SI21064A2 - Amide derivative of amlodipine - Google Patents

Abstract

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

Description

BioOrganics B.V.

The amide derivative of amlodipine

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

Calcium channel blockers (calcium antagonists) are useful in the treatment of heart conditions, including angina and / or hypertension. Dicarboxylate-dihydropyridine derivatives are commonly known to have calcium channel blocking activity. For example, EP 089 167 and corresponding US 4,572,909 describes a class of 2-amino group, 3,5-dicarboxylate dihydropyridine derivatives, as useful calcium channel blockers. These two patents identify one of the most preferred compounds being 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 exhibits good bioavailability and has a long half-life in the body. Many of the acid addition salts are described in these patents, but the maleate salt is identified as the most preferred acid addition salt. However, the marketed product of amlodipine (NORVASC from Pfizer) uses amlodipine besylate (benzene sulfonate) rather than amlodipine maleate. Indeed, in later patents, EP 244 944 and the corresponding US 4,879,303, it is stated that besylate salt has certain advantages over known salts, including good formulation properties. Apparently, the disadvantages of amlodipine maleate were problems with tableting and stability, which led to a leap to the lead-free salt during development. (See Original NDA Review for NDA # 19-787, 10/10/1990, available from the FDA under the Freedom of Information Act). The issues / reasons for stability and tableting are not publicly disclosed in information available to 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 provides a compound of the following formula (1).

h ₃ c. h ₃ co ^ o

or a pharmaceutically acceptable salt thereof.

The compound of formula (1) is useful as a calcium channel blocker, and thus further aspects relate to a pharmaceutical composition comprising 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 an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof to a patient in need of this treatment. Further, the present invention can be used in combination with amlodipine as a composition of a pharmaceutically active ingredient. The compound of formula (1) can be prepared by a process comprising the metabolism of amlodipine or a salt thereof with a carbonyl-activated maleic acid compound.

FIG. 1 shows the ¹ 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 is understood that the compound represented by formula (1) may exist in the form of the free acid or in the corresponding form of the amphoteric ion, and while both forms are included within the meaning of the structural formula, only the free acid form is shown for simplicity. Further, although the compound of formula (1) refers to a singular, it is to be understood that the compound may exist as one of two isomers induced by a chiral center on the 1,4-dihydropyridine ring or as a mixture of isomers; they 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 formed with a metal cation, such as an alkali cation; those formed with ammonia or an amine compound, including mono-, di- or trialkylamine compounds or ring amine compounds, or with acid. More specifically, metal salts include the sodium, potassium and lithium salts of the compounds of formula (1). Ammonia and amine salts include salts made with ammonia, methylamine, dimethylamine, triethylamine, pyridine and amlodipine. Suitable acid salts 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, e.g. glycine or alanine. Preferred salts include salts prepared with a pharmaceutically acceptable acid, in particular 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 (1) relative to amlodipine.

The compounds of formula (1) and its salts are usually solid at room temperature and may be crystalline or amorphous. Crystalline forms include anhydrous forms, hydrated forms, and solvate forms. The compound can be isolated at a relatively high purity, typically over 50% by weight. % pure, preferably over 75% by weight pure, more preferably over 95% by weight pure. However, relatively impure forms such as dissolved forms are also included.

The compound of formula (1) can be prepared by metabolizing amlodipine or a salt thereof with the carbonyl activated maleic acid compound. The reaction is essentially an amidation reaction and is thus favored by the presence of an acid catalyst, an elevated temperature, and the like. and such other amidation conditions as are well known to those skilled in the art. Carbonyl-activated maleic acid means maleic acid or a derivative thereof having a sufficiently activated carbonyl group to facilitate amidation reaction with amlodipine. In some embodiments, carbonyl activation is achieved by the presence of an acid catalyst, typically Lewis acids such as aluminum chloride or phosphoric acid. However, the preferred embodiment is the use of maleic acid anhydride, which provides an activated carbonyl group without the need for a catalyst. Maleic acid per se, and in the absence of a catalyst or activator, is not a compound carbonyl-activated maleic acid and will not readily form a compound of formula (1), even when placed in the presence of amlodipine. The reaction with maleic acid anhydride is given below.

In general, the reaction of formation of a compound of formula (1) can be carried out by bringing the amlodipine free base or its salt in close contact with the activated carbonyl maleic acid compound. The preferred reaction is carried out at an elevated temperature such as 25-100 ° C, more typically 35-50 ° C and in a suitable solvent. Among the solvents suitable for the addition reaction are aprotic solvents, e.g. N, N-dimethylformamide, alcohols such as ethanol and isopropanol, esters such as ethyl acetate and hydrocarbons such as toluene. Amlodipine and the compound carbonyl activated maleic acid are typically combined in appropriate stoichiometric proportions, namely 0.9: 1 to 1: 0.9. However, it is advantageous to use excess amlodipine in the case where the amlodipine salt of a compound of formula (1) is desired. Thus, in cases where a mixture of amlodipine and a compound of formula (1) as described hereinbelow is desired, a large molar excess of amlodipine may be used relative to the activated carbonyl maleic acid compound, e.g. to 50: 1, more typically up to 20: 1, and generally 2: 1 to 10: 1 amlodipine with respect to the molar-based carbonyl-activated maleic acid compound. Also in this embodiment, inactivated carbonyl maleic acid can be provided simultaneously with the activated carbonyl maleic acid compound to form a mixture of amlodipine maleate salt and a compound of formula (1).

The amlodipine free base can be prepared according to the methods generally shown in patent no. U.S. 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 serial 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 jointly owned and co-owned, entitled The Process for the Preparation of Amlodipine, its Derivatives and its Precursors, the entire contents of which are incorporated herein by reference. Maleic acid and its anhydride, as well as acid catalysts, are commercially available.

Compound (1) can be isolated from the reaction medium by conventional methods such as evaporation or precipitation and can be purified by crystallization, e.g. at a reflux temperature in a suitable solvent, e.g. to an ester such as ethyl acetate, to an alcohol such as propan-2-ol, or to a ketone such as acetone. The stereoisomers 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 by processes commonly known in the art.

Treatment of compound (1) with an equivalent amount of acid such as maleic acid, followed by an isolation step such as precipitation, evaporation or lyophilization, produces the acid addition salt of the compound of formula (1) with acid. Other salts of compound (1) can be formed by reaction with an equivalent amount of base, such as e.g. sodium hydroxide to form the sodium 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 from the administration of a calcium channel blocker. 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. with metabolism in the body after administration. Therefore, the compound of formula (1) and its pharmaceutically acceptable salts can be used as a prodrug for amlodipine and can thus be used in the same way and are useful in treating the same heart conditions as amlodipine.

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 such treatment. The specific form of angina is not particularly limited and specifically includes chronic stable, angina pectoris and vasospastic angina (Prinzmetal angina). The compound may be administered by any suitable route, including oral or parenteral. The patients we intend to treat include humans and animals, especially animal mammals.

The compound is typically administered as part of a pharmaceutical composition. Thus, 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 (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Excipients include any inert or inactive material used in the manufacture of the pharmaceutical dosage form. For example, 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 a compound of formula (1), or a pharmaceutically acceptable salt thereof, alone or in admixture with other excipients. Other liquid forms, such as oral fluids in the form of medicinal liquids or suspensions, as well as injectable solutions are included. 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 the following excipients: carriers, diluents, colorants, flavoring agents, lubricants, solubilizing agents, disintegrants, binders and preservatives.

The pharmaceutical composition is usually provided in a single dose. A single dose is typically given once or twice a day, more typically once a day. In the case of a transdermal patch, a single dose (one patch) is generally given at least once a month, more generally at least once every two weeks and typically once a week. The effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof in a unit dose for treating or preventing hypertension or angina is generally within the range of 1 to 100 mg, typically 1 to 50 mg, more typically 1 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 the sake of simplicity, all quantities refer to the corresponding amount of free base provided on the composition.

Another embodiment of the invention relates to the use of a mixture of a 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 may form a useful composition of the pharmaceutically active ingredient. The general composition of a pharmaceutically active ingredient 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, typically 0.5 to 500 parts by weight, more typically 2 to 100 parts by weight of the compound with formula (1) or pharmaceutically acceptable salts thereof. Amlodipine is preferably in the form of an acid addition salt, especially a maleate salt. The compound of formula (1) is preferably an acid addition salt, in particular a 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 the non-carbonyl-activated maleic acid and / or the amount of amlodipine. Alternatively, the composition of the pharmaceutically active ingredient may be formed by mixing the amlodipine compound with the compound of formula (1) (or its corresponding salt forms, etc.) in the desired ratio.

For the formation of a pharmaceutical composition for the treatment of hypertension or angina, the composition of the pharmaceutically active ingredient may be used in the same manner as the compound of formula (1). Specifically, such pharmaceutical composition comprises an effective amount of a pharmaceutically active ingredient composition and a pharmaceutically acceptable excipient as previously described. Similarly, a unit dose of between 1 and 100 mg, typically 1 to 50 mg, more typically 1 to 20 mg, and specific solid oral dosage forms (tablets, capsules, etc.) typically contain about 1, 2.5, 5.0 or 10 mg composition of pharmaceutically active ingredient. For simplicity, the amounts indicated refer to a weight corresponding to the sum of the free base of amlodipine and the compound of formula (1).

The pharmaceutical active ingredient composition 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 of the pharmaceutical compositions described above can be made by known methods and techniques. For example, the tablets may be made by dry granulation / direct compression or the conventional wet granulation method. Similarly, capsules can be made by mixing the ingredients and filling them into capsules. A suitable pharmaceutical composition for the above-described composition of a pharmaceutically active ingredient having good stability can be obtained by selecting excipients such that the pH is less than 7.0 when measured as a 20 wt.% Aqueous suspension as more fully described in U.S. Pat. report serial no. No. 09 / 809,346, filed March 16, 2001, which is jointly owned and operated, and has the title Pharmaceutical compositions containing amlodipine maleate, the entire contents of which are incorporated herein by reference.

Only one use of amlodipine maleamide of formula (1) is a reference standard or reference marker for the evaluation of pure amlodipine maleate and pharmaceutical compositions comprising amlodipine maleate, as more fully described in U.S. Pat. No. 09 / 809,347, filed March 16, 2001, which is jointly owned and entitled The Reference Standard for the determination of the purity or stability of amlodipine maleate and the process thereof, the entire contents of which are incorporated herein by reference.

The following examples illustrate the invention.

Example 1 - Preparation of a compound of formula (1) g of amlodine is dissolved in 50 ml of ethyl acetate and heated to 60 ° C. 1.15 g of maleic anhydride are added to this mixture and the mixture is shaken until the solution is 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 to give a yellow solid.

Yield: 6.1 g (99%)

Melting point: 83 ° C - 86 ° C

Purity: greater than 95% (HPLC) -NMR spectrum:

The ^ -NMR spectrum was measured at 303 K on Bruker Avance-400 in deuterated dimethylsulfoxide at 400 MHz. The spectrum is shown in FIG. 1.

δ determination

1.12 (t, 3H, Jii, i2 = 7.0 Hz, 12-H3)

2.31 (s, 3H, 15-H ₃ )

3.44 (bq, ~ 2H, 9-H ₂ )

3.52 (s, ~ 3 H, 14-H ₃₎

3.58 (bt, 2H, 8-H ₂ )

3.99 (m, ~ 2H, 11-H ₂ )

4.62 (AB q, 2H, 7-H ₂ )

5.32 (s, 1H, 4-H)

6.27 (d, ~ 1H, J ₄ ".5'-12,4 Hz, 4" -H)

6.43 (d, ~ 1H, J ₄ ', 5- = 12.4 Hz, 5-H)

7.13 (dt, 1H, J _3, 4 ^ 4-, 5-7,7 Hz, J ₄ , ₆ - = 1, 6 Hz, 4'-H)

7.23 (dt, 1H, J ₄ -, 5 '= J 5', 6-7,7 Hz, J _{3. 5} - = l, 0 Hz, 5'-H)

7.28 (dd, 1H, J ₃ '_;4' = 7,7 Hz, J _{3; 5} ^ = 1, 0 Hz, 3'-H)

7.34 (dd, 1H, J ₄ -, ₆ - = 1.6 Hz, J ₅ ·, 6- = 7.7 Hz, 6'-H)

8.49 (s, ~ 1H, 1-H)

9.24 (bt, ~ 1H, 9′-NH)

-1010

Example 2 - Preparation of a mixture of amlodipine maleate and amlodipine amide.

g of amlodipine is dissolved in 50 ml of ethyl acetate at 60 ° C. 1.28 g of maleic acid and 0.12 g of maleic anhydride are added to the solution and the mixture is shaken until clear. The mixture was slowly cooled to room temperature while the solid precipitated. 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 are obtained.

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

For the invention described, it will be readily apparent to those skilled in the art that further modifications and modifications to the actual implementation of the concepts and embodiments described herein are readily made or can be learned by practicing the invention without leaving the spirit and scope of the invention, such as is defined by the following claims.

Claims (15)

PATENT APPLICATIONS A compound of formula (1) h ₃ co H COOH Oh Oh Cl (1) or a pharmaceutically acceptable salt thereof. Compound according to claim 1, characterized in that said compound is an alkali salt, an amine salt or an acid addition salt. Compound according to claims 1 or 2, characterized in that said compound is an amine salt. Compound according to claim 3, characterized in that said amine salt is the amlodipine salt of said compound. 5. A compound according to claim 1 or 2, wherein said compound is a maleate salt. 6. A pharmaceutical composition for treating angina or hypertension, characterized in that it comprises an effective amount of a compound of formula (1) -1212 or its pharmaceutically acceptable salts and pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 6, characterized in that said compound of formula (1) is in the form of a pharmaceutically acceptable salt and said composition is in unit dosage form. Pharmaceutical composition according to claims 6 or 7, characterized in that the pharmaceutically acceptable salt is a maleate salt and said compound of formula (1) is contained in an amount corresponding to 1 to 100 mg. A composition of a pharmaceutically active ingredient comprising amlodipine or a pharmaceutically acceptable salt thereof, and a compound of formula (1) or a pharmaceutically acceptable salt thereof. Composition according to claim 9, characterized in that said composition comprises 100 parts by weight of said amlodipine and 0.1 to 1000 parts by weight of said compound of formula (1). -1313 Composition according to claims 9-10, characterized in that said composition comprises said compound of formula (1) in an amount of 0.5 to 500 parts by weight. Composition according to any one of claims 9-11, characterized in that said composition comprises 100 parts of amlodipine maleate and 2 to 100 parts of maleate salt, amlodipine salt or both salt forms of said compound of formula (1). A pharmaceutical composition for treating or preventing angina or hypertension, comprising an effective amount of a composition of a pharmaceutically active substance according to any one of claims 9-11, and a pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 13, characterized in that said pharmaceutical composition is in unit dosage form. 15. A pharmaceutical composition according to claim 14, wherein said effective amount of said composition is a pharmaceutically effective amount within the range of 1 to 20 mg.