HK1169040B - Solid forms and process for preparing - Google Patents

Description

Solid forms and methods of preparation

Cross Reference to Related Applications

This application claims priority from U.S. provisional application No. 61/177,483 filed on day 5, month 13, 2009.

Background

(R) -4 a-ethoxymethyl-1- (4-fluoro-phenyl) -6- (4-trifluoromethyl-benzenesulfonyl) -4, 4a, 5, 6, 7, 8-hexahydro-1H, 1, 2, 6-triaza-cyclopenta [ b ] naphthalene (Compound 1 herein) has been previously disclosed in Clark et al, Bioorganic and Medicinal Chemistry Letters 2008, 18, 1312-:

compound 1 is a member of a class of compounds useful as Glucocorticoid Receptor (GR) antagonists for the modulation of hydrocortisoneOne, the first step. One such known GR antagonist, mifepristone, has been found to be a potent antiglucocorticoid agent in humans (Bertagna (1984) J.Clin.Endocrinol.Metab.59: 25). Mifepristone binds GR with high affinity and has a binding capacity of 10^-9Dissociation constant (K) of M_d)(Cadepond(1997)Annu.Rev.Med.48：129)。

In patients with certain forms of psychiatric disorders, increased levels of hydrocortisone have been found (Krishnan (1992) prog. neuro-Psychophannnacol. & biol. Psychiat. 16: 913. 920). For example, some depressed individuals may respond to treatments that block the effects of hydrocortisone (e.g., administration of GR antagonists) (Van hook (1995) Human Reproduction Update 1: 19-34). In one study, patients with depression secondary to Cushing's Syndrome (Cushing's Syndrome) responded to the high dose (up to 1400 mg/day) of the GR antagonist mifepristone (Nieman (1985) j.clin endocrinol.meta.61: 536). Another study of The treatment of Cushing's syndrome with mifepristone found that The treatment improved The patient's condition, including their mental status (Chrousos, pp 273-.

Psychosis is also associated with Cushing's syndrome (Gerson (1985) Can. J. Psychiatry30: 223-. Mifepristone has been used to treat acute psychiatric disorders secondary to cushing's syndrome. One study showed that relatively high doses (400-800 mg/day) of mifepristone can be used to rapidly reverse acute psychosis in patients with severe cushing's syndrome due to ectopic secretion of ACTH by adrenal and lung cancer (Vander LeIy (1991) ann. lntern. med.114: 143; Van der LeIy (1993) pharmacworld & Science 15: 89-90; Sartor (1996) supra).

If Compound 1 could be administered in solid form, it would be easier to treat psychotic major depression and other conditions and diseases with Compound 1. Solid forms have a number of advantages over oily and gelatinous forms of the compounds, such as, inter alia, ease of handling, ease of dissolution, ease of formulation into solid dosage forms with pharmaceutical excipients. However, previous preparations of compound 1 and its derivatives did not yield compound 1 in solid form. See Bioorganic and medicinal chemistry Letters 2008, 18, 1312-.

What is needed is a solid form of compound 1 and a method of making the solid form. Surprisingly, the present invention meets this need, as well as other needs.

Brief description of the invention

In one embodiment, the present invention provides an amorphous solid form of a compound of formula I:

in another embodiment, the present invention provides a process for preparing an amorphous solid form of a compound of formula I. In one step, the method comprises dissolving a compound of formula I in an acetone, methanol, ethanol, 2-propanol, or 2-methoxyethanol solvent to produce a first solution. In another step, the method comprises contacting the first solution with water, thereby precipitating the compound of formula I.

Drawings

FIG. 1 shows an X-ray diffraction pattern of a compound of formula I and indicates that the compound of formula I is amorphous.

Figure 2 shows the thermogravimetric analysis (TGA) of the compound of formula I.

FIG. 3 shows a Differential Scanning Calorimetry (DSC) test of a compound of formula I.

Detailed Description

The present invention provides amorphous solid forms of the compound of formula I and methods of making the amorphous solid forms. The compounds of formula I are known in the art, but are not in solid form in the art. Solid forms of the compounds are common and can be prepared by precipitation or crystallization methods using single or binary solvent systems known to those skilled in the art. Many solvent systems are used to prepare amorphous or crystalline forms of a compound. However, in some cases, for example for compounds of formula I, the compounds do not readily form amorphous or crystalline forms, and extensive experimentation may be required to determine the solvent systems and conditions used to prepare the amorphous or crystalline forms.

Because the compounds of formula I do not readily form amorphous or crystalline forms, a number of processes and solvent systems have been extensively tested to prepare solid forms of the compounds of formula I. Some of the methods tested utilized a single solvent system of dichloromethane, chlorobenzene, toluene, anisole, heptane, 1, 4-dioxane, tert-butyl methyl ether, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, methyl ethyl ketone, acetone, ethanol, methanol, 2-butanol, 1-propanol, 2-methoxyethanol, acetonitrile, tetrahydrofuran, water, and nitromethane. The compound of formula I was dissolved in the solvent using two different concentrations for each solvent system and a heating/cooling cycle (cycle 8 hours) was performed between room temperature and 50 ℃ for 24 hours, followed by cooling at 4 ℃ for 24 hours and further cooling at-20 ℃ for 24 hours. A single solvent system does not yield a solid form of the compound of formula I.

To prepare the solid form of the compound of formula I, a binary solvent system was also tested. The compound of formula I is dissolved using a solvent other than water and heptane as listed above, and water, heptane or cyclohexane is added as an anti-solvent to reduce the solubility of the compound of formula I in the solvent mixture. Several binary solvent systems were identified that provided solid form: methanol/water, ethanol/water, 2-propanol/water and 2-methoxyethanol/water. Many of the tested solvent systems fail to provide amorphous solid forms of the compound of formula I. Surprisingly, while 2-propanol/water provides an amorphous solid form of the compound of formula I, 1-propanol/water does not. Furthermore, 1-butanol/water and 2-butanol/water do not provide amorphous solid forms of the compound of formula I. The solvent combination may also be cooled from room temperature to-10 ℃ and held at-10 ℃, or-20 ℃ at 0.1 ℃/minute. For example, a binary solvent system, t-butyl methyl ether/heptane, provides an amorphous solid form of the compound of formula I when cooled to-20 ℃.

Accordingly, the present invention provides an amorphous solid form of a compound of formula I:

in other embodiments, the compound of formula I is characterized by an X-ray diffraction pattern, substantially as shown in figure 1. Thermogravimetric analysis (TGA) showed that there was about a 10% weight loss of the compound of formula I when heated to 40-45 ℃ up to about 150 ℃ with no additional weight loss (see figure 2). Differential Scanning Calorimetry (DSC) analysis showed the endothermic peak of the amorphous solid form of the compound of formula I to be at about 66 ℃ (see figure 3).

Amorphous solid forms of the compounds of formula I can be prepared by a variety of methods. In some embodiments, the amorphous solid form may be prepared by dissolving the compound of formula I in a good solvent at elevated temperature to prepare a saturated solution, and then cooling the solution to allow the compound of formula I to come out of solution to form a precipitate.

Alternatively, amorphous solid forms of the compound of formula I may be prepared by dissolving the compound of formula I in a good solvent and then adding the anti-solvent to the good solvent. An anti-solvent is a solvent in which the compound of formula I is insoluble or poorly soluble, such that the solubility of the compound of formula I in a mixture of good solvent and anti-solvent is reduced to the point where the compound of formula I comes out of solution. Solvents that may be used to dissolve compounds of formula I include, but are not limited to, methylene chloride, chlorobenzene, toluene, anisole, 1, 4-dioxane, t-butyl methyl ether, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, methyl ethyl ketone, acetone, ethanol, methanol, 2-butanol, 1-propanol, 2-methoxyethanol, acetonitrile, tetrahydrofuran, nitromethane, acetic acid, dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone. Other good solvents may be used in the present invention.

Antisolvents which may be used in the process of the present invention include, but are not limited to, polar-protic solvents, C₅-C₁₀Alkyl and C₅-C₁₀A cycloalkyl group. Polar protic solvents that may be used as antisolvents in the present invention include, but are not limited to, water. C useful as an antisolvent in the present invention₅-C₁₀Alkyl groups include, but are not limited to, pentane, hexane, heptane, octane, nonane, decane, and isomers thereof. C₅-C₁₀The alkyl group may be linear or branched, saturated or unsaturated. The antisolvent may also be C₅-C₁₀Cycloalkyl groups such as cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane and cyclodecane. C₅-C₁₀Cycloalkyl groups may be partially or fully saturated or unsaturated. Other solvents may be used as the antisolvent in the present invention.

In another embodiment, the present invention provides a process for preparing an amorphous solid form of a compound of formula I. In one step, the process comprises dissolving a compound of formula I in an acetone, methanol, ethanol, 2-propanol, or 2-methoxyethanol solvent to produce a first solution. In another step, the method comprises contacting the first solution with water, thereby precipitating the compound of formula I. In other embodiments, the solvent is methanol, ethanol, 2-propanol, or 2-methoxyethanol. In some other embodiments, the solvent is methanol, ethanol, or 2-propanol. In still other embodiments, the solvent is ethanol.

The ratio of solvent to anti-solvent can be any useful ratio. In some embodiments, the ratio of solvent to anti-solvent is from about 5: 1 to about 1: 10 (volume/volume). In other embodiments, the ratio of solvent to anti-solvent is from about 2: 1 to about 1: 2 (volume/volume). In some other embodiments, the ratio of solvent to anti-solvent is about 1: 1 (volume/volume). In still other embodiments, the ratio of solvent to anti-solvent is from about 1: 1 to about 1: 5 (volume/volume). In still other embodiments, the ratio of solvent to anti-solvent is about 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, or about 1: 10 (volume/volume). Other ratios of solvent to antisolvent may be used in the present invention.

In some embodiments, an anti-solvent may be added to the first solution. In other embodiments, the first solution is added to the anti-solvent. When the first solution is added to the anti-solvent, the anti-solvent may be stirred vigorously and the first solution added dropwise to precipitate the compound of formula I. For example, when the anti-solvent is water, then the first solution can be added to the water.

In other embodiments, the present invention provides methods of preparing amorphous solid forms of the compounds of formula I. In one step, the process comprises dissolving a compound of formula I in 1, 4-dioxane to produce a first solution. In another step, the process comprises contacting the first solution with heptane, thereby precipitating the compound of formula I.

In some other embodiments, the present invention provides a process for preparing an amorphous solid form of the compound of formula I using a binary solvent system of tert-butyl methyl ether and heptane. In one step, the process comprises dissolving a compound of formula I in tert-butyl methyl ether to produce a first solution. In another step, the method includes contacting the first solution with heptane to produce a second solution. The process also involves cooling the second solution to less than about 0 ℃, thereby precipitating the compound of formula I. In some embodiments, the second solution is cooled to about-20 ℃. Other temperatures may be used to prepare amorphous solid forms of the compound of formula I. The second solution may be cooled for any suitable period of time. In some embodiments, cooling may be for minutes or 1 hour. In other embodiments, cooling may be for hours or up to 1 day. In other embodiments, cooling may be for several days, e.g., 1, 2, 3, 4, 5 or more days.

After precipitation, the solid form of the compound of formula I is isolated by filtration and dried.

I. Examples of the embodiments

Example 1: precipitation of formula I from a single solvent mixture

The compound of formula I is dissolved in a solvent and subjected to a heating/cooling cycle (8 hour cycle) between room temperature and 50 ℃ for 24 hours, followed by cooling at 4 ℃ for 24 hours and further cooling at-20 ℃ for 24 hours.

TABLE 1 precipitation from a single solvent mixture

Solvent(s)	Product I1	Product II2
			Methylene dichloride	Clear solution	Oil-like substance
Chlorobenzene	Clear solution	Oil-like substance
			Toluene	Clear solution	Oil-like substance
Anisole	Clear solution	Oil-like substance
			Heptane (Heptane)	Colloid	-
1, 4-dioxane	Clear solution	Oil-like substance
			Tert-butyl methyl ether2	Clear solution	Oil-like substance
Acetic acid butyl ester	Clear solution	Oil-like substance
			Acetic acid isopropyl ester	Clear solution	Oil-like substance
Ethyl acetate	Clear solution	Oil-like substance
			Methyl isobutyl ketone	Clear solution	Oil-like substance
Methyl ethyl ketone	Clear solution	Oil-like substance
			Acetone (II)	Clear solution	Oil-like substance
Ethanol	Clear solution	Oil-like substance
			Methanol	Clear solution	Glass-like article
2-Butanol	Clear solution	Oil-like substance
			1-Butanol	Clear solution	Oil-like substance
1-propanol	Clear solution	Oil-like substance
			2-propanol	Clear solution	Oil-like substance
2-methoxy ethanol	Clear solution	Oil-like substance
			Acetonitrile	Clear solution	Oil-like substance
Tetrahydrofuran (THF)	Clear solution	Oil-like substance
			Water (W)	Colloid	-
Nitromethane	Clear solution	Oil-like substance

¹The concentration was 25-30mg/0.5 mL.²The concentration was 25-30mg/0.1 mL. The method further comprises sonicating for 10 minutes at room temperature and evaporating the solvent.

Example 2: precipitation of formula I from a solvent: antisolvent mixture

Formula I is dissolved in a suitable solvent at room temperature. The anti-solvent was added in the appropriate ratio and the slurry was stirred at room temperature (unless otherwise provided). Any solid formed was isolated by filtration and dried.

TABLE 2 precipitation from alcohol/anti-solvent mixtures

Solvent(s)	Anti-solvent	Solvent to anti-solvent ratio	Product of1
				Methanol	Water (W)	1∶1	Precipitation of
Methanol	Water (W)	10∶1	No precipitation
				Ethanol	Water (W)	1∶1	Precipitation of
Ethanol	Water (W)	10∶1	No precipitation
				Ethanol	Cyclohexane2	1∶2	No precipitation
1-propanol	Water (W)	1∶1	No precipitation
				1-propanol	Water (W)	10∶1	No precipitation
1-propanol	Cyclohexane2	1∶2	No precipitation
				2-propanol	Water (W)	1∶1	Precipitation of
2-propanol	Water (W)	10∶1	No precipitation
				1-Butanol	Water (W)	2∶1	No precipitation
2-Butanol	Water (W)	2∶1	No precipitation
				2-methoxy ethanol	Water (W)	1∶1	Precipitation of
2-methoxy ethanol	Water (W)	10∶1	No precipitation
				2-methoxy ethanol	Cyclohexane2	1∶2	No precipitation

¹Any precipitate that forms is an amorphous precipitate.²Cooled from room temperature to-10 ℃ at 0.1 ℃/min and held at-10 ℃ for 4 days.

TABLE 3 precipitation from solvent/anti-solvent mixtures

Solvent(s)	Anti-solvent	Solvent to anti-solvent ratio	Product of1
				Methylene dichloride	Heptane (Heptane)	1∶2	No precipitation
Chlorobenzene	Heptane (Heptane)	1∶2	No precipitation
				Toluene	Heptane (Heptane)	1∶2	No precipitation
Anisole	Heptane (Heptane)	1∶2	No precipitation
				1, 4-dioxane	Heptane (Heptane)	1∶2	Precipitation of
Tert-butyl methyl ether2	Heptane (Heptane)	1∶2	No precipitation
				Acetic acid butyl ester	Heptane (Heptane)	1∶2	No precipitation
Acetic acid isopropyl ester	Heptane (Heptane)	1∶2	No precipitation
				Ethyl acetate	Heptane (Heptane)	1∶2	No precipitation
Methyl isobutyl ketone	Heptane (Heptane)	1∶2	No precipitation
				Methyl ethyl ketone	Heptane (Heptane)	1∶2	No precipitation
Acetone (II)	Water (W)	1∶1	Precipitation of
				Acetone (II)	Water (W)	10∶1	No precipitation

Acetonitrile	Water (W)	1∶2	No precipitation
				Acetonitrile	Water (W)	10∶1	No precipitation
Tetrahydrofuran (THF)	Heptane (Heptane)	1∶2	No precipitation
				Nitromethane	Heptane (Heptane)	1∶2	No precipitation
Acetic acid	Water (W)	1∶3	No precipitation
				Dimethyl formamide	Water (W)	1∶3	No precipitation
Dimethyl sulfoxide	Water (W)	1∶3	No precipitation
				N-methyl pyrrolidone	Water (W)	1∶3	No precipitation

¹Any precipitate that forms is an amorphous precipitate,²after cooling at-20 ℃ for 5 days, an amorphous precipitate formed.

Example 3: precipitation of formula I from ethanol/water

The precipitation was carried out under a nitrogen atmosphere. A22-L baffled jacketed (bucketed) reaction flask equipped with an overhead stirrer, thermocouple, addition funnel, and Jumbo HTU was rinsed with a mixture of 1L water and 0.25L ethanol prior to use. Water was added to the flask and stirred, and Jumbo was fixed at 20.0 ℃. The purified compound of formula I (381.1g) from a rotary evaporator (rotovap bulb) was dissolved in ethanol (4.0L) and the solution was filtered through a rinsed glass tampon into a rinsed Pyrex bottle. The rotary spherical digester and funnel were rinsed with ethanol (0.3L). The solutions were mixed and then transferred (500mL each) to an addition funnel. The solution was added to vigorously stirred water in a thin stream over 1 hour 48 minutes, resulting in a white precipitate. During the addition of the compound of the formula I, the temperature is maintained at 21 to 25 ℃. The empty Pyrex bottle was rinsed with ethanol (50mL), and the rinse was added to the addition funnel and then to the flask. The white suspension was stirred at 20-25 ℃ for 78 min. The solid was isolated by vacuum filtration on a medium pore glass funnel; the filter cake breaks up and shrinks. The flask was rinsed with 4: 1 water/ethanol (1900mL) and the rinse was added to the funnel. The filter cake was deliquored and then transferred to a Pyrex drying tray and the cake was broken up. The dishes were placed in a vacuum oven maintained at 40-50 ℃ under a nitrogen purge until constant weight. 364g of the compound of the formula I are isolated.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety as if each reference had been individually incorporated by reference.

Claims (9)

1. An amorphous solid form of a compound of formula I:

2. the amorphous solid form of claim 1, characterized by an X-ray diffraction pattern substantially as shown in figure 1.

3. A process for preparing an amorphous solid form of a compound of formula I:

the method comprises the following steps:

dissolving a compound of formula I in a solvent selected from the group consisting of acetone, methanol, ethanol, 2-propanol, and 2-methoxyethanol to produce a first solution; and

contacting the first solution with water, wherein the ratio of solvent to water is 1: 1 (volume/volume),

thereby precipitating the compound of formula I.

4. The process of claim 3, wherein the solvent is selected from the group consisting of methanol, ethanol, 2-propanol, and 2-methoxyethanol.

5. The process of claim 4, wherein the solvent is selected from the group consisting of methanol, ethanol, and 2-propanol.

6. The method of claim 5, wherein the solvent is ethanol.

7. The method of claim 6, wherein the first solution is added to water.

8. A process for preparing an amorphous solid form of a compound of formula I:

the method comprises the following steps:

dissolving a compound of formula I in 1, 4-dioxane to produce a first solution; and

contacting the first solution with heptane, wherein the ratio of 1, 4-dioxane to heptane is 1: 2 (v/v), thereby precipitating the compound of formula I.

9. A process for preparing an amorphous solid form of a compound of formula I:

the method comprises the following steps:

dissolving a compound of formula I in tert-butyl methyl ether to produce a first solution; and

contacting the first solution with heptane to produce a second solution, wherein the ratio of tert-butyl methyl ether to heptane is 1: 2 (volume/volume); and

the second solution is cooled to below 0 ℃, thereby precipitating the compound of formula I.