NL1018758C1 - New amlodipine aspartate derivative useful as a calcium channel blocker for treating angina or hypertension - Google Patents

Abstract

Amlodipine aspartate derivative (I) is new. Amlodipine aspartate derivative of formula (I) and its salts are new. An Independent claim is also included for the preparation of (I).

Description

ASPARTATE 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. For example, EP 089 167 and according to US 4,572,909 describe a class of derivatives of 2-amino-3,5-dicarboxylate dihydropyridine as being useful calcium channel blockers. 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: cvr ^ NHz H3COvVv ° - / CH3 ^ oo &

Amlodipine shows good bioavailability and has a long half-life in the body. While it is taught in these patents that a variety of acid addition salts are suitable, the maleate salt has been identified as the most preferred acid addition salt. However, the commercial product of amlodipine (NORVASC from Pfizer) Ί0Ί 87 5 8 * 2 uses amlodipine besylate (benzene sulfonate) and not amlodipinema leaat. 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, which is available from the FDA under the Freedom of Information Act.) The items / causes of stability and tabletting are not described publicly in the FDA-available information.

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); H3Yt ^ ° ^ nY "cooh H3caYA ^ ° ^ _ / CH3 COOH o o 25 lY01 Ό (ï) 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 1018758-3 pharmaceutically acceptable salt thereof. Furthermore, the present invention can be used in combination with amlodipine as a pharmaceutical composition with active ingredients.

FIG. 1 shows a -NMR spectrum of the compound produced in Example 1.

Fig. 2 shows a 13 C NMR spectrum of the compound produced in Example 1.

The compound of formula (1) can be described as N- (2 - {[4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl-1,4-dihydro-2 pyridinyl] methoxy} ethyl) aspartic acid. It will be understood that the compound represented by the formula (1) may exist as the free acid or as the corresponding zwitterion form and, although 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 the single form, the compound may exist as one of several enantiomers due to the presence of two chiral centers; one on the 1,4-dihydropyridine ring and the other on the amino-s-substituent. The individual enantiomers as well as mixtures thereof are all encompassed 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, including mono-, di- or tri-alkyl amine compounds and ring amine compounds; 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 1018758-4 include inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, acetic, propionic, maleic, fumaric, tartaric, benzoic, methanesulfonic and benzenesulfonic acids. Salts can also be formed with ambivalent compounds such as amino acids, eg glycine or alanine. The salt of the compound of formula (1) can be a mono-salt, a di-salt or a mixed salt. Preferred salts include salts made with a pharmaceutically acceptable acid, especially maleic acid.

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 90 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 maleic acid. The reaction is illustrated below.

25 | COOH T T °

+ || -► H3CO ^ AvAn ^ -Ov ^, CH3 I.

0 T O | i 0 T o Nx> oh cooh rlr

30 U kJ

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 maleic acid in close contact with each other. However, only contacting amlodipine and maleic acid under mild conditions, such as good conditions for the formation of an acid addition salt, can result in low conversion rates and very low yields; eg no formation due to short contact times. The reaction is essentially a Michael addition and is thus accelerated by using conditions of higher pH, higher temperature and longer reaction or contact time. The reaction is preferably carried out in a melt phase or in a solution. A "melting phase" means that amlodipine is melted at least briefly while it is in the presence of maleic acid. When the run is in solution, the temperature is preferably at least 60 ° C, more preferably at least 80 ° C, and generally within the range of 85 ° C to 110 ° C. Solvents suitable for the addition reaction include non-polar solvents, for example N, N-dimethylformamide, alcohols such as ethanol and isopropanol, esters such as ethyl acetate and carbohydrates such as toluene.

The amlodipine and maleic acid are normally combined in approximately stoichiometric ratios, namely 0.9: 1 to 1: 0.9. A suitable method of conducting the reaction is to melt amlodipine maleate. Although the millic acid is actually pre-combined with the amlodipine, it is specifically considered to be within the scope of the present invention. Alternatively, the free base of amlodipine and amlodipine maleate can be combined in a solvent or dry mixed and melted etc. to carry out the reaction.

In certain embodiments, it is desirable to use an excess of amlodipine, such as where a mixture of amlodipine and a compound of formula (1) is desired. As discussed more fully below, a large molar excess of 35 amlodipine to maleic acid can be used, e.g., up to 50: 1, more commonly up to 20: 1, and generally 2: 1 to 10: 1 amlodipine to maleic acid on a molar basis to make the desired mixture.

1018758 · 6

The free base of amlodipine can be prepared according to the general procedures described in U.S. Pat. 4,572,909. Another useful synthetic scheme for making high yield and purity amlodipine and its salts via phthalimidoamlodipine as an intermediate is described in commonly owned provisional application No. 60 / 258,613, filed December 29, 2000, the entire contents of which is incorporated herein by reference, and in commonly owned co-pending U.S. patent application 09 / 809,351, which was filed March 16, 2001 and is entitled "Process for Making Amlodipine, Derivatives thereof and Precursors therefor", the entire contents of which are incorporated herein by reference. Maleic acid is commercially available.

The compound (1) can be isolated from the reaction medium by conventional methods such as evaporation, precipitation or by extraction and crystallization. Similarly, the compound of formula (1) can be purified by recrystallization from a solution or hot slurry, for example at the reflux temperature in a suitable solvent, eg an ester such as ethyl acetate, an alcohol such as ethanol, propan-2-ol or butan-2-ol, or a ketone such as acetone.

The enantiomers 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.

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 reaction with an equivalent amount of a base, such as, for example, sodium hydroxide, to form a sodium or 1018758 * 7 disodium 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 may benefit from the administration of a calcium channel blocking agent.

The calcium channel blocking activity of the compound of the invention (the ability to inhibit the transport of calcium in a cell) has been demonstrated by the degree of reduction in the contraction of isolated heart tissue, induced by the addition of calcium ions, in vitro. measure.

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 stable angina pectoris and vasospastic angina (Prinzmetal's angina). The compound can be administered by any suitable route, including orally or parenterally. The "patients" intended to be treated include humans and non-human animals, especially non-human mammals.

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 35 used in making a pharmaceutical dosage form. Tablet excipients include, but are not limited to, calcium phosphate, cellulose, starch or lactose. Capsules such as 1018758 * 8 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 injectable solutions. The pharmaceutical preparation can be formulated for 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 20 patch) is generally applied at least once a month, more commonly tenminster 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 0.1 - 100 mg, often 1 - 100 mg, more often 1 - 50 mg and normally 1 - 20 mg. In solid oral dosage forms (tablets, capsules, etc.), the pharmaceutical preparation generally contains 30 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 1018758 * 9 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 the free base or an acid addition salt, especially the maleate salt. The mixture can be obtained directly by controlling the reaction conditions and the time of forming the compound of formula (1); eg, using elevated temperatures, longer contact, proper proportions of maleic acid to amlodipine, etc. 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 for treating hypertension or angina. Specifically, such a pharmaceutical composition comprises an effective amount of the pharmaceutical composition with active ingredients and a pharmaceutically acceptable excipient as previously described. Similarly, the unit dose contains between 0.1 and 100 mg, generally 1 - 100, more generally 1 - 50 mg, such as 1 - 20 mg, and specifically the solid oral dosage forms (tablets, capsules, etc.) .) generally 1, 2.5, 5.0 or 10 mg of the pharmaceutical composition with active ingredients.

1018758 * 10

For simplicity, said amounts refer to the weight corresponding to the sum of the free base of amlodipine and the compound of formula (1).

The active ingredient pharmaceutical composition 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.

All 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 formulation for the above-described active ingredient formulation with good stability can be obtained by selecting the excipients so as to have a pH less than 7.0 when measured as a 20 wt% 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, Derivatives thereof and Precursors therefor", the entire contents of which are incorporated herein by reference.

Another use of the amlodipine aspartate 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 U.S. patent application 09 / 809,347, filed March 16, 2001, entitled "Reference Standard for Determining Purity or Stability or Amlodipine Maleate and * 018758 · 11 Methods therefor," the entire contents of which are incorporated herein by reference.

The following Examples illustrate the invention.

5

Example 1 16 g of amlodipine and 12 g of amlodipine maleate were melted in a 300 ml bottle. The molten substance was cooled to room temperature and dissolved in 300 ml of dichloromethane. The mixture was extracted with 300 ml of a 1 M NaOH solution. The organic layer was discarded and the water layer was acidified with 55 ml of a 6 M HCl solution. The mixture was extracted with 300 ml of dichloromethane. The layers were separated and the organic layer was dried over Na2 SO4. The mixture was evaporated to dryness and the resulting waxy solid was recrystallized from ethanol. The resulting tacky solid was dried in a vacuum oven at 40 ° C, leaving 4.7 g of an off-white product.

Yield: 4.7 g (39%).

Melting point: 178 ° C - 183 ° C (decomposed).

Purity: higher than 90%.

25 6G-CI

^ -NMR spectrum: o ^ O O

14 ^ 4fYo ^ 12 3 "[A) H ^ NHVY ^ ifVH

30

The 1 H NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated dimethyl sulfoxide at 400 MHz. It is shown in Fig. 1.

101875812 δ assignment 1.12 (t, 3H, Jn 12 = 7.0 Hz, 3x H-12); 2.36 (s, 3H, 3x H-15); 5 2.87 (m, ~ 2H, 2x H-3 "); 3.23 (m, ~ 2H, 2x H-9); 3.52 (S, ~ 3H, 3x H-14); 3.76 (bs, 2H, XH-8); 4.00 (m, 3H, 2x H-11 + H-2 "); 4.65 (m, 2H, 2x H-7); 5.33 (S, 1H, H-4); 7.13 (dt, 1H, J31 / 4 = J4.5 = 7.6 Hz, J4.6 = 1.8 Hz, H-4 '); 7.26 (m, 2H, H-3 '+ H-5'); 7.37 (d, 1H, J5, 6. = 7.8'Hz, H-6 '); 8.61 (S, 1H, NH).

13 C NMR spectrum:

The 13 C NMR spectrum was measured at 303.2 K on a Bruker Avance-400 in deuterated dimethyl sulfoxide at 100.6 MHz. It is shown in Fig. 2.

δ Award Ö Award 25 14.18 (C-12); 66.64, 66.69 (C-7, C-8); 18.33 (C-15); 101.92, 102.40 (C-3, C-5); 35.77 (C-3 "); 127.54 (C-5 '); 36.85 (C-4); 127.88 (C-4'); 45.63, 45.74 (C-9 ); 129.07 (C-2 '); 50.58 C-14); 131.11 (C-6'); 56.42 (C-2 "); 166.43 (C-10); 59.50 (C-11); 167.28 (C-13); 170.55, 171.49 (C-1 ", C-4").

Example 2 - A mixture of amlodipine maleate and the compound of formula (1) 2.00 g of amlodipine maleate was dissolved in 80 ml of 2-propanol at 92 ° C. The clear, light yellow colored 1018758 «13 solution was refluxed for 10 minutes and then allowed to cool to ambient temperature without stirring.

A solid was formed and the suspension was allowed to cool to 4 ° C. The solid was filtered and washed with 5 ml of cold 2-propanol and dried under vacuum at ambient temperature for 1 hour.

Yield: 1.86 g of a mixture containing 1% of the compound of formula (1) and 99% amlodipine maleate.

10

Example 3

Pharmaceutical preparations (tablets) containing the compound of formula (1).

per 5 mg tablet per 10 mg tablet 15 Compound of formula (1) 5.0 mg 10.0 mg (Amlodipine aspartate)

Calcium hydrogen phosphate 63.0 mg 126.0 mg some ex

Magnesia Oxide 4.0 mg 8.0 mg 20 Microcrystalline Cellosis 126.0 mg 252.0 mg

Wet rium starch glycol leaves 4.0 mg 8.0 mg

Magnesium stearate 2.0 mg 4.0 mg

Total 204.0 mg 408.0 mg 25 Production method:

The amlodipine aspartate is sieved through a 500 μl strainer.

The anhydrous calcium hydrogen phosphate, the magnesium oxide, the microcrystalline cellulose, the sodium starch glycollate and the magnesium stearate are sieved through an 850 µ screen.

The amlodipine aspartate, the magnesium oxide and about 30% of the amount of microcrystalline cellulose (MCC) are added for 10 minutes. 14 at about 25 rpm mixed in a free-fall mixer.

The remaining amount of MCC, anhydrous calcium hydrogen phosphate and sodium starch glycollate are added and the mixture is stirred at about 25 rpm for 15 minutes. mixed.

The magnesium stearate is added and the powder mixture is stirred for an additional 5 minutes at 25 rpm. mixed.

Amlodipine aspartate tablets are pressed.

15

Example 4

Pharmaceutical preparations (tablets) containing the compound of formula (1).

per 5 mg tablet per 10 mg tablet 20 Compound of formula (1) 5.0 mg 10.0 mg (Amlodipine aspartate)

Calcium hydrogen phosphate 63.0 mg 126.0 mg anhydrous

Microcrystalline fine cellose 126.0 mg 252.0 mg 25 Sodium starch glycollate 4.0 mg 8.0 mg

Magnesium stearate 2.0 mg 4.0 mg

Total 200.0 mg 400.0 mg

Production method: 30 - The amlodipine aspartate is sieved through a 500 μτη sieve.

The anhydrous calcium hydrogen phosphate, the magnesium oxide, the microcrystalline cellulose, the 1018758 * 15 sodium starch glycollate and the magnesium stearate are screened through an 850 µm screen.

The amlodipine aspartate, the microcrystalline cellulose, the anhydrous calcium hydrogen phosphate and the sodium starch flour glycollate are transferred to a free-fall mixer and the mixture is stirred at about 25 rpm for 15 minutes. mixed.

The magnesium stearate is added and the powder mixture is stirred for an additional 5 minutes at 25 rpm. mixed.

Amlodipine aspartate tablets are pressed.

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 by practicing the invention, without departing from the spirit and scope of the invention as defined by the following claims.

f0187 5 8 * »

Claims (23)

1. Compound of formula (1) H3CYnT ^ O ^ nY "cooh h3cov ^ AsJL.o.___, ch3 cooho o Qra ^ (1) or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein said compound is a 11alkali metal salt, an amine salt or an acid addition salt. A compound according to claim 1 or 2, wherein the compound is an amine salt. The compound of claim 3, wherein the amine salt is an amlodipine salt of this compound. 5 J ^ CI CX (1) or a pharmaceutically acceptable salt thereof. A compound according to claim 1 or 2, wherein the compound is a maleate salt. 6. Pharmaceutical preparation for the treatment of angina or hypertension, which is an effective amount of a compound of formula (1): H3CY "V ^ °" '' ^ Y''C00h H3COvAsAs.O ^ CH3 cooh oo (J ^ (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical preparation according to claim 6, wherein the compound of formula (1) is in a pharmaceutically acceptable salt form and the preparation is in unit dose form. A pharmaceutical composition according to claim 6 or 35, wherein the pharmaceutically acceptable salt is a 1018758 «maleate salt and the compound of formula (1) is present in an amount corresponding to 0.1-100 mg. Pharmaceutical preparation according to any one of claims 6-8, wherein the preparation is in a unit dose form and the compound of formula (1) is present in an amount corresponding to 1.0-100 mg. 10. A process comprising: reacting amlodipine or a salt thereof with maleic acid to form a compound of formula (1) or a salt thereof: Η H Η3Υίγ ° —No ^ cOOH HaCO2 AA / O ^ CHa COOH OO u ^ (1). 11. A method according to claim 10, wherein this reaction step is carried out at a temperature above 60 ° C. The method of claim 10 or 11, wherein the reaction step is performed at a pH greater than 7. The method of any of claims 10-25 12, wherein the reaction step is performed in a melt phase. A method according to any of the preceding claims 10-12, wherein the reaction step is performed in a solvent. A method of treating or preventing angina or hypertension, comprising administering an effective amount of the compound / composition according to any one of claims 1-9 to a patient in need. 16. Pharmaceutical composition with active ingredients, which is a mixture of amlodipine or a pharmaceutically acceptable salt thereof and a compound of formula (1) f0T8758i "'ν ^ ο ^ γ ^ αιοκ Π’ ^ νΥΥ ^ 3 COOH ο ο The composition of claim 16, wherein the composition contains 100 parts by weight of the amlodipine and 0.1-1000 parts by weight of the compound of formula (1). 18. A composition according to claim 16 or 17, wherein the composition contains the compound of formula (1) in an amount of 0.5-500 parts by weight. 19. A composition according to any one of claims 16-18, wherein the composition contains 100 parts of amlodipine maleate and 2-100 parts of the compound of formula (1) or the maleate salt thereof. 20. 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 16-19 and a pharmaceutically acceptable excipient. The pharmaceutical preparation according to claim 20, wherein said pharmaceutical preparation is a unit dose form. The pharmaceutical composition according to claim 21, wherein the effective amount of this pharmaceutical composition with active ingredients is in the range of 1 - 20 mg. 23. A method of treating or preventing angina or hypertension, comprising administering to an patient in need an effective amount of a pharmaceutical composition with active ingredients according to any one of claims 16-19 and / or a 1018758 effective amount of a pharmaceutical preparation according to any one of claims 20-22. 1018758