CA2114678C - Crystals of n-(trans-4-isopropylcyclohexylcarbonyl)- d-phenylalanine and methods for preparing them - Google Patents
Crystals of n-(trans-4-isopropylcyclohexylcarbonyl)- d-phenylalanine and methods for preparing themInfo
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- CA2114678C CA2114678C CA002114678A CA2114678A CA2114678C CA 2114678 C CA2114678 C CA 2114678C CA 002114678 A CA002114678 A CA 002114678A CA 2114678 A CA2114678 A CA 2114678A CA 2114678 C CA2114678 C CA 2114678C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Abstract
Stable crystals of N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine may be produced by treating this compound with a solvent at a temperature of at least 10°C and forming crystals in the solvent at a temperature of at least 10°C. For example, crystals may be formed by crystallization out of solution, or may be formed from solid particles of the compound suspended in a solvent. Crystals formed in this way have different melting points, infra red spectrum and X-ray diffraction patterns from previously known forms of the compound and have enhanced processability, e.g., stability to grinding.
Description
CRYSTALS OF N-(TRANS-4-ISOPROPYLCYCLOHEXYLCARBONYL)-D-PHENYLALANINE AND METHODS FOR PREPARING THEM
~ BACKGROUND OF THE INVENTION
s The present invention relates to a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine and to methods for the production of that crystalline form.
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine of formula (I) is a known substance having therapeutic utility in depressing blood glucose levels.
C) H
~ ~ X COOH (I) CH3 \ ~ V
~' N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine is disclosed in Japanese Patent Application Laid Open No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484) and in J. Med. Chem. 32, 1436.
The Japanese application describes how the compound may be crystallized from aqueous methanol to yield crystals having a melting point of 129 to 130~C. These crystals are in a crystalline form referred to herein as ~B-type". The X-ray powder diffraction pattern and infra-red spectrum of B-type crystals are shown in Figs. 1 and 3s 2 respectively.
CA 02ll4678 l999-0l-2l The known B-type crystals suffer from problems of instability, especially when subjected to mechanical grinding. The instability results, for example, in conversion of the B-type crystals into other forms. The instability of the B-type crystals means that they are not ideal for use in medicine. It is in general desirable that a medicinal product containing a crystalline active ingredient have a composition which is well defined and stable in terms of the crystalline form of the active ingredient. Conversion of one crystalline form into unknown amounts of different, or amorphous forms during processing or storage is undesirable and in many cases would be regarded as analogous to the appearance of unquantified amounts of impurities in the product.
The present inventors have discovered a method for producing a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having improved stability over the known B-type. For instance, zo the crystals according to one aspect of the present invention have enhanced stability to grinding. Such crystals are therefore more suitable for use in medicines than those of the B-type. The crystals having enhanced stability have been designated "H-type" by the inventors.
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a method for the production of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine comprising treating N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine with a solvent at a temperature of at least 10~C and forming the crystals in the solvent at a temperature of at least 10~C.
In one embodiment of this method N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is dis-CA 02ll4678 l999-0l-2l solved in the solvent at a temperature of at least 10~C
to form a solution and crystals are then crystallized from the solution at a temperature of at least 10~C.
Alternatively, N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine is combined at a temperatre of at least 10~C with a solvent in which it is incompletely soluble at that temperature, to form a suspension of solid N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine, and said suspension is maintained at a 10 temperature of at least 10~C.
According to a second aspect of the invention there are provided crystals of N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine as obtainable by the method of the first aspect.
According to a still further aspect, crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine are provided which have at least one, and preferably all, of the following properties:
(a) a melting point in the range of 136 to 142~C;
(b) an X-ray diffraction pattern having maxima at approximately 2~=8.1, 13.1, 19.6 and 19.9~; and (c) an infra red spectrum having absorptions at about 1714, 1649, 1542 and 1214 cm~1. Such crystals are designated IlH-typel' herein.
Crystals of the second aspect of the invention desirably comprise enhanced amounts of H-type crystals relative to the starting N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a powder S-ray diffraction pattern of B-type crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine;
Fig. 2 shows an infra red absorption spectrum of B-35 type crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine;
CA 02ll4678 l999-0l-2l Fig. 3 shows a powder X-ray diffraction pattern of H-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine;
Fig. 4 shows an infra red absorption spectrum of H-type crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine.
Fig. 5 shows differential scanning calorimeter (DSC) traces of: B-type crystals before grinding (Fig.
5a); H-type crystals before grinding (Fig. 5b); B-type crystals after grinding.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As was indicated above one aspect of the present invention provides N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine in H-type crystalline form.
Examples of the physical properties of the H-type crystals are as follows.
The inventors have measured the melting point of H-type crystals and found it to be in the range of 136~ to 142~. By contrast, when the melting point of B-type crystals was measured by the same technique a melting point of 128~ to 131~C was found.
Examples of powder X-ray diffraction patterns of H-type and B-type crystals may be found at Figs. 3 and 1 respectively. The diffraction pattern of the H-type crystals shows maxima at 2~ values of 8.1, 13.1, 19.6 and 19.9~ where 2~ is the angle between the primary beam projection and the diffracted beam. There are no reflections at these 2~ values in the diffraction pattern of the B-type crystals. The diffraction pattern of H-type crystals also displays strong reflections at 2~ values between about 15 and 17~ while the B-type crystals give only weak reflections in this range of 2~.
H-type crystals of the present invention preferably display a powder X-ray diffraction pattern substantially the same as that shown in Fig. 3.
CA 02ll4678 l999-0l-2l Table 1 below sets out the principal reflections in the powder pattern of H-type crystals in terms of 2~
values and intensity. The data were obtained using a Philips PW1700 powder diffractometer and a scan speed of 0. 05~/sec.
degree intens- degree intens- degree intens-ity ity ity 5.5 S 5.7 M 8.1 S
8.5 W 9.0 W 10.4 W
11.1 M 11.5 S 12.0 W
13.1 S 14.3 W 15.2 S
15.4 M 15.9 S 16.2 S
17.0 W 17.3 W 18.2 W
18.6 W 18.9 W 19.6 S
19.9 S 21.1 W 21.5 W
22.1 W 23.1 W 23.7 W
24.5 W 29.9 W
S; strong, M; medium, W; weak An example of an infra red adsorption spectrum of H-type crystals, obtained by the KBr method is shown at Fig. 4, and that of B-type crystals as obtained by the same method is shown at Fig. 2. The infra red spectrum of the H-type crystals is characterized by absorptions at around 1714 cm~l, 1649 cm~l, 1542 cm~l and 1214 cm~l, which absorptions are not present in the spectrum of the B-type crystals. H-type crystals of the present invention preferably display an infra red spectrum substantially the same as that shown in Fig. 4.
The inventors carried out elementary analysis of both H-type and B-type crystals and the results are CA 02ll4678 l999-0l-2l shown in Table 2. These confirm that the two crystal types have the same chemical composition (C1gH27NO3) C H N
Calculated data (H- or B-71.89 8.57 4.41 type) (%) Measured data (H-type) (%) 71.98 8.69 4.33 Measured data (B-type) (%) 71.82 8.66 4.27 H-type crystals are preferably substantially stable to grinding. Stability to grinding may be assessed by measurement of an appropriate physical property before and after grinding. Where the physical property remains substantially unchanged substantial stability to grinding is indicated. Suitable physical properties for measurement include melting point, differential scanning, colorimeter trace X-ray diffraction pattern and infra red absorption spectrum, particularly the X-ray diffraction pattern.
As mentioned above the first aspect of the invention provides a method for the production of crystals of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine the method comprising treating N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine with a solvent at a temperature of at least 10~C and forming crystals in the solvent at a temperature of at least 1 o o C .
In one embodiment N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine is dissolved in the solvent at a temperature of at least 10~C. The solution may be produced by dissolving in a solvent any one or more of amorphous N-(trans-4-isopropylcyclohexylcar-30 bonyl)-D-phenylalanine, B-type crystals of the compound, and solvates of the compound such as hydrates, CA 02ll4678 l999-0l-2l methanolates, ethanolates, isopropanolates and acetonitrilates.
Crystals may then be formed by crystallization from solution, the crystallization from solution taking place at a temperature between 10~C and the boiling point of the solvent. The crystals thus formed generally comprise enhanced amounts of H-type crystals relative to the starting N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine. Preferably, the product is predominantly H-type crystals.
The dissolution and crystallization at a temperature of at least 10~C may be carried out in several ways as will be apparent to those of skill in the art. For instance, N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine may be dissolved in a solvent, or mixture of solvents in which it is readily soluble at elevated temperatures but in which it is only sparingly soluble at lower temperatures (which are still at least 10~C). Dissolution at elevated temperature is, in this case, followed by cooling during which the desired H-type crystals crystallize out of solution.
Solvents which are suitable for use in this way include esters, such as methyl acetate and ethyl acetate, toluene and acetonitrile. Mixed solvents comprising a good solvent in which N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine is readily soluble, as a first solvent, preferably, in amounts of at least 1 weight % at 30~C, and a poor solvent in which it is more sparingly soluble, as a second solvent, preferably, in amounts of not more than 0.01% at 30~C may also be employed provided that crystallization from the mixture at a temperature of at least 10~C is possible using the selected solvent mixture. A preferred solvent mixture is a solution which is a mixture of a first solvent selected from the group consisting of acetone, ethanol and isopropanol with water as a second solvent.
The concentration of the first solvent is preferably from 30 to 60 vol% of the solvent mixture.
The temperature of the solution is preferably 15 to 50~C
An alternative way of achieving crystallization from solution at a temperature of 10~C is to utilize the difference in solubility of the crystals in different solvents. For example, N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine may be dissolved in a o good solvent in which it is highly soluble, as a first solvent, such as one in which it is soluble in amounts of at least 1 weight % at 30~C and the solution subsequently mixed with a poor solvent in which it is more sparingly soluble, as a second solvent, such as one in which it is soluble in amounts of not more than 0.01%
at 30~C. Thus, the solution of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine in the good solvent might be added to the poor solvent, while maintaining a temperature in excess of 10~C, or the poor solvent might be added to the solution of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine in the good solvent, again while maintaining a temperature in excess of 10~C.
Examples of good solvents include lower alcohols, such as methanol, ethanol and isopropanol, as well as acetone, tetrahydrofuran and dioxane. Examples of poor solvents are water, hexane and diethyl ether.
Preferably, the first solvent is selected from the group consisting of acetone, ethanol and isopropanol, and the second solvent is water. The temperature of the solution iS preferably from 15 to 50~C.
Whichever of the two alternative crystallization methods is employed it is important that the crystallization temperature be at least 10~C up to the boiling point of the solvent. If the temperature employed is lower than 10~C it is not possible to obtain good yields of H-type crystals. Preferably, CA 02ll4678 l999-0l-2l crystallization is effected at a temperature in the range of 10~ to 60~C, more preferably at least 15~C, especially preferably from 20~ to 60~C and most preferably from 15 to 50~C.
Crystals which have come out of solution are preferably separated from the solvent e.g., by filtration or centrifuging and are desirably then dried for example at a temperature in the range of from 20~C
to 100~C.
In an alternative embodiment of the first aspect of the invention solid N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine is suspended at a temperature of at least 10~C in a solvent in which it is incompletely soluble, preferably only sparingly soluble, 15 at that temperature. A suspension results in which particles of solid are dispersed, and remain incompletely dissolved in the solvent. Preferably the solids are maintained in a state of suspension by agitation e.g., by shaking or stirring. The suspension 20 iS kept at a temperature of 10~C or higher thereby to effect a transformation of the starting solids into product crystals.
The solid N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine suspended in suitable solvent may be of 25 any type, such as amorphous, or in the form of B-type crystals and may be a solvate, e.g. hydrate, methanolate, ethanolate, isopropanolate or acetonitrilate. The amorphous powder may be derived by drying a solvate. Preferably, the suspension is 30 maintained at a temperature of at least 10~C for sufficiently long that the product crystals contain enhanced amounts of N-(trans-4-isopropyl-cyclohexyl-carbonyl)-D-phenylalanine.
Solvents suitable for use in this embodiment of the 35 invention include water, esters such as methyl acetate and ethyl acetate, as well as toluene. Good solvents in CA 02ll4678 l999-0l-2l which N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine is more readily soluble for example in amounts of at least 1% by weight at 30~C, such as lower alcohols e.g. methanol, ethanol and isopropanol, as well as acetone, acetonitrile, tetrahydrofuran and dioxane may also be used provided they are used in combination with a solvent in which N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine is only poorly soluble for example in amounts of 0.01 weight % or less, e.g. water, hexane or diethyl ether. Where a mixed solvent is employed the concentration of good solvent is generally 70% by volume or less. Where it exceeds 70% by volume the solubility of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine in the mixed solvent would be SO high that the yield of desired H-type crystals would be disadvantageously low. Generally, the use of a mixed solvent gives rise to favourable results. A solvent which is a mixture of a first good solvent selected from the group consisting of acetone, ethanol and isopropanol with water as a second solvent is effective. A
concentration of the good solvent in the solvent mixture of from 25 to 50 vol % of the solvent mixture is preferred. The temperature of the suspension is preferably at 15 to 50~C. Preferably, the amount of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine dispersed in the solvent is from 0.5% to 30% by weight of the resulting suspension. If it is more than 30% by weight then the slurry properties of the suspension are poor and it will be difficult to agitate. On the other hand, it is not efficient in terms of the volume of solvent required to use less than 0.5% by weight.
Preferably the suspension includes from 1% to 15% by weight.
The suspension is maintained at a temperature from 10~C to the boiling point of the solvent, in general above 15~C as from 20~C to 70~C or from 15~C to 50OC.
CA 02ll4678 l999-0l-2l Temperatures below 10~C do not facilitate transformation of the solids to H-type crystals. The time for which the suspension is left before H-type crystals may be collected from it varies depending on the nature of the solvent(s) used, the temperature and other factors, such as the quantity of solids in suspension and the size of the solid particles.
Generally, however, it may be in the range of from 10 minutes to 48 hours. By adding H-type crystals of N-10 (trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine to the dispersion as seed crystals, the time required to form H-type crystals may be shortened. The end point in formation of H-type crystals can be determined by sampling crystals from the suspension, for example by 15 filtration during the course of the conversion followed by measuring the powder X-ray diffraction pattern or infra red absorption spectrum of the crystals.
It is preferable to allow the crystals to remain in suspension for a period long enough to convert them to 20 the H-type, such as a period exceeding 12 hours, or to carry out crystallization slowly, such as for a period exceeding 6 hours, at the industrial scale.
The H-type crystals as obtained in the manner mentioned above can be separated from suspension by 25 filtration or centrifugation. In isolating them, cooling may be effected, if desired. In that case, the cooling temperature is preferably no lower than 10~C. The isolated crystals are dried, for example at a temperature in the range of from 20 to 120~C.
According to another aspect of the invention there is provided a pharmaceutical composition comprising crystals as obtainable by the method of the first aspect, in particular H-type crystals, and a pharmaceutically acceptable excipient, diluent or 35 carrier.
CA 02ll4678 l999-0l-2l According to a still further aspect of the invention there is provided a method of manufacture of a pharmaceutical composition comprising mixing an effective amount of crystals as obtainable by the method of the first aspect of the invention, in particular H-type crystals and a pharmaceutically acceptable excipient diluent or carrier.
According to a still further aspect of the invention there is provided a method for treatment of a 10 human or other mammal to depress its blood glucose level comprising administering an effective amount of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine crystals as obtainable by the methods of the present invention, in particular B-type crystals.
Examples Embodiments of the invention are illustrated below by way of example only.
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-20 alanine for use in the following examples was obtained by the method described in Example 3 of Japanese patent application laid open no. 63-54321. The product contained crystals of B-type.
25 (A) H-Type Crystals by Crystallization from Solution Example A1 20 ml of an acetone solution of 5g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine were added dropwise to a stirred mixture of acetone (40ml) and 30 water (60ml) at 25~C. After cooling to 10~C, the precipitated crystals were filtered and dried at 90~C at reduced pressure overnight. 4.5g of dry crystals were obtained. The crystals had a melting point of 138 to 141~C. The powder X-ray diffraction pattern and the 35 infra-red absorption spectrum were measured and the crystals were thus identified as H-type.
CA 02ll4678 l999-0l-2l Example A2 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (4g) was dissolved in a mixture of ethanol (50ml) and water (50ml) at 45~C. The solution was cooled with stirring. H-type crystals of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine (O.lg) prepared in Example A1 were added at a temperature of 37~C and the solution was cooled further to 25~C. The crystals were filtered and dried at 60~C overnight and at reduced pressure. 2.5g of dry crystals were obtained. The crystals had a melting point of 138 to 141~C. The powder X-ray diffraction pattern and the infra-red absorption spectrum enabled the crystals to be identified as H-type.
Example A3 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (0.5g) was dissolved in acetonitrile at 45~C and the solution was cooled to 25~C. The precipitated crystals were filtered and dried at 90~C under reduced pressure. 0.48g of dry crystals were obtained. The crystals had a melting point of 138 to 141~C. Their powder X-ray diffraction pattern and infra red absorption spectrum were consistent with their being H-type crystals.
Comparative Example A1 The procedure of Example A1 was followed butcooling to 5~C was employed. 4.6g of dry crystals were obtained. The crystals had a melting point of 128 to 131~C. The powder X-ray diffraction pattern and the infra-red absorption spectrum of the crystals were measured and the crystals were identified as B-type.
.. ..
CA 02ll4678 l999-0l-2l Comparative Example A2 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (5g) was dissolved in a mixture of ethanol (60ml) and water (40ml) at 30~C. The solution was cooled to 5~C with stirring. The precipitated crystals were filtered and dried at 90~C under reduced pressure, and overnight. 3.3g of dried crystals were obtained. The crystals had a melting point of 128 to 131~C and their powder X-ray diffraction pattern and infra-red o absorption spectrum indicated that they were of the B-type.
Comparative Example A3 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (5g) was dissolved in a mixture of methanol (70ml) and water (30ml) at 40~C. The solution was cooled to 5~C with stirring. The precipitated crystals were filtered and dried at 90~C under reduced pressure overnight. 3.5g of dry crystals were obtained. Once again, the crystals had a melting point of 128 to 131~C.
The powder X-ray diffraction pattern and the infra-red absorption spectrum were consistent with the crystals being B-type.
(B) H-Type Crystals from Suspension Example B1 B-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (3g) were dispersed in 300ml of water and stirred at 30~C for 1 day. The crystals were filtered and dried at 90~C under reduced pressure overnight. 2.9g of dry crystals were obtained. The powder X-ray diffraction pattern and the infra-red absorption spectrum were recorded and indicated that the crystals were of H-type.
CA 02ll4678 l999-0l-2l Example B2 B-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (4g) were dispersed in a mixture of acetone (40ml) and water (60ml) and stirred at 200C overnight. The crystals were subsequently filtered off and dried at 90~C under reduced pressure overnight. 3.6g of dry crystals were obtained. Powder X-ray diffraction and infra-red absorption spectroscopy indicated that the product crystals were of H-type.
Example B3 Hydrate of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine for use in this example was prepared as follows. 20g of B-type crystals of N-(trans-4-15 isopropylcyclohexylcarbonyl)-D-phenylalanine were dis-solved in a mixture of ethanol (300ml) and water (200ml) at 30~C. The solution was cooled to 5~C with stirring.
The precipitated crystals were filtered off and dried at 40~C under reduced pressure for 2 hours. 13.9g of dried 20 crystals resulted.
4.2g of the hydrate was dispersed in a mixture of ethanol (30ml) and water (70ml) and stirred at 45~C
overnight. The crystals were filtered off and dried at 90~C under reduced pressure overnight. 3.8g of dried 25 crystals were obtained. These were found to be of the H-type by powder X-ray diffraction and infra-red spectroscopy.
Example B4 4.2g of the hydrate of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine prepared as in Example B3 was dispersed in a mixture of ethanol (3Oml) and water (70ml). 40mg of H-type crystals were added and the dispersion was stirred at 45~C for 1 hour.
The crystals were filtered off and dried at 90~C
under reduced pressure overnight. 3.9g of dry crystals CA 02ll4678 l999-0l-2l were obtained. These were found to be of the H-type by X-ray diffraction and infra-red absorption spectroscopy.
Example B5 B-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (5g) were dispersed in a mixture of isopropanol (25ml) and water (75ml) and stirred at 50~C for 10 hours. The resulting crystals were filtered off and dried at 90~C under reduced 10 pressure overnight. 4.4g of dry crystals were obtained.
These were found to be of the H-type by X-ray diffraction and infra-red spectroscopy.
Comparative Example B1 4g of B-type crystals of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine were dispersed in a mixture of acetone (40ml) and water (60ml) and stirred at 5~C overnight. The crystals were filtered off and dried at 90~ under reduced pressure overnight. 3.6g of 20 dry crystals were obtained. The powder X-ray diffraction pattern and the infra-red absorption spectrum were measured and the crystals were found to be of the B-type.
25 (C) Stability to Grindinq In order to demonstrate the stability of H-type crystals to grinding the following experiment was carried out.
H-type crystals of N-(trans-4-isopropylcyclohexyl-30 carbonyl)-D-phenylalanine and the previously known B-type crystals were each mechanically-ground in a grinder, and the X-ray diffraction pattern of each powder was measured and compared with the spectrum before grinding. No change was observed in the H-type 35 crystals before and after grinding but changes were CA 02ll4678 l999-0l-2l observed in the diffraction pattern of the B-type crystals.
Similarly, the differential scanning calorimeter (DSC) trade for each of the H-type, and B-type crystals s was measured before and after grinding. Fig. 5a shows the DSC trace of B-type crystals before grinding. The crystals show a sharp melting point at around 130~C. The DSC trade of H-type crystals before grinding is shown in Fig. 5b. These crystals also demonstrated a sharp melting point at around 140~C. The DSC trade of the H-type crystals was unchanged by grinding. By contrast, the trace shown in Fig. 5c for B-type crystals after grinding differs from the trace obtained before grinding and new troughs are visible in the trace.
Additional Examples of the preparation of H-type crystals are as follows.
Example D1 44g of hydrate of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine, containing 18 g of water, were dissolved in ethanol (292ml). The solution was added dropwise to a suspension of H-type crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (0.4g), prepared in Example Al, in a mixture of water (340ml) and ethanol (88ml) at 42~C in three hours, simultaneously with addition of water (350ml). The resulting mixture was stirred at the same temperature overnight, then the precipitated crystals were filtered and dried under reduced pressure to give 22g of dry crystals which had a melting point of 139~C. The crystals were identified as H-type by powder X-ray diffraction pattern and infra-red absorption spectrum.
Example D2 46g of hydrate of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine, containing 18g of water, were CA 02ll4678 l999-0l-2l dissolved in ethanol (307ml). The solution was added dropwise to a suspension of H-type crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (0.4g), prepared in Example A1, in a mixture of water (429 ml) and ethanol (98ml) at 42~C in 40 minutes. Water was added in 5 hours, and then the resulting mixture was stirred at the same temperature overnight. The precipitated crystals filtered and dried under reduced pressure to give 25g of dry crystals which had a melting 10 point of 138~C. The crystals were identified as H-type by powder X-ray diffraction pattern and infra-red absorption spectrum.
ExamPle D3 48g of hydrate of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine, containing 19 g of water, were dissolved in ethanol (228ml). The solution was added to a mixture of water (323ml) and ethanol (118ml) at 45~C. After cooling to 40~C, H-type crystals of N-20 (trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (0.45g), prepared in Example A1, and then water (317ml) were added in 2.5 hours, and the resulting mixture was stirred at the same temperature overnight. The precipitated crystals filtered and dried under reduced 25 pressure to give 27g of dry crystals which had a melting point of 139~C. The crystals were identified as H-type by powder X-ray diffraction pattern and infra-red absorption spectrum.
~ BACKGROUND OF THE INVENTION
s The present invention relates to a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine and to methods for the production of that crystalline form.
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine of formula (I) is a known substance having therapeutic utility in depressing blood glucose levels.
C) H
~ ~ X COOH (I) CH3 \ ~ V
~' N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine is disclosed in Japanese Patent Application Laid Open No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484) and in J. Med. Chem. 32, 1436.
The Japanese application describes how the compound may be crystallized from aqueous methanol to yield crystals having a melting point of 129 to 130~C. These crystals are in a crystalline form referred to herein as ~B-type". The X-ray powder diffraction pattern and infra-red spectrum of B-type crystals are shown in Figs. 1 and 3s 2 respectively.
CA 02ll4678 l999-0l-2l The known B-type crystals suffer from problems of instability, especially when subjected to mechanical grinding. The instability results, for example, in conversion of the B-type crystals into other forms. The instability of the B-type crystals means that they are not ideal for use in medicine. It is in general desirable that a medicinal product containing a crystalline active ingredient have a composition which is well defined and stable in terms of the crystalline form of the active ingredient. Conversion of one crystalline form into unknown amounts of different, or amorphous forms during processing or storage is undesirable and in many cases would be regarded as analogous to the appearance of unquantified amounts of impurities in the product.
The present inventors have discovered a method for producing a crystalline form of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having improved stability over the known B-type. For instance, zo the crystals according to one aspect of the present invention have enhanced stability to grinding. Such crystals are therefore more suitable for use in medicines than those of the B-type. The crystals having enhanced stability have been designated "H-type" by the inventors.
SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a method for the production of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine comprising treating N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine with a solvent at a temperature of at least 10~C and forming the crystals in the solvent at a temperature of at least 10~C.
In one embodiment of this method N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is dis-CA 02ll4678 l999-0l-2l solved in the solvent at a temperature of at least 10~C
to form a solution and crystals are then crystallized from the solution at a temperature of at least 10~C.
Alternatively, N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine is combined at a temperatre of at least 10~C with a solvent in which it is incompletely soluble at that temperature, to form a suspension of solid N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine, and said suspension is maintained at a 10 temperature of at least 10~C.
According to a second aspect of the invention there are provided crystals of N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine as obtainable by the method of the first aspect.
According to a still further aspect, crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine are provided which have at least one, and preferably all, of the following properties:
(a) a melting point in the range of 136 to 142~C;
(b) an X-ray diffraction pattern having maxima at approximately 2~=8.1, 13.1, 19.6 and 19.9~; and (c) an infra red spectrum having absorptions at about 1714, 1649, 1542 and 1214 cm~1. Such crystals are designated IlH-typel' herein.
Crystals of the second aspect of the invention desirably comprise enhanced amounts of H-type crystals relative to the starting N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a powder S-ray diffraction pattern of B-type crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine;
Fig. 2 shows an infra red absorption spectrum of B-35 type crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine;
CA 02ll4678 l999-0l-2l Fig. 3 shows a powder X-ray diffraction pattern of H-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine;
Fig. 4 shows an infra red absorption spectrum of H-type crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine.
Fig. 5 shows differential scanning calorimeter (DSC) traces of: B-type crystals before grinding (Fig.
5a); H-type crystals before grinding (Fig. 5b); B-type crystals after grinding.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As was indicated above one aspect of the present invention provides N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine in H-type crystalline form.
Examples of the physical properties of the H-type crystals are as follows.
The inventors have measured the melting point of H-type crystals and found it to be in the range of 136~ to 142~. By contrast, when the melting point of B-type crystals was measured by the same technique a melting point of 128~ to 131~C was found.
Examples of powder X-ray diffraction patterns of H-type and B-type crystals may be found at Figs. 3 and 1 respectively. The diffraction pattern of the H-type crystals shows maxima at 2~ values of 8.1, 13.1, 19.6 and 19.9~ where 2~ is the angle between the primary beam projection and the diffracted beam. There are no reflections at these 2~ values in the diffraction pattern of the B-type crystals. The diffraction pattern of H-type crystals also displays strong reflections at 2~ values between about 15 and 17~ while the B-type crystals give only weak reflections in this range of 2~.
H-type crystals of the present invention preferably display a powder X-ray diffraction pattern substantially the same as that shown in Fig. 3.
CA 02ll4678 l999-0l-2l Table 1 below sets out the principal reflections in the powder pattern of H-type crystals in terms of 2~
values and intensity. The data were obtained using a Philips PW1700 powder diffractometer and a scan speed of 0. 05~/sec.
degree intens- degree intens- degree intens-ity ity ity 5.5 S 5.7 M 8.1 S
8.5 W 9.0 W 10.4 W
11.1 M 11.5 S 12.0 W
13.1 S 14.3 W 15.2 S
15.4 M 15.9 S 16.2 S
17.0 W 17.3 W 18.2 W
18.6 W 18.9 W 19.6 S
19.9 S 21.1 W 21.5 W
22.1 W 23.1 W 23.7 W
24.5 W 29.9 W
S; strong, M; medium, W; weak An example of an infra red adsorption spectrum of H-type crystals, obtained by the KBr method is shown at Fig. 4, and that of B-type crystals as obtained by the same method is shown at Fig. 2. The infra red spectrum of the H-type crystals is characterized by absorptions at around 1714 cm~l, 1649 cm~l, 1542 cm~l and 1214 cm~l, which absorptions are not present in the spectrum of the B-type crystals. H-type crystals of the present invention preferably display an infra red spectrum substantially the same as that shown in Fig. 4.
The inventors carried out elementary analysis of both H-type and B-type crystals and the results are CA 02ll4678 l999-0l-2l shown in Table 2. These confirm that the two crystal types have the same chemical composition (C1gH27NO3) C H N
Calculated data (H- or B-71.89 8.57 4.41 type) (%) Measured data (H-type) (%) 71.98 8.69 4.33 Measured data (B-type) (%) 71.82 8.66 4.27 H-type crystals are preferably substantially stable to grinding. Stability to grinding may be assessed by measurement of an appropriate physical property before and after grinding. Where the physical property remains substantially unchanged substantial stability to grinding is indicated. Suitable physical properties for measurement include melting point, differential scanning, colorimeter trace X-ray diffraction pattern and infra red absorption spectrum, particularly the X-ray diffraction pattern.
As mentioned above the first aspect of the invention provides a method for the production of crystals of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine the method comprising treating N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine with a solvent at a temperature of at least 10~C and forming crystals in the solvent at a temperature of at least 1 o o C .
In one embodiment N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine is dissolved in the solvent at a temperature of at least 10~C. The solution may be produced by dissolving in a solvent any one or more of amorphous N-(trans-4-isopropylcyclohexylcar-30 bonyl)-D-phenylalanine, B-type crystals of the compound, and solvates of the compound such as hydrates, CA 02ll4678 l999-0l-2l methanolates, ethanolates, isopropanolates and acetonitrilates.
Crystals may then be formed by crystallization from solution, the crystallization from solution taking place at a temperature between 10~C and the boiling point of the solvent. The crystals thus formed generally comprise enhanced amounts of H-type crystals relative to the starting N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine. Preferably, the product is predominantly H-type crystals.
The dissolution and crystallization at a temperature of at least 10~C may be carried out in several ways as will be apparent to those of skill in the art. For instance, N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine may be dissolved in a solvent, or mixture of solvents in which it is readily soluble at elevated temperatures but in which it is only sparingly soluble at lower temperatures (which are still at least 10~C). Dissolution at elevated temperature is, in this case, followed by cooling during which the desired H-type crystals crystallize out of solution.
Solvents which are suitable for use in this way include esters, such as methyl acetate and ethyl acetate, toluene and acetonitrile. Mixed solvents comprising a good solvent in which N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine is readily soluble, as a first solvent, preferably, in amounts of at least 1 weight % at 30~C, and a poor solvent in which it is more sparingly soluble, as a second solvent, preferably, in amounts of not more than 0.01% at 30~C may also be employed provided that crystallization from the mixture at a temperature of at least 10~C is possible using the selected solvent mixture. A preferred solvent mixture is a solution which is a mixture of a first solvent selected from the group consisting of acetone, ethanol and isopropanol with water as a second solvent.
The concentration of the first solvent is preferably from 30 to 60 vol% of the solvent mixture.
The temperature of the solution is preferably 15 to 50~C
An alternative way of achieving crystallization from solution at a temperature of 10~C is to utilize the difference in solubility of the crystals in different solvents. For example, N-(trans-4-isopropylcyclo-hexylcarbonyl)-D-phenylalanine may be dissolved in a o good solvent in which it is highly soluble, as a first solvent, such as one in which it is soluble in amounts of at least 1 weight % at 30~C and the solution subsequently mixed with a poor solvent in which it is more sparingly soluble, as a second solvent, such as one in which it is soluble in amounts of not more than 0.01%
at 30~C. Thus, the solution of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine in the good solvent might be added to the poor solvent, while maintaining a temperature in excess of 10~C, or the poor solvent might be added to the solution of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine in the good solvent, again while maintaining a temperature in excess of 10~C.
Examples of good solvents include lower alcohols, such as methanol, ethanol and isopropanol, as well as acetone, tetrahydrofuran and dioxane. Examples of poor solvents are water, hexane and diethyl ether.
Preferably, the first solvent is selected from the group consisting of acetone, ethanol and isopropanol, and the second solvent is water. The temperature of the solution iS preferably from 15 to 50~C.
Whichever of the two alternative crystallization methods is employed it is important that the crystallization temperature be at least 10~C up to the boiling point of the solvent. If the temperature employed is lower than 10~C it is not possible to obtain good yields of H-type crystals. Preferably, CA 02ll4678 l999-0l-2l crystallization is effected at a temperature in the range of 10~ to 60~C, more preferably at least 15~C, especially preferably from 20~ to 60~C and most preferably from 15 to 50~C.
Crystals which have come out of solution are preferably separated from the solvent e.g., by filtration or centrifuging and are desirably then dried for example at a temperature in the range of from 20~C
to 100~C.
In an alternative embodiment of the first aspect of the invention solid N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine is suspended at a temperature of at least 10~C in a solvent in which it is incompletely soluble, preferably only sparingly soluble, 15 at that temperature. A suspension results in which particles of solid are dispersed, and remain incompletely dissolved in the solvent. Preferably the solids are maintained in a state of suspension by agitation e.g., by shaking or stirring. The suspension 20 iS kept at a temperature of 10~C or higher thereby to effect a transformation of the starting solids into product crystals.
The solid N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine suspended in suitable solvent may be of 25 any type, such as amorphous, or in the form of B-type crystals and may be a solvate, e.g. hydrate, methanolate, ethanolate, isopropanolate or acetonitrilate. The amorphous powder may be derived by drying a solvate. Preferably, the suspension is 30 maintained at a temperature of at least 10~C for sufficiently long that the product crystals contain enhanced amounts of N-(trans-4-isopropyl-cyclohexyl-carbonyl)-D-phenylalanine.
Solvents suitable for use in this embodiment of the 35 invention include water, esters such as methyl acetate and ethyl acetate, as well as toluene. Good solvents in CA 02ll4678 l999-0l-2l which N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine is more readily soluble for example in amounts of at least 1% by weight at 30~C, such as lower alcohols e.g. methanol, ethanol and isopropanol, as well as acetone, acetonitrile, tetrahydrofuran and dioxane may also be used provided they are used in combination with a solvent in which N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine is only poorly soluble for example in amounts of 0.01 weight % or less, e.g. water, hexane or diethyl ether. Where a mixed solvent is employed the concentration of good solvent is generally 70% by volume or less. Where it exceeds 70% by volume the solubility of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine in the mixed solvent would be SO high that the yield of desired H-type crystals would be disadvantageously low. Generally, the use of a mixed solvent gives rise to favourable results. A solvent which is a mixture of a first good solvent selected from the group consisting of acetone, ethanol and isopropanol with water as a second solvent is effective. A
concentration of the good solvent in the solvent mixture of from 25 to 50 vol % of the solvent mixture is preferred. The temperature of the suspension is preferably at 15 to 50~C. Preferably, the amount of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine dispersed in the solvent is from 0.5% to 30% by weight of the resulting suspension. If it is more than 30% by weight then the slurry properties of the suspension are poor and it will be difficult to agitate. On the other hand, it is not efficient in terms of the volume of solvent required to use less than 0.5% by weight.
Preferably the suspension includes from 1% to 15% by weight.
The suspension is maintained at a temperature from 10~C to the boiling point of the solvent, in general above 15~C as from 20~C to 70~C or from 15~C to 50OC.
CA 02ll4678 l999-0l-2l Temperatures below 10~C do not facilitate transformation of the solids to H-type crystals. The time for which the suspension is left before H-type crystals may be collected from it varies depending on the nature of the solvent(s) used, the temperature and other factors, such as the quantity of solids in suspension and the size of the solid particles.
Generally, however, it may be in the range of from 10 minutes to 48 hours. By adding H-type crystals of N-10 (trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine to the dispersion as seed crystals, the time required to form H-type crystals may be shortened. The end point in formation of H-type crystals can be determined by sampling crystals from the suspension, for example by 15 filtration during the course of the conversion followed by measuring the powder X-ray diffraction pattern or infra red absorption spectrum of the crystals.
It is preferable to allow the crystals to remain in suspension for a period long enough to convert them to 20 the H-type, such as a period exceeding 12 hours, or to carry out crystallization slowly, such as for a period exceeding 6 hours, at the industrial scale.
The H-type crystals as obtained in the manner mentioned above can be separated from suspension by 25 filtration or centrifugation. In isolating them, cooling may be effected, if desired. In that case, the cooling temperature is preferably no lower than 10~C. The isolated crystals are dried, for example at a temperature in the range of from 20 to 120~C.
According to another aspect of the invention there is provided a pharmaceutical composition comprising crystals as obtainable by the method of the first aspect, in particular H-type crystals, and a pharmaceutically acceptable excipient, diluent or 35 carrier.
CA 02ll4678 l999-0l-2l According to a still further aspect of the invention there is provided a method of manufacture of a pharmaceutical composition comprising mixing an effective amount of crystals as obtainable by the method of the first aspect of the invention, in particular H-type crystals and a pharmaceutically acceptable excipient diluent or carrier.
According to a still further aspect of the invention there is provided a method for treatment of a 10 human or other mammal to depress its blood glucose level comprising administering an effective amount of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine crystals as obtainable by the methods of the present invention, in particular B-type crystals.
Examples Embodiments of the invention are illustrated below by way of example only.
N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-20 alanine for use in the following examples was obtained by the method described in Example 3 of Japanese patent application laid open no. 63-54321. The product contained crystals of B-type.
25 (A) H-Type Crystals by Crystallization from Solution Example A1 20 ml of an acetone solution of 5g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine were added dropwise to a stirred mixture of acetone (40ml) and 30 water (60ml) at 25~C. After cooling to 10~C, the precipitated crystals were filtered and dried at 90~C at reduced pressure overnight. 4.5g of dry crystals were obtained. The crystals had a melting point of 138 to 141~C. The powder X-ray diffraction pattern and the 35 infra-red absorption spectrum were measured and the crystals were thus identified as H-type.
CA 02ll4678 l999-0l-2l Example A2 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (4g) was dissolved in a mixture of ethanol (50ml) and water (50ml) at 45~C. The solution was cooled with stirring. H-type crystals of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine (O.lg) prepared in Example A1 were added at a temperature of 37~C and the solution was cooled further to 25~C. The crystals were filtered and dried at 60~C overnight and at reduced pressure. 2.5g of dry crystals were obtained. The crystals had a melting point of 138 to 141~C. The powder X-ray diffraction pattern and the infra-red absorption spectrum enabled the crystals to be identified as H-type.
Example A3 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (0.5g) was dissolved in acetonitrile at 45~C and the solution was cooled to 25~C. The precipitated crystals were filtered and dried at 90~C under reduced pressure. 0.48g of dry crystals were obtained. The crystals had a melting point of 138 to 141~C. Their powder X-ray diffraction pattern and infra red absorption spectrum were consistent with their being H-type crystals.
Comparative Example A1 The procedure of Example A1 was followed butcooling to 5~C was employed. 4.6g of dry crystals were obtained. The crystals had a melting point of 128 to 131~C. The powder X-ray diffraction pattern and the infra-red absorption spectrum of the crystals were measured and the crystals were identified as B-type.
.. ..
CA 02ll4678 l999-0l-2l Comparative Example A2 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (5g) was dissolved in a mixture of ethanol (60ml) and water (40ml) at 30~C. The solution was cooled to 5~C with stirring. The precipitated crystals were filtered and dried at 90~C under reduced pressure, and overnight. 3.3g of dried crystals were obtained. The crystals had a melting point of 128 to 131~C and their powder X-ray diffraction pattern and infra-red o absorption spectrum indicated that they were of the B-type.
Comparative Example A3 N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine (5g) was dissolved in a mixture of methanol (70ml) and water (30ml) at 40~C. The solution was cooled to 5~C with stirring. The precipitated crystals were filtered and dried at 90~C under reduced pressure overnight. 3.5g of dry crystals were obtained. Once again, the crystals had a melting point of 128 to 131~C.
The powder X-ray diffraction pattern and the infra-red absorption spectrum were consistent with the crystals being B-type.
(B) H-Type Crystals from Suspension Example B1 B-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (3g) were dispersed in 300ml of water and stirred at 30~C for 1 day. The crystals were filtered and dried at 90~C under reduced pressure overnight. 2.9g of dry crystals were obtained. The powder X-ray diffraction pattern and the infra-red absorption spectrum were recorded and indicated that the crystals were of H-type.
CA 02ll4678 l999-0l-2l Example B2 B-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (4g) were dispersed in a mixture of acetone (40ml) and water (60ml) and stirred at 200C overnight. The crystals were subsequently filtered off and dried at 90~C under reduced pressure overnight. 3.6g of dry crystals were obtained. Powder X-ray diffraction and infra-red absorption spectroscopy indicated that the product crystals were of H-type.
Example B3 Hydrate of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine for use in this example was prepared as follows. 20g of B-type crystals of N-(trans-4-15 isopropylcyclohexylcarbonyl)-D-phenylalanine were dis-solved in a mixture of ethanol (300ml) and water (200ml) at 30~C. The solution was cooled to 5~C with stirring.
The precipitated crystals were filtered off and dried at 40~C under reduced pressure for 2 hours. 13.9g of dried 20 crystals resulted.
4.2g of the hydrate was dispersed in a mixture of ethanol (30ml) and water (70ml) and stirred at 45~C
overnight. The crystals were filtered off and dried at 90~C under reduced pressure overnight. 3.8g of dried 25 crystals were obtained. These were found to be of the H-type by powder X-ray diffraction and infra-red spectroscopy.
Example B4 4.2g of the hydrate of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine prepared as in Example B3 was dispersed in a mixture of ethanol (3Oml) and water (70ml). 40mg of H-type crystals were added and the dispersion was stirred at 45~C for 1 hour.
The crystals were filtered off and dried at 90~C
under reduced pressure overnight. 3.9g of dry crystals CA 02ll4678 l999-0l-2l were obtained. These were found to be of the H-type by X-ray diffraction and infra-red absorption spectroscopy.
Example B5 B-type crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine (5g) were dispersed in a mixture of isopropanol (25ml) and water (75ml) and stirred at 50~C for 10 hours. The resulting crystals were filtered off and dried at 90~C under reduced 10 pressure overnight. 4.4g of dry crystals were obtained.
These were found to be of the H-type by X-ray diffraction and infra-red spectroscopy.
Comparative Example B1 4g of B-type crystals of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine were dispersed in a mixture of acetone (40ml) and water (60ml) and stirred at 5~C overnight. The crystals were filtered off and dried at 90~ under reduced pressure overnight. 3.6g of 20 dry crystals were obtained. The powder X-ray diffraction pattern and the infra-red absorption spectrum were measured and the crystals were found to be of the B-type.
25 (C) Stability to Grindinq In order to demonstrate the stability of H-type crystals to grinding the following experiment was carried out.
H-type crystals of N-(trans-4-isopropylcyclohexyl-30 carbonyl)-D-phenylalanine and the previously known B-type crystals were each mechanically-ground in a grinder, and the X-ray diffraction pattern of each powder was measured and compared with the spectrum before grinding. No change was observed in the H-type 35 crystals before and after grinding but changes were CA 02ll4678 l999-0l-2l observed in the diffraction pattern of the B-type crystals.
Similarly, the differential scanning calorimeter (DSC) trade for each of the H-type, and B-type crystals s was measured before and after grinding. Fig. 5a shows the DSC trace of B-type crystals before grinding. The crystals show a sharp melting point at around 130~C. The DSC trade of H-type crystals before grinding is shown in Fig. 5b. These crystals also demonstrated a sharp melting point at around 140~C. The DSC trade of the H-type crystals was unchanged by grinding. By contrast, the trace shown in Fig. 5c for B-type crystals after grinding differs from the trace obtained before grinding and new troughs are visible in the trace.
Additional Examples of the preparation of H-type crystals are as follows.
Example D1 44g of hydrate of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine, containing 18 g of water, were dissolved in ethanol (292ml). The solution was added dropwise to a suspension of H-type crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (0.4g), prepared in Example Al, in a mixture of water (340ml) and ethanol (88ml) at 42~C in three hours, simultaneously with addition of water (350ml). The resulting mixture was stirred at the same temperature overnight, then the precipitated crystals were filtered and dried under reduced pressure to give 22g of dry crystals which had a melting point of 139~C. The crystals were identified as H-type by powder X-ray diffraction pattern and infra-red absorption spectrum.
Example D2 46g of hydrate of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine, containing 18g of water, were CA 02ll4678 l999-0l-2l dissolved in ethanol (307ml). The solution was added dropwise to a suspension of H-type crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (0.4g), prepared in Example A1, in a mixture of water (429 ml) and ethanol (98ml) at 42~C in 40 minutes. Water was added in 5 hours, and then the resulting mixture was stirred at the same temperature overnight. The precipitated crystals filtered and dried under reduced pressure to give 25g of dry crystals which had a melting 10 point of 138~C. The crystals were identified as H-type by powder X-ray diffraction pattern and infra-red absorption spectrum.
ExamPle D3 48g of hydrate of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine, containing 19 g of water, were dissolved in ethanol (228ml). The solution was added to a mixture of water (323ml) and ethanol (118ml) at 45~C. After cooling to 40~C, H-type crystals of N-20 (trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (0.45g), prepared in Example A1, and then water (317ml) were added in 2.5 hours, and the resulting mixture was stirred at the same temperature overnight. The precipitated crystals filtered and dried under reduced 25 pressure to give 27g of dry crystals which had a melting point of 139~C. The crystals were identified as H-type by powder X-ray diffraction pattern and infra-red absorption spectrum.
Claims (20)
1. Crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine having at least one of the following properties:
(a) a melting point in the range of 136 to 142°C;
(b) a powder X-ray diffraction pattern with reflection maxima at approximately 2~ of about 8.1°, 13.1°, 19.6° and 19.9°; and (c) an infra red absorption spectrum with absorption bands in the region of 1714, 1649, 1542 and 1214 cm-1.
(a) a melting point in the range of 136 to 142°C;
(b) a powder X-ray diffraction pattern with reflection maxima at approximately 2~ of about 8.1°, 13.1°, 19.6° and 19.9°; and (c) an infra red absorption spectrum with absorption bands in the region of 1714, 1649, 1542 and 1214 cm-1.
2. Crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine according to claim 1 having all three of the properties (a), (b) and (c).
3. Crystals of N-(trans-4-isopropylcyclohexylcar-bonyl)-D-phenylalanine having at least one of an X-ray powder diffraction pattern as shown in Fig. 3 and an infra red spectrum as shown in Fig. 4.
4. Crystals according to any one of claims 1 and 3 in the substantial absence of solvent.
5. A pharmaceutical composition for reducing blood glucose levels in a mammal, comprising as active ingredient crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine as defined in claim 1, and a pharmaceutically acceptable carrier therefor.
6. Use of crystals of N-(trans-4-isopropylcyclohexyl-carbonyl)-D-phenylalanine as defined in claim 1 for reducing blood glucose levels in a mammal.
7. A method for the production of crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine having at least one of the following properties:
(a) a melting point in the range of 136-142°C;
(b) a powder X-ray diffraction pattern with reflection maxima at 2~ of about 8.1°, 13.1°, 19.6°
and 19.9°;
(c) an infra red absorption spectrum with absorption bands in the region of 1714, 1649, 1542 and 1214 cm-1, comprising dissolving or suspending an N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine not possessing any of said properties in a solvent in which it is completely or incompletely soluble at a temperature of at least 15°C and up to the boiling point of the solvent and permitting said crystals to crystallize from or form in said solvent at a temperature of 15°C or in excess thereof.
(a) a melting point in the range of 136-142°C;
(b) a powder X-ray diffraction pattern with reflection maxima at 2~ of about 8.1°, 13.1°, 19.6°
and 19.9°;
(c) an infra red absorption spectrum with absorption bands in the region of 1714, 1649, 1542 and 1214 cm-1, comprising dissolving or suspending an N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine not possessing any of said properties in a solvent in which it is completely or incompletely soluble at a temperature of at least 15°C and up to the boiling point of the solvent and permitting said crystals to crystallize from or form in said solvent at a temperature of 15°C or in excess thereof.
8. The method according to claim 7, wherein the N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is dissolved in a solvent in which it is soluble at a temperature greater than 15°C to form a solution and from which it may be precipitated by cooling to a lower temperature of 15°C or higher and crystals are then crystallized from the solution at a temperature of 15°C
or in excess thereof by reducing the temperature of the solution to a temperature of 15°C or in excess thereof.
or in excess thereof by reducing the temperature of the solution to a temperature of 15°C or in excess thereof.
9. The method according to claim 7, wherein the N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is dissolved in a first solvent from which it may be precipitated by addition of a second solvent and the crystallization from solution in the first solvent is effected at a temperature of 15°C or in excess thereof by adding to the solution a second solvent miscible with the first solvent selected such that the solubility of said N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl-alanine in the mixture of the first solvents and second solvent is less than in the first solvent, the solubility being reduced to an extent such that crystals crystallize from the solvent mixture at a temperature in excess of 15°C.
10. The method according to claim 7, wherein the N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is combined at a temperature of at least 15°C with a solvent in which it is incompletely soluble at that temperature to form a suspension of solid N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine, and said suspension is maintained at a temperature of at least 15°C, thereby to form said crystals from said solids.
11. The method according to claim 7 further comprising separating said crystals from the solvent at a temperature in excess of 15°C.
12. The method according to claim 8, wherein the solvent is a mixture of a first solvent selected from the group consisting of acetone, ethanol and isopropanol with water as a second solvent.
13. The method according to claim 12, wherein the concentration of the first solvent is from 30 to 60 vol%
of the solvent mixture.
of the solvent mixture.
14. The method according to claim 12, wherein the temperature of the solution is from 15 to 50°C.
15. The method according to claim 9, wherein the first solvent is selected from the group consisting of acetone, ethanol and isopropanol and the second solvent is water.
16. The method according to claim 15, wherein the temperature of solution is from 15 to 50°C.
17. The method according to claim 10, wherein the solvent is a mixture of a first solvent selected from the group consisting of acetone, ethanol and isopropanol with water as a second solvent.
18. The method according to claim 17, wherein the concentration of first solvent in the solvent mixture is from 25 to 50 vol% of he solvent mixture.
19. The method according to claim 10, wherein the solvent is water.
20. The method according to claim 17, wherein the temperature of the suspension is from 15 to 50°C.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4202686A JP2508949B2 (en) | 1991-07-30 | 1992-07-29 | Crystal of N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine and process for producing the same |
| DE69217762T DE69217762T2 (en) | 1991-07-30 | 1992-07-29 | Crystals of N- (Trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine and process for their preparation |
| DE2001199058 DE10199058I2 (en) | 1991-07-30 | 1992-07-29 | Crystals of N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine and process for their preparation |
| EP92306895A EP0526171B1 (en) | 1991-07-30 | 1992-07-29 | Crystals of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine and methods for preparing them |
| ES92306895T ES2100291T3 (en) | 1991-07-30 | 1992-07-29 | CRYSTALS OF N- (TRANS-4-ISOPROPILCICLOHEXILCARBONIL) -D-PHENYLALANINE AND METHODS TO PREPARE THEM. |
| AT92306895T ATE149483T1 (en) | 1991-07-30 | 1992-07-29 | CRYSTALS OF N-(TRANS-4- ISOPROPYLCYCLOHEXYLCARBONYL)-D-PHENYLALANINE AND METHOD FOR THE PRODUCTION THEREOF |
| DK92306895.1T DK0526171T3 (en) | 1991-07-30 | 1992-07-29 | Crystals of N- (trans-4-isopropylcyclohexylcarbonyl) -phenylalanine and processes for their preparation |
| US08/166,144 US5488150A (en) | 1991-07-30 | 1993-12-14 | Crystals of N-(trans-4-isopropylcyclohexycarbonyl)-D-phenylalanine and methods for preparing them |
| CA002114678A CA2114678C (en) | 1991-07-30 | 1994-02-01 | Crystals of n-(trans-4-isopropylcyclohexylcarbonyl)- d-phenylalanine and methods for preparing them |
| US08/190,460 US5463116A (en) | 1991-07-30 | 1994-02-02 | Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them |
| BR1100807-5A BR1100807A (en) | 1991-07-30 | 1997-05-12 | Crystals of n- (trans-4-isopropylcyclohexylcarbonyl) -d-phenylalanine and processes for preparing them |
| LU90843C LU90843I2 (en) | 1991-07-30 | 2001-09-28 | Starlix-nateglinide and its pharmaceutically acceptable derivatives |
| NL300063C NL300063I2 (en) | 1991-07-30 | 2001-09-28 | Crystals of N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine and methods for their preparation. |
| LU90846C LU90846I2 (en) | 1991-07-30 | 2001-10-03 | Starlix-nateglinide and its pharmaceutically acceptable derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18969691 | 1991-07-30 | ||
| JP19945391 | 1991-08-08 | ||
| CA002114678A CA2114678C (en) | 1991-07-30 | 1994-02-01 | Crystals of n-(trans-4-isopropylcyclohexylcarbonyl)- d-phenylalanine and methods for preparing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2114678A1 CA2114678A1 (en) | 1995-08-02 |
| CA2114678C true CA2114678C (en) | 1999-04-27 |
Family
ID=27169694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002114678A Expired - Lifetime CA2114678C (en) | 1991-07-30 | 1994-02-01 | Crystals of n-(trans-4-isopropylcyclohexylcarbonyl)- d-phenylalanine and methods for preparing them |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5488150A (en) |
| EP (1) | EP0526171B1 (en) |
| JP (1) | JP2508949B2 (en) |
| AT (1) | ATE149483T1 (en) |
| BR (1) | BR1100807A (en) |
| CA (1) | CA2114678C (en) |
| DE (2) | DE69217762T2 (en) |
| DK (1) | DK0526171T3 (en) |
| ES (1) | ES2100291T3 (en) |
| LU (2) | LU90843I2 (en) |
| NL (1) | NL300063I2 (en) |
Families Citing this family (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022105A1 (en) | 1996-11-15 | 1998-05-28 | Ajinomoto Co., Inc. | Tabletted preparation |
| GB9713730D0 (en) | 1997-06-30 | 1997-09-03 | Ciba Geigy Ag | Organic compounds |
| US6559188B1 (en) | 1999-09-17 | 2003-05-06 | Novartis Ag | Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes |
| US6878749B2 (en) * | 1999-09-17 | 2005-04-12 | Novartis Ag | Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes |
| CO5200844A1 (en) | 1999-09-17 | 2002-09-27 | Novartis Ag | A COMBINATION THAT INCLUDES NATEGLINED AND WHEN AT LEAST ANOTHER ANTI-DIABETIC COMPOUND USED FOR THE TREATMENT OF METABOLIC DISORDERS, ESPECIALLY DIABETES, OR OF A DISEASE OR CONDITION ASSOCIATED WITH DIBETES |
| PT1741445E (en) | 2000-01-21 | 2013-11-11 | Novartis Ag | Combinations comprising dipeptidylpeptidase-iv inhibitors and antidiabetic agents |
| PE20020617A1 (en) | 2000-08-22 | 2002-08-05 | Novartis Ag | COMPOSITION INCLUDING AN AT1 RECEPTOR ANTAGONIST AND AN INSULIN SECRETION POTENTIAL OR AN INSULIN SENSITIZER |
| JP4158192B2 (en) * | 2000-10-18 | 2008-10-01 | 味の素株式会社 | Method for producing acylphenylalanine |
| PT1334963E (en) | 2000-10-18 | 2007-09-20 | Ajinomoto Kk | Process for producing nateglinide crystal |
| RU2283104C2 (en) * | 2000-10-24 | 2006-09-10 | Адзиномото Ко., Инк. | Hydrophilic nateglinide-containing pharmaceutical preparation |
| BR0114846A (en) * | 2000-10-24 | 2004-02-25 | Ajinomoto Kk | Method for Producing Nateglinide Type B Crystals Substantially Free of Type H Crystals |
| EP1334720B1 (en) * | 2000-10-24 | 2008-09-03 | Ajinomoto Co., Inc. | Nateglinide-containing preparations |
| AR035425A1 (en) * | 2001-01-30 | 2004-05-26 | Teijin Ltd | ACID DICHLORHYDRATE CRYSTAL 3- (3-AMIDINOFENIL) -5 - [({[1- (IMINOETIL) -4-PIPERIDIL] METHYL} AMINO) METHYL] BENZOIC AND PROCESS TO PREPARE |
| WO2003022251A1 (en) * | 2001-09-12 | 2003-03-20 | Alembic Limited | Novel stable crystal form of n-trans-4-isopropylcyclohexyl carbonyl)-d-phenylalanine and process of preparation |
| TW200304813A (en) * | 2002-03-11 | 2003-10-16 | Novartis Ag | Salts of organic acid |
| CA2482669A1 (en) * | 2002-04-15 | 2003-10-23 | Novartis Ag | Crystal forms of n-(trans-4-isopropylcyclohexylcarbonyl)-d-phenylalanine |
| AU2003236243A1 (en) * | 2002-04-15 | 2003-10-27 | Ajinomoto Co., Inc. | Novel nateglinide crystal |
| US7411089B2 (en) | 2002-04-15 | 2008-08-12 | Ajinomoto Co., Inc. | Nateglinide crystals |
| JP4137053B2 (en) * | 2002-04-29 | 2008-08-20 | バイオコン・リミテッド | Novel form of N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine |
| US6861553B2 (en) * | 2002-07-03 | 2005-03-01 | Teva Pharmaceuticals Industries Ltd. | Process for preparing nateglinide and intermediates thereof |
| AU2003256454A1 (en) * | 2002-07-03 | 2004-01-23 | Teva Pharmaceutical Industries Ltd. | Process for preparing nateglinide and intermediates thereof |
| US7534913B2 (en) * | 2002-07-18 | 2009-05-19 | Teva Pharmaceutica Industries Ltd. | Crystalline form of nateglinide |
| US7358390B2 (en) * | 2002-07-18 | 2008-04-15 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
| US7148376B2 (en) * | 2002-07-18 | 2006-12-12 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
| US20050075400A1 (en) * | 2002-07-18 | 2005-04-07 | Ronit Yahalomi | Polymorphic forms of nateglinide |
| US7420084B2 (en) * | 2002-07-18 | 2008-09-02 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
| WO2004020396A1 (en) * | 2002-08-28 | 2004-03-11 | Dr. Reddy's Laboratories Limited | Crystalline form of nateglinide and process for preparation thereof |
| WO2004074330A1 (en) * | 2003-02-18 | 2004-09-02 | Konishi Co., Ltd. | Curing resin, method for producing same and curing resin composition |
| HU227073B1 (en) * | 2003-07-10 | 2010-06-28 | Richter Gedeon Nyrt | Process for the preparation of chirally pure n-(trans-4-isopropyl-cyclohexylcarbonyl)-d-phenyl-alanine (nateglinide) and it's crystalline forms and the cristalline form g |
| CA2563793A1 (en) * | 2004-05-07 | 2005-11-24 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
| US7425648B2 (en) | 2005-01-03 | 2008-09-16 | A.M.S.A. Anonima Materie Sintetiche E. Affini S.P.A. | Process for the preparation of nateglinide, preferably in B-form |
| GT200600381A (en) | 2005-08-25 | 2007-03-28 | ORGANIC COMPOUNDS | |
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| JP5152699B2 (en) * | 2006-03-31 | 2013-02-27 | 味の素株式会社 | Method for producing carboxylic acid chloride compound |
| WO2008068615A1 (en) * | 2006-12-06 | 2008-06-12 | Pfizer Inc. | Crystalline forms of ( 3 s ) -3- [n- (n' - (2-tert-butylphenyl) oxamyl) alaninyl] amino-5- (2 ', 3 ', 5 ', 6 ' -tetrafluoro phenoxy) -4-0x0penta noic acid |
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| WO2011064376A1 (en) | 2009-11-30 | 2011-06-03 | Novartis Ag | Imidazole derivatives as aldosterone synthase inhibitors |
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| US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
| US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
| UY35144A (en) | 2012-11-20 | 2014-06-30 | Novartis Ag | APELINE SYNTHETIC LINEAR MIMETICS FOR THE CARDIAC INSUFFICIENCY TREATMENT |
| EA028583B1 (en) | 2013-02-14 | 2017-12-29 | Новартис Аг | Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors |
| CN105612172A (en) | 2013-07-25 | 2016-05-25 | 诺华股份有限公司 | Cyclic polypeptides for the treatment of heart failure |
| US9340582B2 (en) | 2013-07-25 | 2016-05-17 | Novartis Ag | Bioconjugates of synthetic apelin polypeptides |
| MA41580A (en) | 2015-01-23 | 2017-11-29 | Novartis Ag | SYNTHETIC APELIN FATTY ACID CONJUGATES WITH IMPROVED HALF-LIFE |
| UY38072A (en) | 2018-02-07 | 2019-10-01 | Novartis Ag | COMPOSITIONS DERIVED FROM BUTANOIC ESTER SUBSTITUTED WITH BISPHENYL AS INHIBITORS OF NEP, COMPOSITIONS AND COMBINATIONS OF THE SAME |
| CN109369443A (en) * | 2018-11-05 | 2019-02-22 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of preparation method of new Nateglinide H crystal form |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US196222A (en) * | 1877-10-16 | Improvement in belt-tighteners | ||
| JPS6354321A (en) * | 1985-03-27 | 1988-03-08 | Ajinomoto Co Inc | Blood sugar lowering agent |
-
1992
- 1992-07-29 DE DE69217762T patent/DE69217762T2/en not_active Expired - Lifetime
- 1992-07-29 ES ES92306895T patent/ES2100291T3/en not_active Expired - Lifetime
- 1992-07-29 EP EP92306895A patent/EP0526171B1/en not_active Expired - Lifetime
- 1992-07-29 DK DK92306895.1T patent/DK0526171T3/en active
- 1992-07-29 AT AT92306895T patent/ATE149483T1/en active
- 1992-07-29 DE DE2001199058 patent/DE10199058I2/en active Active
- 1992-07-29 JP JP4202686A patent/JP2508949B2/en not_active Expired - Lifetime
-
1993
- 1993-12-14 US US08/166,144 patent/US5488150A/en not_active Expired - Lifetime
-
1994
- 1994-02-01 CA CA002114678A patent/CA2114678C/en not_active Expired - Lifetime
-
1997
- 1997-05-12 BR BR1100807-5A patent/BR1100807A/en active IP Right Grant
-
2001
- 2001-09-28 NL NL300063C patent/NL300063I2/en unknown
- 2001-09-28 LU LU90843C patent/LU90843I2/en unknown
- 2001-10-03 LU LU90846C patent/LU90846I2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE69217762D1 (en) | 1997-04-10 |
| DK0526171T3 (en) | 1997-08-25 |
| ES2100291T3 (en) | 1997-06-16 |
| DE69217762T2 (en) | 1997-10-09 |
| NL300063I2 (en) | 2002-02-01 |
| JPH05208943A (en) | 1993-08-20 |
| LU90843I2 (en) | 2002-02-04 |
| NL300063I1 (en) | 2001-12-01 |
| BR1100807A (en) | 1999-12-28 |
| CA2114678A1 (en) | 1995-08-02 |
| LU90846I2 (en) | 2002-02-04 |
| DE10199058I1 (en) | 2002-01-24 |
| EP0526171A2 (en) | 1993-02-03 |
| EP0526171B1 (en) | 1997-03-05 |
| ATE149483T1 (en) | 1997-03-15 |
| JP2508949B2 (en) | 1996-06-19 |
| DE10199058I2 (en) | 2006-04-27 |
| US5488150A (en) | 1996-01-30 |
| EP0526171A3 (en) | 1993-05-05 |
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