid monohydrate (2.187 g, 12.56 mmol) was added and the reaction mixture was heated to reflux until all the carboxylic acid dissolved. The reaction mixture was allowed to cool to ambient temperature, the precipitated ls were filtered, washed with isopropanol (5 ml) and diethyl ether (20 ml), and dried over P205 to give 3.238 g (97.4%) of the 3-carboxy-N—ethyl-N,N—dimethylpropanaminium 2,6- dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate. M.p. 150.7°C. 1H-NMR (D20, D88) 6: 1.36 (tt, J=2.0, 7.3 Hz, 3H); 2.05 (m, 2H); 2.47 (t, J=7.0 Hz, 2H); 3.07 (s, 6H); 3.31 (m, 2H); 3.41 (q, J=7.3 Hz, 2H); 6.20 (s, 1H, C=CH).
LCMS ESI+ (m/Z): 160 [M+H]+.
Anal. Calc. for CBH17NOZ' C5H4N204 (49.5%): C 49.52, H 6.71, N 13.33.
Found: C 49.59, H 6.69, N 13.26.
Preparation of 3-carboxy-N—ethyl-N,N—dimethylpropanaminium dihydrogen phosphate (4 e) W0 46736 9 To a solution of 4-[ethy|(dimethy|)ammonio]butanoate (3) (6.4 g, 40 mmol) in water (10 ml) a solution of 85% aq. H3PO4 (4.73 g, 40 mmol) in acetone (10 ml) was added and the resulting on was stirred at ambient temperature for 10 min. The reaction mixture was evaporated and azeotropically dried several times with acetone by rotary evaporator at 45°C. The obtained white crystalline substance was dried over P205 to give 9.82 g (95%) ofthe 3-carboxy—N—ethyI-N,N—dimethylpropan- 1-aminium dihydrogen phosphate. M.p. 110-135°C. 1H-NMR (D20, D88) 8: 1.36 (tt, J=1.8, 7.3 Hz, 3H); 2.06 (m, 2H); 2.50 (t, J=7.0 Hz, 2H); 3.06 (s, 6H); 3.32 (m, 2H); 3.41 (q, J=7.3 Hz, 2H). LCMS ESI+ (m/Z): 160 [M+H]+. ion assays: water content (Fisher) 0.356%, betaine content (HCIO4) — 95.682%.
Anal. Calc. for C8H17N02' 0.052 H20 (0.356%) - 1.07 H3PO4 (39.6%): C 36.26; H 7.73; N 5.29.
Found: C 36.20, H 7.72, N 5.11.
The purity ofthe obtained 3—carboxy-N—ethyl—N,N—dimethylpropanaminium dihydrogen phosphate was sed by crystallization from methanol. Thus, the 3- carboxy-N—ethyI-N,N—dimethylpropanaminium dihydrogen phosphate (6.9 g) was crystallized from methanol (40 ml) to afford 5.326 g (77%) of the purified 3-carboxy- N—ethyI-N,N—dimethylpropanaminium dihydrogen phosphate with mp. 139°C.
Calc. for CBH17N02' H3PO4 ): C 37.36; H 7.84; N 5.45.
Found: C 37.52, H 7.85, N 5.39 Cardioprotective activity Fifty male, 10 weeks old Wistar rats weighing 200-250 g were housed under standard ions °C, 12 h light-dark cycle) with unlimited access to food (R3 diet, Lactamin AB, Sweden) and water.
Rats were adapted to local conditions for two weeks before the start of treatment.
Meldonium dihydrate at a dose of 20 mg/kg, gamma-butyrobetaine at a dose of 20 mg/kg and 3-carboxy-N—ethyl-N,N—dimethylpropanaminium salts at dose of 20mg/kg were administered p.0. daily for 8 weeks. Control rats received water.
Isolated rat heart infarction study The isolated rat heart experiment was performed essentially as described earlier (Liepinsh et al., J. vasc. Pharmacol. 2006; 48(6):314-9). Twenty-four hours after the last drug stration hearts were excised and retrogradely perfused via W0 2012/146736 10 the aorta at a constant pressure with oxygenated Krebs-Henseleit buffer at 37°C.
The heart rate, left ventricle end-diastolic pressure and left ventricle ped pressure were uously recorded. Coronary flow was measured using an ultrasound flow detector (HSE) and the PowerLab 8 /30 system from ruments. The hearts were perfused for 20 min to stabilize the hemodynamic functions and then ion was performed for 60 min by constricting threads through a plastic tube. Successful occlusion was confirmed by a coronary flow decrease of about 40 percent. Reperfusion was achieved by releasing the threads.
At the end of the 150-min reperfusion period, the risk zone was delineated with 0.1% methylene blue. The hearts were then sectioned transversely from the apex to the base in five slices 2 mm in thickness and incubated in 1% nyltetrazolium chloride in phosphate buffer (pH 7.4, 37°C) for 10 min to stain viable tissue red and necrotic tissue white. Computerized planemetric analysis of Sony A900 photographs was performed using Image—Pro Plus 6.3 software to ine the area at risk and area of is expressed as a % of the left ventricle. The obtained values were then used to calculate the infarct size (IS) as a % of risk area according to the formula: Infarct Size = Area of Necrosis/Area at Risk x 100%.
Effects in isolated rat heart infarction model The anti-infarction effect of examined substances was investigated in an isolated rat heart infarction model. During occlusion of left coronary artery, the coronary flow in all experimental groups was decreased for 40% (from 11 ml/min to 7 ml/min). er, the drop of developed left ventricular pressure for 50% was observed.
The heart rate during the occlusion period did not change significantly. In reperfusion stage, coronary flow, ped left ventricular pressure, idp/dt values were recovered till about 80% of l level. There were no significant differences n control and treatment groups.
Effects of Meldonium dihydrate (20 mg/kg), gamma—butyrobetaine (20 mg/kg) and 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salts (20 mg/kg) after 2 weeks of treatment on t size in the isolated rat heart infarction experiment are presented in Table 7, Tab/e2, Table 3, Table 4, Table 5, Table 6 Table 1 Effects of Meldonium dihydrate, gamma-butyrobetaine and oxy-N-ethyl-N,N- dimethylpropanaminium 2—(acetyloxy)benzoate on infarct size Infarct size, % of control Control 100.0 $5.9 Meldonium dihydrate 20 mg/kg 117.9 $7.9 butyrobetaine 20 mg/kg 87.6 $11.4 3-Carboxy-N-ethyl-N,N— dimethylpropanaminium 2— 61.6 $6.7*’#‘$ (acetyloxy)benzoate 20 mg/kg Table 2 Effects of Meldonium dihydrate, gamma-butyrobetaine and 3-carboxy-N—ethyl-N,N- dimethylpropanaminium (2E)carboxyacrylate on infarct size Infarct size, % of control l 100.0 $5.9 Meldonium dihydrate 20 mg/kg 117.9 $7.9 Gamma-butyrobetaine 20 mg/kg 87.6 $11.4 3-carboxy-N-ethyl-N,N- dimethylpropanaminium (2E)—3- 46.5 i7_o*.#.$ carboxyacrylate 20 mg/kg Table 3 Effects of Meldonium dihydrate, butyrobetaine and 3-carboxy-N-ethyl-N,N- dimethylpropanaminium 2,6-dioxo-1,2,3,6-tetrahydropyrimidine—4—carboxylate on infarct size Infarct size, % of control Meldonium dihydrate 20 mg/kg 117.9 $7.9 Gamma-butyrobetaine 20 mg/kg 87.6 $11.4 oxy—N-ethyl-N,N- dimethylpropanaminium 2,6- 60.6 $6.7*’#’$ dioxo-1,2,3,6-tetrahydropyrimidine- 4-carboxylate 20 mg/kg Table 4 Effects of Meldonium dihydrate, gamma-butyrobetaine and 3-carboxy-N-ethyl-N,N- ylpropanaminium dihydrogen phosphate on infarct size Infarct size, % of control Control 100.0 :59 Meldonium dihydrate 20 mg/kg 117.9 $7.9 butyrobetaine 20 mg/kg 87.6 $11.4 3-carboxy-N-ethyl-N,N- dimethylpropan—1—aminium 56.1 :4.4*’#‘$ dihydrogen phosphate 20 mg/kg Table 5 Effects of Meldonium dihydrate, gamma—butyrobetaine and 3-carboxy—N-ethyl-N,N- dimethylpropan—1-aminium 3-carboxypropanoate on infarct size Infarct size, % of control Meldonium dihydrate 20 mg/kg 117.9 $7.9 Gamma-butyrobetaine 20 mg/kg 87.6 111.4 3-carboxy-N-ethyl-N,N- dimethylpropanaminium 3- 62.9 14.7”?“$ carboxypropanoate 20 mg/kg Each values in mentioned Tables from 1-5 represents the mean i s.e.m. of 9-10 animals. *p<0.05 compared with control group; #p<0.05 compared with Gamma- butyrobetaine group, $p<0.05 compared with ium dihydrate group As it is presented in Tables 7-5, Meldonium dihydrate treatment at a dose of 20 mg/kg had no therapeutical ; gamma-butyrobetaine has decreased infarct size by 12.4 %. 3—Carboxy-N-ethyl-N,N-dimethylpropanaminium tyloxy)benzoate at dose of 20 mg/kg decreased infarction size by 38.4 %.
Carboxy-N-ethyl-N,N—dimethylpropanaminium -carboxyacrylate at dose of mg/kg decreased infarction size by 53.5 %. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium 2,6—dioxo-1,2,3,6— ydropyrimidine—4—carboxylate at dose of 20 mg/kg decreased infarction size by 39.4 %. 3-Carboxy-N-ethyI-N,N-dimethylpropan—1—aminium dihydrogen phosphate at dose of 20 mg/kg decreased infarction size by 43.9 %. 3-Carboxy-N-ethyI-N,N-dimethylpropan—1—aminium 3-carboxypropanoate at dose of 20 mg/kg decreased infarction size by 37.1 %.

Claims (1)

  1. Claims 1. 1. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium (2E)carboxyacrylate COOH - OOC N COOH 2. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium oxo-1,2,3,6- 5 tetrahydropyrimidinecarboxylate HN NH COO- O N COOH 3. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium dihydrogen phosphate H PO - 2 4 N COOH 4. A process for preparing 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salt 10 comprising: a. adding N,N-dimethylethylamine to ethyl 4-bromobutanoate in appropriate solvent to obtain xy-N-ethyl-N,N-dimethyloxo butanaminium bromide; b. passing 4-ethoxy-N-ethyl-N,N-dimethyloxobutanaminium 15 bromide through ion exchange resin column to obtain 4- [ethyl(dimethyl)ammonio] butanoate; c. adding acid selected from the group, consisting of fumaric acid, orotic acid and phosphoric acid in appropriate solvent to obtain the ponding 3-carboxy-N-ethyl-N,N-dimethylpropanaminium 20 salt. 5. A process according to claim 4, wherein in step a) the appropriate solvent is acetonitrile or acetone. 6. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium salt, selected from the group consisting of 3-carboxy-N-ethyl-N,N-dimethylpropanaminium (2E) 25 yacrylate, 2,6-dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate and dihydrogenphosphate for use as a medicament. 7. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium salt, selected from the group consisting of 3-carboxy-N-ethyl-N,N-dimethylpropanaminium, (2E) carboxyacrylate and 2,6-dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate and dihydrogenphosphate for use in treatment of cardiovascular diseases. 5 8. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium salt, selected from the group consisting of 3-carboxy-N-ethyl-N,N-dimethylpropanaminium, (2E) carboxyacrylate and 2,6-dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate and dihydrogenphosphate for use ing to claim 7, wherein the cardiovascular disease is ischemic heart disease. 10 9. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium salt, selected from the group consisting of 3-carboxy-N-ethyl-N,N-dimethylpropanaminium, (2E) carboxyacrylate and 2,6-dioxo-1,2,3,6-tetrahydropyrimidinecarboxylate and dihydrogenphosphate for use according to claim 8, wherein wherein the ic heart disease is myocardial tion. 15 10. 3-Carboxy-N-ethyl-N,N-dimethylpropanaminium salt, as herein described with nce to the examples. 11. A process for a preparing 3-carboxy-N-ethyl-N,N-dimethylpropanaminium salt, which process is substantially as herein described with nce to the examples.
NZ616467A 2011-04-27 2012-04-27 Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease NZ616467B2 (en)

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EP11163872 2011-04-27
EP11163840 2011-04-27
EP11163872.2 2011-04-27
EP11163871 2011-04-27
EP11163841 2011-04-27
EP11163840.9 2011-04-27
EP11163871.4 2011-04-27
EP11163841.7 2011-04-27
EP11163839 2011-04-27
EP11163839.1 2011-04-27
PCT/EP2012/057806 WO2012146736A1 (en) 2011-04-27 2012-04-27 Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease

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