SI21065A2 - Aspartate derivative of amlodipine - Google Patents

Abstract

An amlodipine derivative having the following formula is useful, either alone or in combination with amlodipine, as a pharmaceutical in treating angina and hypertension.

Description

Aspartate derivative of amlodipine

The present invention relates to a new compound, to methods for its preparation and its use in the treatment of medical disorders. In particular, the present invention relates to a novel derivative of amlodipine.

Calcium channel blockers (calcium antagonists) are useful in the treatment of heart conditions, including angina and / or hypertension. Dicarboxylate-dihydropyridine derivatives are generally known to have calcium channel blocking activity. E.g. EP 089 167 and the corresponding US 4,572,909 describe a class of 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as useful calcium channel blockers. These patents identify that one of the most preferred compounds is 2 - [(2aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, now commonly known as amlodipine, has the following formula:

Amlodipine has good bioavailability and a long half-life in the body. Many of the acid addition salts are described in these patents, but the most preferred acid addition salt is the maleate salt. However, the marketed product of amlodipine (NORVASC from Pfizer) uses amlodipine besylate (benzene sulfonate) rather than amlodipine maleate. Indeed, the following patent EP 244 944 and the corresponding US 4,879,303 state that the besylate salt has certain advantages over the known salts, including good formulation properties. Apparently, the disadvantages of amlodipine maleate were problems with tableting and stability, so this caused a leap during development into the besylate salt. (See Original NDA Review for NDA # 19-787 dated 10/10/1990, obtainable from the FDA under the Freedom of Information Act). Questions a / causes of stability and tableting are not publicly available in information available from the FDA.

The present invention relates to the discovery of a new derivative of amlodipine, to its use and to processes for its preparation. Specifically, the present invention is a compound of the following formula (1)

or a pharmaceutically acceptable salt thereof.

The compound of formula (1) is useful as a calcium channel blocker, and thus further aspects of the invention pertain to a pharmaceutical composition that both administers an effective amount of a compound of formula (1) or its pharmaceutically acceptable salts and a pharmaceutically acceptable excipient, as well as a method for treating angina or hypertension by administering to the patient in need of treatment an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof. Further, the present invention can be used in combination with amlodipine as a composition of a pharmaceutically active ingredient.

FIG. 1 shows the N-NMR compounds prepared in Example 1.

3

FIG. 2 shows the C-NMR compounds prepared 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 is understood that a compound of formula (1) may exist as a free acid form or as a form of a corresponding amphoteric ion, but for simplicity only the free acid form is shown, although both forms are included in the meaning of the structural formula. Furthermore, although a compound of formula (1) is singularly mentioned, it should be understood that the compound can exist as one of many enantiomers due to the presence of two chiral centers; one on the 1,4-dihydropyridine ring and the other on the amino nitrogen substituent. The individual enantiomers as well as mixtures thereof are all covered by the singular compound.

The compound of formula (1) may be in the form of a salt and is typically a pharmaceutically acceptable salt. Salts include those obtained with a metal cation as an alkali cation; those obtained with ammonia or an amine compound, including mono-, di- or trialkylamine compounds and ring amine compounds, or with acid. Specifically, the metal salts of the sodium, potassium and lithium salts of the compounds of formula (1) are included. Ammonia and amine salts are salts prepared with ammonium, methylamine, dimethylamine, triethylamine, pyridine and amlodipine. Suitable acid salts are salts of inorganic and organic acids such as hydrochloric, sulfuric, phosphoric, acetic, propionic, maleic, fumamic, tartaric, benzoic, methanesulfonic and benzenesulfonic acids. Salts can also be formed with ambivalent compounds such as amino acids, e.g. glycine or alanine. The salt of the compound of formula (1) may be a mono-salt, a di-salt or a mixed salt. Preferred salts are salts prepared with a pharmaceutically acceptable acid, in particular maleic acid.

The compound of formula (1) and its salts are normally solid at room temperature and may be crystalline or amorphous. Crystalline forms are anhydrous forms, hydrated forms and solvate forms. The compound may be isolated at a relatively high purity, typically greater than 50% by weight, preferably over 75% by weight, more preferably over 90% by weight, pure. However, relatively impure forms are also included as are dissolved forms.

The compound of formula (1) can be prepared by metabolizing amlodipine or a salt thereof with maleic acid. The reaction is shown below.

In general, the reaction of preparing a compound of formula (1) can be carried out by bringing the amlodipine free base or its salt and maleic acid in close contact with one another. However, they can only result from contacting amlodipine and maleic acid under mild conditions such as good acid addition salt conditions, low conversion rates and very low yields. E.g. no formation due to short contact times. The reaction is essentially Michael's addition and is thus accelerated using conditions of higher pH, higher temperature and longer reaction or contact time. The reaction is preferably carried out in the melt phase or in solution. The melt phase means that amlodipine melts at least instantaneously when it is in the presence of maleic acid. When carried out in solution, the temperature is preferably at least 60 ° C, more preferably at least 80 ° C and typically in the range of 85 ° C to 110 ° C. Among the solvents suitable for the addition reaction are semi-aprotic solvents, e.g. Ν, Ν-dimethylformamide, alcohols such as ethanol and isopropanol, esters such as ethyl acetate, and hydrocarbons such as toluene.

Amlodipine and maleic acid are usually combined in approximately stoichiometric proportions, namely 0.9: 1 to 1: 0.9. An advantageous process for carrying out the reaction is to melt amlodipine maleate. While maleic acid is actually pre-combined with amlodipine, this is specifically considered to be within the scope of the present invention. On the other hand, amlodipine free base and amlodipine maleate can be combined in a solvent or mixed dry and melted, etc. to perform the reaction.

In certain embodiments, it is desirable to use excess amlodipine, as in the case where a mixture of amlodipine and a compound of formula (1) is desired. As discussed more thoroughly below, a large molar excess of amlodipine with respect to maleic acid, e.g. to 50: 1, more typically up to 20: 1 and generally 2: 1 to 10: 1 of amlodipine against maleic acid on a molar basis to give the desired mixture.

The amlodipine free base can be prepared according to the procedures generally disclosed in US 4,572,909. Another useful synthesis scheme for the preparation of amlodipine or its salts in good yields and purity via the phthalimidoamlodipine intermediate is described in provisional application no. No. 60 / 258,613, filed Dec. 29, 2000, jointly owned, the entire contents of which are incorporated herein by reference, and U.S. Pat. No. 09 / 809,351, filed March 16, 2001, is a jointly-owned and jointly-owned process entitled The Process for the Preparation of Amlodipine, its Derivatives and its Precursors, and its entire contents are incorporated herein by reference. Maleic acid is commercially available.

Compound (1) can be isolated from the reaction medium by conventional methods such as evaporation, precipitation, or by extraction or crystallization. Similarly, the compound of formula (1) can be purified by recrystallization from solution or hot suspension, e.g. at reflux temperature in a suitable solvent, e.g. to 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 may be separated by crystallization or chromatography, optionally in the form of salts, e.g. as a salt with an optically active base or acid, according to methods generally known in the art.

By treating compound (1) with an equivalent amount of acid, such as maleic acid, followed by an isolation step, such as precipitation, evaporation or lyophilization, the acid addition salt of the compound of formula (1) is obtained with an acid. Other salts of compound (1) can be prepared by reaction with an equivalent amount of base, such as e.g. sodium hydroxide to give the sodium or disodium salt of the compound of formula (1).

The compound of formula (1) and its pharmaceutically acceptable salts are useful calcium channel blockers and can thus be used to treat any cardiac condition that would benefit the administration of a calcium channel blocker.

The calcium channel blocking activity of the compound of the invention (the ability to inhibit calcium movement into a cell) has been demonstrated by measuring the degree of contraction reduction of isolated cardiac tissue induced by the addition of calcium ions in vitro.

In particular, the compound of formula (1) and its pharmaceutically acceptable salts may be used to treat or prevent hypertension or angina by administering an effective amount to a patient in need of treatment. The specific form of angina is not particularly limited and specifically includes chronic stable angina and vasospastic angina (Prinzmetal angina). The compound can be administered by any suitable route, including oral or parenteral. The patients they are intended to treat are humans and non-human animals, especially non-human mammals.

The compound is typically administered as part of a pharmaceutical composition. Therefore, a further aspect of the invention is a pharmaceutical composition for treating or preventing hypertension or angina, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Excipients are any inert or inactive material used in the preparation of the pharmaceutical dosage form. E.g. excipients for tablets include, but are not limited to, calcium phosphate, cellulose, starch or lactose. Capsules such as those made from gelatin may contain or carry a 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 slurries or suspensions, as well as injectable solutions. The pharmaceutical composition 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 each of the following excipients, such as carriers, diluents, colorants, flavors, lubricants, solubilizers, disintegrants, binders and preservatives.

The pharmaceutical composition is usually in unit dose. A single dose is typically given once or twice daily, more typically once daily. In the case of a transdermal patch, a single dose (one patch) is generally administered at least once a month, more generally at least twice a week and typically once a week. The effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof in a unit dose to treat or prevent hypertension or angina is generally in the range of 0.1 to 100 mg, typically 1 to 100, more typically 1 to 50 mg, normal 1 up to 20 mg. In solid oral dosage forms (tablets, capsules, etc.), the pharmaceutical composition typically contains about 1, 2.5, 5.0, or 10 mg of a compound of formula (1) or a pharmaceutically acceptable salt thereof. For simplicity, all quantities refer to the corresponding amount of free base intended for the composition.

Another embodiment of the invention relates to the use of a mixture 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 composition of pharmaceutically active ingredients. In general, the composition of pharmaceutically active ingredients comprises (a) 100% by weight. parts of amlodipine or a pharmaceutically acceptable salt thereof; and (b) about 0.1 to about 1000 wt. parts, typically 0.5 to 500 wt. parts, more typically 2 to 100 wt. parts of a compound of formula (1) or a pharmaceutically acceptable salt thereof. Amlodipine is preferably in the form of an acid addition salt, especially a maleate salt. The compound of formula (1) is preferably a free base or an acid addition salt, in particular a maleate salt. The mixture can be obtained directly by controlling the reaction conditions and the duration of formation of a compound of formula (1); e.g. using elevated temperatures, prolonged contact, appropriate maleic acid to amlodipine ratios, etc. On the other hand, the composition of the pharmaceutically active ingredients can be formed by mixing the amlodipine compound with the compound of formula (1) or its corresponding salt forms, etc.) in the desired ratio.

The pharmaceutical active ingredient composition can be used in a similar manner as the compound of formula (1) for the formation of a pharmaceutical composition for the treatment of hypertension or angina. A specific such pharmaceutical composition comprises an effective amount of a composition of pharmaceutically active ingredients and a pharmaceutically acceptable excipient as previously described. Similarly, a unit dose contains between 0.1 and 100 mg, typically 1 to 100, more typically 1 to 50 mg, than 1 to 20 mg, and specifically contains solid oral dosage forms (tablets, capsules, etc.) typically 1, 2, 5, 5.0 or 10 mg of the pharmaceutically active ingredient composition. For simplicity, the amounts indicated refer to a mass corresponding to the sum of the free base of amlodipine and the compound of formula (1).

The composition of pharmaceutically active ingredients alone 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 of such treatment.

All the pharmaceutical compositions described above can be prepared by known methods and techniques. E.g. tablets may be prepared by dry granulation / direct compression or by conventional wet granulation process. Similarly, capsules can be prepared by mixing the ingredients and filling the capsule. A suitable pharmaceutical composition for the above-described composition of pharmaceutically active ingredients with good stability can be obtained by selecting excipients to have a pH below 7.0 when measured as a 20 wt.% Aqueous suspension, as more specifically described in U.S. Patent Application no. No. 09 / 809,346, filed Mar. 16, 2001, which is simultaneously in the process and is jointly owned, entitled Pharmaceutical compositions comprising amlodipine maleate, and its entire contents are incorporated herein by reference.

Another use of amlodipine aspartate of formula (1) is as a reference standard or reference marker for evaluating the purity of amlodipine maleate and pharmaceutical compositions comprising amlodipine maleate, as more specifically described in U.S. patent application no. No. 09 / 809,347, filed Mar. 16, 2001, jointly owned, with reference to the Reference Standard for Determining the Purity or Stability of Amlodipine Maleate and Processes thereto, and its entire contents are incorporated herein by reference.

The following examples illustrate the invention.

Example 1 1 g of amlodipine and 12 g of amlodipine maleate are melted in a 300 ml flask. The molten substance was cooled to room temperature and dissolved in 300 ml of dichloromethane. The mixture was extracted with 300 ml of 1 M NaOH solution. The organic layer was discarded and the aqueous layer was acidified with 55 ml of 6 M HCl solution. The mixture was extracted with 300 ml of dichloromethane. The layers were separated and the organic layer was dried over Na ₂ SO ₄ . The mixture was evaporated to dryness and the resulting waxy solid recrystallized from ethanol. The resulting sticky solid was dried in a vacuum oven at 40 ° C to give 4.7 g of a dirty white product.

Yield: 4.7 g (39%)

Melting point: 178 ° C-183 ° C (dec.) Purity: above 90% < 1 > H-NMR spectrum:

The < 1 > H-NMR spectrum was measured at 303.2 K on Bruker Avance-400 in deuterated dimethylsulfoxide at 400 MHz. It is presented in FIG. 1.

δ allocation

1.12 (t, 3H, J _{11) 12} = 7.0 Hz, 3xH-12);

2.36 (s, 3H, 3xH-15);

2.87 (m, ~ 2H, 2xH-3);

3.24 (m, ~ 2H, 2xH-9);

3.52 (s, ~ 3H, 3xH-14);

3.76 (bs, 2H, 2xH-8);

4.00 (m, 3H, 2xH-1 1 + H-2);

4.65 (m, 2H, 2xH-7);

5.33 (s, 1H, H-4);

7.13 (dt, 1H, J ₃ ', 4' = J ₄ ', 5' = 7.6 Hz, J ₄ , ₆ = 1.8, 8 Hz, H-4 ');

7.26 (m, 2H, H-3 '+ H-5');

7.37 (d, 1H, J ₅ , 6- = 7.8 Hz, H-6 ');

8.61 (s, 1H, NH).

¹³ C-NMR spectrum

-1010

Ο

The C-NMR spectrum was measured at 303.2 K on Bruker Avance-400 in deuterated dimethylsulfoxide at 100.6 MHz. It is presented in FIG. 2.

δ Assignment δ Assignment 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 ¹ ); 45.63, 45.74 (C-9); 129.07 (C-2 ¹ ); 50.58 (C-14); 131.11 (C-6 ¹ ); 56.42 (C-2); 166.43 (C-10); 59,50 (C-11); 167.28 170.55, 171.49 (C-13); (C-1, C-4).

Example 2

Mixture of amlodipine maleate and compounds of formula (1)

2.00 g of amlodipine maleate are dissolved in 80 ml of 2-propanol at 92 ° C. The clear light yellow colored solution was refluxed for 10 minutes and then allowed to cool to room temperature without stirring. A solid is formed and the suspension is allowed to cool to 4 ° C. The solid was filtered off, washed with 5 ml of cold 2-propanol and dried under vacuum for 1 hour at room temperature.

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

Example 3

Pharmaceutical compositions (tablets) containing a compound of formula (1)

-1111

per 5 mg tablet per 10 mg tablet compound of formula (1) (amlodipine aspartate) 5.0 mg 10.0 mg anhydrous calcium hydrogen phosphate 63,0 mg 126.0 mg magnesium oxide 4.0 mg 8.0 mg microcrystalline cellulose 126.0 mg 252,0 mg sodium starch glycolate 4.0 mg 8.0 mg magnesium stearate 2.0 mg 4.0 mg together 204.0 mg 408,0 mg

Preparation process:

Amlodipine aspartate is sieved through a 500 pm sieve.

Anhydrous calcium hydrogen phosphate, magnesium oxide, microcrystalline cellulose, sodium starch glycolate and magnesium stearate were sieved through a 850 pm sieve. Amlodipine aspartate, magnesium oxide and about 30% of the amount of microcrystalline cellulose (MCC) were stirred in a free-fall mixer for 10 minutes at about 25 rpm.

The remaining amount of MCC, anhydrous calcium hydrogen phosphate and sodium starch glycolate were added and the mixture was stirred for 15 minutes at about 25 rpm.

Magnesium stearate was added and the powder mixture was stirred for another 5 minutes at about 25 rpm.

Amlodipine aspartate tablets are compressed.

Example 4

Pharmaceutical compositions (tablets) containing a compound of formula (1)

per 5 mg tablet per 10 mg tablet

-1212

compound of formula (1) (amlodipine aspartate) 5.0 mg 10.0 mg anhydrous calcium hydrogen phosphate 63,0 mg 126.0 mg microcrystalline cellulose 126.0 mg 252,0 mg sodium starch glycolate 4.0 mg 8.0 mg magnesium stearate 2.0 mg 4.0 mg together 200.0 mg 400,0 mg

Preparation process:

Amlodipine aspartate is sieved through a 500 pm sieve.

Anhydrous calcium hydrogen phosphate, magnesium oxide, microcrystalline cellulose, sodium starch glycolate and magnesium stearate were sieved through a 850 pm sieve. Amlodipine aspartate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and sodium starch glycolate were transferred to a free-fall mixer and the mixture was stirred for 15 minutes at about 25 rpm.

Magnesium stearate was added and the powder mixture was stirred for another 5 minutes at about 25 rpm.

Amplodipine aspartate tablets are compressed.

It will be readily apparent to those skilled in the art that the described invention can easily make further modifications and modifications to the actual implementation of the concepts or embodiments described herein or may be learned by practicing the invention without departing from the spirit and scope of the invention as defined by the following claims .

Claims (16)

PATENT APPLICATIONS A compound of formula (1) or a pharmaceutically acceptable salt thereof. Compound according to claim 1, characterized in that it is an alkali salt, an amine salt or an acid addition salt. A compound according to claim 1 or 2, wherein the compound is an amine salt. Compound according to claim 3, characterized in that the amine salt is the amlodipine salt of the compound. 5. A compound according to claim 1 or 2 wherein the compound is a maleate salt. Pharmaceutical composition for the treatment of angina or hypertension, characterized in that it comprises an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 6, characterized in that the compound of formula (1) is in the form of a pharmaceutically acceptable salt and the composition is in unit dosage form. -1414 Pharmaceutical composition according to claim 6 or 7, characterized in that the pharmaceutically acceptable salt is a maleate salt and contains a compound of formula (1) in an amount corresponding to 0.1 to 100 mg. Pharmaceutical composition according to any one of claims 6-8, characterized in that the composition is in unit dosage form and contains a compound of formula (1) in an amount corresponding to 1.0 to 100 mg. 10. A composition of pharmaceutically active ingredients comprising a mixture of amlodipine or a pharmaceutically acceptable salt thereof, and a compound of formula (1) or a pharmaceutically acceptable salt thereof. Composition according to claim 10, characterized in that it comprises 100 wt. parts of amlodipine and 0.1 to 1000 wt. parts of the compound of formula (1). Composition according to claim 10 or 11, characterized in that the composition comprises a compound of formula (1) in an amount of 0.5 to 500 wt. parts. Composition according to any one of claims 10 to 12, characterized in that the composition comprises 100 parts of amlodipine maleate and 2 to 100 parts of a compound of formula (1) or a maleate salt thereof. A pharmaceutical composition for treating or preventing angina or hypertension, comprising an effective amount of a composition of pharmaceutically active ingredients according to any one of claims 10 to 13 and a pharmaceutically acceptable excipient. -1515 Pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition is in unit dosage form. Pharmaceutical composition according to claim 15, characterized in that the effective amount of the composition of the pharmaceutically active ingredients is in the range of 1 to 20 mg.