NL1018757C1 - New amlodipine maleamide useful as a calcium channel blocker for treating angina or hypertension - Google Patents

Abstract

Amlodipine maleamide (I) or its salts, are new. Amlodipine maleamide of formula (I) or its salts, are new: Independent claims are also included for: (1) a composition comprising (I) and optionally amlodipine; and (2) a process for preparing (I).

Description

AMIDE DERIVATIVE OF AMLODIPINE

The present invention relates to a new compound, to methods of preparing it and to its use in the treatment of medical disorders. In particular, the present invention relates to a new derivative of Amlodipine.

Calcium channel blockers (calcium channel blockers) are useful in treating heart disease, including angina and / or hypertension. Dicarboxylate dihydropyridine derivatives are well known to have calcium channel blocking activity. EP 089 167 and according to US 4,572,909 describe a class of 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as useful calcium channel blocking agents. These patents identify that one of the most preferred compounds is 2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, now commonly known as amlodipine, has the following formula: · cYr ^ —NHz H3C ° YtT ° ^ CH3 25 0 0 σα

Amlodipine shows good bioavailability and has a long half-life in the body. While these patents teach that a variety of acid addition salts are suitable, the maleate salt is identified as the most preferred acid addition salt. However, the commercial product of amlodipine (NORVASC from Pfizer) '1018757 * 2 uses amlodipine besylate (benzene sulfonate) and not amlodipinema leaate. Indeed, the subsequent patent EP 244 944 and according to US 4,879,303 indicate that the besylate salt offers certain advantages over the known salts, including good formulation properties. Apparently amlodipine maleate suffered from tabletting and stability problems and this led to the switch to the besylate salt during development. (See "Reviews of Original NDA" for NDA # 19-787 of 10.10.90, available from the FDA under the Freedom of Information Act). The items / causes of stability and tabletting are not publicly described in the information available from the FDA.

The present invention relates to the discovery of a new derivative of amlodipine, its use and methods of making it. Specifically, the present invention provides a compound of the following formula (1);

H3CCVtt ° ^ 'CH3 0 ^ ° ° H

o o 25 ^ (1) or a pharmaceutically acceptable salt thereof.

The compound of formula (1) is useful as a calcium channel blocking agent and further aspects of the invention therefore pertain to a pharmaceutical composition comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable an acceptable excipient, as well as to a method of treating angina or hypertension by administering to an patient in need an effective amount of a compound of formula (1) or a fOT8757w 3 pharmaceutically acceptable salt thereof. Furthermore, the present invention can be used in combination with amlodipine as a pharmaceutical composition with active ingredients. The compound of formula (1) can be made by a method comprising reacting amlodipine or a salt thereof with a carbonyl activated maleic acid compound.

Fig. 1 shows the h NMR spectrum for the material of Example 1.

The compound of formula (1) can be described as (Z) -4- [(2 - {[4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl 1,4-dihydro-2-pyridinyl] methoxy} -ethyl) amino] -4-oxo-2-butenoic acid. It will be understood that the compound represented by formula 15 (1) may exist as the free acid form or as the corresponding zwitterion form and, while both forms are included within the meaning of the structural formula, only the free acid form is shown for simplicity . Furthermore, it should be understood that although the compound of formula (1) is referred to in singular, the compound may exist as one of two isomers caused by a chiral center on the 1,4-dihydropyridine ring, or as a mixture of isomers, all of which are embraced by the single term "compound".

The compound of formula (1) can be in the form of a salt and is generally a pharmaceutically acceptable salt. Salts include those formed with a metal cation such as an alkali metal cation; Those formed with ammonia or an amine compound; or with an acid. More specifically, metal salts include sodium, potassium and lithium salts of the compound of formula (1). Ammonium and amine salts include salts made with ammonia, methylamine, dimethylamine, triethylamine, pyridine and amlodipine. Suitable acids for the salts include inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, acetic, propionic, 1018757 * 4 maleic, fumaric, tartaric, benzoic, methanesulfonic and benzenesulfonic acids. Salts can also be formed with ambivalent compounds such as amino acids, e.g. glycine or alanine. Preferred salts include salts made with a pharmaceutically acceptable acid, especially maleic acid. Another preferred salt is the salt formed with amlodipine and the compound of formula (1), especially in a 1: 1 molar ratio of the compound of formula 10 (1) with amlodipine.

The compound of formula (1) and its salts are normally solid at room temperature and they can be crystalline or amorphous. The crystalline forms include anhydrate forms, hydrated forms and solvate forms. The compound can be isolated and thus be of relatively high purity, generally more than 50 wt% pure, preferably more than 75 wt% pure, more preferably more than 95 wt% pure. However, relatively impure forms are also included, such as dissolved forms.

The compound of formula (1) can be made by reacting amlodipine or a salt thereof with a carbonyl-activated maleic acid compound. The reaction is essentially an amidation reaction and is thus aided by the presence of an acidic catalyst, elevated temperature, etc. and the like other amidation conditions well known to those skilled in the art. A "carbonyl-activated maleic acid compound" means maleic acid or a derivative thereof that has a sufficiently activated carbonyl group to facilitate the amidation reaction with amlodipine. In some embodiments, the carbonyl activation is accomplished by the presence of an acidic catalyst, generally a Lewis acid such as aluminum chloride or phosphoric acid. However, the preferred embodiment is to use maleic anhydride, which provides an activated 1018757e carbonyl group without the need for a catalyst. Maleic acid as such and in the absence of a catalyst or activator is not a carbonyl-activated millic acid compound and will not readily form a compound of formula (1), even when brought in the presence of amlodipine. The reaction with maleic anhydride is shown below.

10

H3co ^ i_A ^ ° - ^ CH3 + I ^ cOOH

if Qyci 15

In general, the formation reaction of the compound of formula (1) can be carried out by bringing the free base of amlodipine or a salt thereof and the carbonyl-activated maleic acid compound in close contact with each other. Preferably, the reaction is carried out at an elevated temperature, such as 25-100 ° C, more usually 35-50 ° C, and in a suitable solvent. Solvents suitable for the addition reaction include polar aprotic solvents, for example N, N-dimethylformamide, alcohols such as ethanol and isopropanol, esters such as ethyl acetate, and hydrocarbons such as toluene. The amlodipine and the carbonyl-activated maleic acid compound are normally combined in approximately stoichiometric ratios, namely 0.9: 1 to 1: 0.9. However, an excess of amlodipine may be advantageous in case the amlodipine salt of the compound of formula (1) is desired. Also in cases 35. where a mixture of amlodipine and a compound of formula (1) is desired, as discussed more fully below, a large molar excess of amlodipine to carbonyl-activated maleic acid compound can be used, e.g., up to 50: 1, more commonly up to 20: 1 and generally 2: 1 to 10: 1 amlodipine to carbonyl-activated maleic acid compound on a molar basis. Also, in this embodiment, a non-carbonyl-activated maleic acid compound can be provided simultaneously with the carbonyl-activated maleic acid compound to form a mixture of amlodipine maleate salt and a compound of formula (1).

The free base of amlodipine can be prepared according to the methods generally set forth in US Patent 4,572,909. Another useful synthetic scheme for making amlodipine or salts thereof with good yields and purity via a 15 phthalimidoamlodipine intermediate is described in commonly owned provisional application No. 60 / 258,613, filed December 29, 2000, of which all contents are incorporated herein by reference, and in commonly owned co-pending U.S. Patent Application 09 / 809,351, filed March 16, 2001, entitled "Process for Making Amlodipine, Its Derivatives and Precursors therefore ", the entire contents of which are incorporated herein by reference. Maleic acid and its anhydride as well as acidic catalysts are all commercially available.

The compound (1) can be isolated from the reaction medium by conventional methods such as evaporation or precipitation, and it can be purified by crystallization, for example at the reflux temperature in a suitable solvent, for example an ester such as ethyl acetate, an alcohol such as propane-2 -ol, or a ketone such as acetone. The stereoisomers can be separated by crystallization or chromatography, optionally in the form of a salt, for example, as a salt with an optically active base or acid, by methods well known in the art.

1018757 * 7

Treatment of compound (1) with an equivalent amount of an acid such as maleic acid, optionally followed by an isolation step such as precipitation, evaporation or freeze drying, produces an acid addition salt of the compound of formula (1) with the acid. Other salts of compound (1) can be formed by reacting with an equivalent amount of a base such as, for example, sodium hydroxide to form a sodium salt of the compound of formula (1).

The compound of formula (1) and pharmaceutically acceptable salts thereof are useful calcium channel blocking agents and thus can be used to treat any heart disease that would benefit from the administration of a calcium channel blocking agent. In addition, the compound of formula (1) can be converted to amlodipine by hydrolysis of the amide bond. Hydrolysis of the amide bond can occur in vivo, e.g. due to body metabolism after administration. Therefore, the compound of formula (1) and pharmaceutically acceptable salts thereof can be used as a "prodrug" for amlodipine and thus they can be used in the same way and they are useful in treating the same heart diseases as amlodipine.

In particular, the compound of formula (1) and pharmaceutically acceptable salts thereof can be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need. The specific form of angina is not particularly limited and specifically includes chronic stable angina pectoris and vasospastic angina (Prinzmetal's angina). The compound can be administered by any suitable route, including orally or parenterally. The 35 "patients" intended to be treated include humans and non-human animals, especially non-human mammals.

f0t8757 · 8

The compound is usually administered as part of a pharmaceutical preparation. Therefore, a further aspect of the invention is a pharmaceutical composition for treating hypertension or angina, which contains an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Excipients include any inert or inactive material used in making a pharmaceutical dosage form. Tablet excipients include, but are not limited to, calcium phosphate, cellulose, starch or lactose. Capsules such as those made from gelatin may contain or carry the compound of formula (1) or a pharmaceutically acceptable salt thereof alone or in admixture with other excipients. Liquid dosage forms are also included, such as oral liquids in the form of drinks or suspensions, as well as non-injectable solutions. The pharmaceutical preparation can be formulated by transdermal administration in the form of a patch. All of the pharmaceutical compositions described above may optionally contain one or more of any of the following excipients: carriers, diluents, dyes, flavors, lubricants, solvents, disintegrants, binders and preservatives.

The pharmaceutical preparation is normally provided in a unit dose. A unit dose is generally administered once or twice a day, more usually once a day. In the case of a transdermal patch, the unit dose (one patch) is generally applied at least once a month, more usually at least once every two weeks and usually once a week. An effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof in a unit dose for treating or preventing hypertension or angina is generally in the range of 1 - 100 mg, 1018757-9 often 1 - 50 mg, usually 1 - 20 mg. In solid oral dosage forms (tablets, capsules, etc.), the pharmaceutical preparation generally contains 1, 2.5, 5.0 or 10 mg of the compound of formula (1) or a pharmaceutically acceptable salt thereof. For simplicity, all amounts refer to the corresponding amount of the free base provided in the composition.

Another embodiment of the invention relates to the use of a mixture of the compound of formula (1) or a pharmaceutically acceptable salt thereof with amlodipine or a pharmaceutically acceptable salt thereof. The combination of these two pharmaceutically active agents can form a useful pharmaceutical composition with active ingredients. Generally, the active ingredient pharmaceutical composition comprises (a) 100 parts by weight of amlodipine or a pharmaceutically acceptable salt thereof and (b) about 0.1 to about 1000 parts by weight, usually 0.5-500 parts by weight, more generally 2 - 100 parts by weight of a compound of formula (1) or a pharmaceutically acceptable salt thereof. The amlodipine is preferably in the form of an acid addition salt, especially the maleate salt. The compound of formula (1) is preferably an acid addition salt, especially the maleate salt, or an amlodipine salt or a mixture thereof. The mixture can be obtained directly by controlling the ratio of the carbonyl-activated maleic acid compound to non-carbonyl-activated maleic acid and / or the amount of amlodipine. Alternatively, the active ingredient pharmaceutical composition can be formed by mixing the amlodipine compound with the compound of formula (1) (or their respective salt forms, etc.) in the desired ratio.

The active ingredient pharmaceutical composition can be used in the same manner as the compound of formula (1) to form a pharmaceutical composition 101875710 for the treatment of hypertension or angina. Specifically, such a pharmaceutical composition contains an effective amount of the pharmaceutical composition with active ingredients and a pharmaceutically acceptable excipient as previously described. Similarly, the unit dose contains between 1 and 100 mg, generally 1 - 50 mg, more often 1 - 20 mg, and specifically the solid oral dosage forms (tablets, capsules, etc.) generally contain about 1, 2, 5, 5.0 or 10 mg of the pharmaceutical composition with active ingredients. For simplicity, said amounts refer to the weight corresponding to the sum of the free base of the amlodipine and the compound of formula (1).

The pharmaceutical composition with active ingredients as such or in the form of a pharmaceutical composition can be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need thereof.

All of the pharmaceutical preparations described above can be made by known methods and techniques. For example, the tablets can be made by dry granulation / direct compression or by a conventional wet granulation method. Similarly, capsules can be made by mixing the ingredients and filling the capsule. A suitable pharmaceutical composition for the above-described active ingredient pharmaceutical composition having good stability can be obtained by selecting the excipients so as to have a pH less than 7.0 when measured as a 20% aqueous slurry as more fully described in commonly owned co-pending U.S. Patent Application 09 / 809,351, filed March 16, 2001, entitled "Process for Making Amlodipine, Its Derivatives and 101875711 Precursors therefore ", the entire contents of which are incorporated by reference herein.

Another use of the amlodipine maleeamide of formula (1) is as a reference standard or reference marker for assessing the purity of amlodipine maleate and pharmaceutical preparations containing amlodipine maleate, as more fully described in commonly owned United States Patent Application 10 09 / 809,347 which was filed March 16, 2001 and is entitled "Reference Standard for Determining the Purity or Stability of Amlodipine Maleate and Methods Therefor," the entire contents of which are incorporated by reference.

The following Examples illustrate the invention.

Example 1 - Preparation of the compound of formula (1)

5 g of amlodipine was dissolved in 50 ml of ethyl acetate and heated to 60 ° C. 1.15 g of maleic anhydride was added to the mixture and the mixture was shaken until the solution was clear. The mixture was cooled to room temperature and left overnight. The mixture was evaporated to dryness and then dried in a high vacuum oven at 25 ° C

for 3 hours, leaving a yellow solid.

Yield: 6.1 g (99%)

Melting point: 83 ° C - 86 ° C 30 Purity: higher than 95% (HPLC) H.NMR spectrum:

The 1 H NMR spectrum was measured at 303 K on a Bruker Avance-400 in deuterated dimethyl sulfoxide at 400 MHz. The spectrum is shown in Fig. 1.

101875? ^ 12 δ assignment 1.12 (t, 3H, J1l l2 = 7.0 Hz, 12-H3) 2.31 (s, 3H, 15-H3) 5 3.44 (bq, -2H, 9-H2) 3.52 (s, ~ 3H, 14-H3) 3.58 (bt, 2H, 8-H2) 3.99 (ra, ~ 2H, 11-H2) 4.62 (ABq, 2H, 7-H2) 5.32 (S, 1H, 4-H) 6.27 (d, ~ 1H, J4.1 <5, = 12.4 Hz, 4 "-H) 6.43 (d, ~ 1H, J4.1> 5, = 12.4 Hz, 5 "-H) 7.13 (dt, 1H, J314, = = 7.7 Hz, = 1.6 Hz, 4'-H) 15 7.23 (dt, 1H, J4, = <5, = J5I> 6, = 7.7 Hz, J3.5, = 1.0 Hz, 5'-H) 7.28 (dd, 1H, J31 <4, = 7.7 Hz, J315. = 1, 0 Hz, 3'-H) 7.34 (dd, 1H, J41f6, = 1.6 Hz, J5,6I = 7.7 Hz, 20 6'-H) 8.49 (S, ~ 1H, 1- H) 9.24 (bt, -1H, 9'-NH).

Example 2 - Preparation of a mixture of amlodipineralate and amlodipine amide 5 g of amlodipine was dissolved in 50 ml of ethyl acetate at 60 ° C. 1.28 g of maleic acid and 0.12 g of maleic anhydride were added to the solution and the mixture was shaken until clear. The mixture was slowly cooled to room temperature during which time a solid precipitate formed. The solid was filtered off and washed with 10 ml of ethyl acetate. After drying in a vacuum oven at 35 ° C for 18 hours, 5.55 g of a solid was obtained.

35

According to HPLC analysis, the content of the compound of formula (1) relative to amlodipine maleate was 1.8%.

10t 8757 * 13

Having described the invention, it will be readily apparent to those skilled in the art that further changes and modifications in the actual implementation of the ideas and embodiments described herein can be easily made or learned in the practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

1018757 *

Claims (22)

1. Compound of formula (1) h H HCO3 AA AA OCH3 CH3 O COOH A compound according to claim 1, wherein said compound is an alkali metal salt, an amine salt or an acid addition salt. A compound according to claim 1 or 2, wherein this compound is an amine salt. A compound according to claim 3, wherein this amine salt is an amlodipine salt of the compound. A compound according to claim 1 or 2, wherein this compound is a maleate salt. XI V- * (1) or a pharmaceutically acceptable salt thereof. 6. Pharmaceutical composition for treating angina or hypertension, which is an effective amount of a compound of formula (1) H3CCL AJL / O ^ CH3 O COOH H 1 T kJ (1) 30 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. A pharmaceutical composition according to claim 6, wherein the compound of formula (1) is in a pharmaceutically acceptable salt form and the composition is in unit dose form. 1018757 « A pharmaceutical composition according to claim 6 or 7, wherein the pharmaceutically acceptable salt is a maleate salt and the compound of formula (1) is present in an amount corresponding to 1 - 100 mg. A method comprising: reacting amlodipine or a salt thereof with a carbonyl-activated maleic acid compound to form a compound of formula (1) or a salt thereof: The method of claim 9, wherein the carbonyl-activated maleic acid compound is maleic anhydride. 10. H H 3 COYyVOs / CH 3 ° cooh o o 15 ^ (1). The method of claim 9, wherein the carbonyl-activated maleic acid compound is maleic acid in the presence of an acidic catalyst. The method of claim 11, wherein said acidic catalyst is a Lewis acid. The method of any of claims 9-12, wherein the reaction step is performed in a solvent. 14. A method of treating or preventing angina or hypertension, comprising administering an effective amount of the compound / composition according to any one of claims 1-8 to a patient in need thereof. 15. Pharmaceutical composition with active ingredients, containing amlodipine or a pharmaceutically acceptable salt thereof and a compound of formula (1) 1018757 · H3CO ^ AJk.O ^ CH3 Ο COOH Ο Ο ΓΎα (1) or a pharmaceutically acceptable salt thereof. The composition of claim 15, wherein the composition contains 100 parts by weight of the amlodipine and 0.1-1000 parts by weight of the compound of formula (1). 17. A composition according to claims 15-16, wherein this composition contains the compound of formula (1) in an amount of 0.5-500 parts by weight. The composition according to any one of claims 15-17, wherein said composition contains 100 parts of amlodipine maleate and 2 - 100 parts of the maleate salt, the amlodipine salt or both salt forms of the compound of formula (1). A pharmaceutical composition for treating or preventing angina or hypertension, containing an effective amount of the active ingredient pharmaceutical preparation according to any one of claims 15-18 and a pharmaceutically acceptable excipient. The pharmaceutical preparation according to claim 19, wherein said pharmaceutical preparation is a unit dose form. 21. A pharmaceutical composition according to claim 20, wherein the effective amount of the pharmaceutical composition with active ingredients is in the range of 1 - 20 mg. 22. A method of treating or preventing angina or hypertension, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition with active ingredients according to any one of claims 15-18 and / or a pharmaceutical composition according to any one of claims 19-21. 1018757 *