JP2002531550A - Crystal forms of benzoquinolin-3-one derivatives as inhibitors of 5α-reductase - Google Patents

Abstract

(57) [Summary] The present invention relates to a pharmaceutically active substance. More specifically, the present invention relates to a novel crystalline form of an octahydrobenzo [f] quinolin-3-one derivative, a pharmaceutical preparation containing this crystalline form as an active ingredient, and a method of using and producing the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutically active substance. More specifically, the present invention relates to a novel crystalline form of an octahydrobenzo [f] quinolin-3-one derivative, a pharmaceutical preparation containing this crystalline form as an active ingredient, and a method of using and producing the same.

US Pat. No. 5,541,190 (herein incorporated by reference) (hereinafter the '190 patent) discloses certain benzo [f] quinolinone derivatives that are potent inhibitors of 5α-reductase. It has been disclosed. 5α-reductase mediates the conversion of testosterone to the more potent androgen 5α-dihydrotestosterone (DHT). Certain undesirable physiological conditions, such as benign prostatic hyperplasia, male pattern baldness,
Acquired acne, seborrhea, androgenetic alopecia, hirsutism and prostate cancer are commonly known to be DHT-dependent androgen-mediated conditions. Therefore, the above-mentioned benzo [f] quinolinone derivative is useful for treatment of a disease in which inhibition of 5α-reductase is desired.

[0003] One of the benzo [f] quinolinone derivatives disclosed in the '190 patent is trans (-)
-(4aR) -8-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one ("Compound 1"). Compound 1 is also described in Examples 64 and 68b of the '190 patent and in J. Org. Chem., 61, 4450 (1996).

[0004] Certain crystalline forms ("Form A") have been found to be prepared by the procedure described in Example 64 of the '190 Patent. In addition, it has been found that Example 68b of the '190 patent describes a mixture of different crystal forms (designated "Form B"). A further different crystalline form ("Form C") has also been found to be disclosed in J. Org. Chem., 61, 4450, 4454 (1996).

[0005] All of these known crystal forms are known to have various disadvantages in drug development. For example, Form A is difficult to crystallize and is often observed as a mixture of other types. Such mixtures are metastable and transform into other forms of the solid state. Mixtures of different crystalline forms ("B-form"), for example, exhibit different solubilities for different forms;
Formulation for a variety of reasons, including that it is often more difficult to accurately adjust the effective dose of the compound, and the attractiveness of developing it commercially is not. In addition, this mixture is metastable and difficult to formulate consistently. Form C is also known to be inconvenient because, for example, it is difficult to crystallize in pure form and is often found as a metastable mixture.

[0006] Clinical and non-clinical studies continue to show that Compound 1 is effective in treating and preventing certain androgen-mediated conditions. Therefore, there is a need to find a pharmaceutically acceptable crystalline form of Compound 1 that is not only chemically, thermodynamically and physically stable, but also reproducible.

Unexpectedly, it has been found that compound 1 is obtained in yet another crystalline form ("Form I"). Type I has been found to have many unexpected and beneficial properties. For example, Form I offers various stability and formulation advantages.

[0008] The present invention provides Form I of Compound 1. The present invention further provides Form I substantially free of other forms.

Another embodiment of the present invention is directed to inhibiting 5α-reductase and also to benign prostatic hyperplasia, male pattern baldness, acne acne, seborrhea, male pattern baldness, hirsutism and prostate cancer Provides a method of using type I to treat E. coli.

[0010] The present invention also provides a pharmaceutical formulation comprising a Type I compound as an active ingredient, together with one or more pharmaceutically acceptable excipients.

In addition, the present invention provides a method for crystallizing from ether-based or alkane-based solvents, or mixtures thereof, such as ethyl ether, diethyl ether, methyl t-butyl ether, heptane, hexane, or methyl t-butyl ether / heptane. To give trans-(-)-(4aR) -8-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one from I Provided is a method for producing Form I, comprising obtaining a form.

Unless otherwise indicated, “type” as used herein means “crystalline form”.

The term “substantially free of other forms” refers to Form I in which the other forms are mixed in less than about 20% by weight; preferably, the other forms are more than about 10% by weight. Less; more preferably less than 5% of other forms, and even more preferably, less than 2% of other crystalline forms. "Substantially free of other forms" is especially preferred that other forms are less than about 1%.

When formulating Compound I of Form I as a pharmaceutical preparation, “formulation substantially without other forms” refers to all of the other forms being less than about 20% by weight. Preferably,
The term refers to less than about 10% of all other types in the formulation. More preferably, the term refers to all less than about 5% of the other types in the formulation. The detection limit for the type that is undesirable in the formulation will vary depending on the type content and the amount of excipient used in the formulation.

The term “mammal” refers to a mammalian network of higher vertebrates. The term "mammal" includes, but is not limited to, humans.

The term “treatment” as used herein includes prophylaxis of the condition or amelioration or elimination of the condition once it has developed.

[0017] Various analytical techniques useful for identifying and characterizing different crystalline forms of a drug include:
Examples include X-ray powder diffraction, differential scanning calorimetry (DSC), solid state NMR, and infrared spectrum. The most widely used technique is powder X-ray diffraction. Each different crystalline form of the drug creates a powder diffraction pattern that can uniquely identify the crystalline form,
It is somewhat similar to how fingerprints uniquely identify an individual.

Powder X-ray diffraction data were collected using a Siemens D5000 X-ray diffractometer at 2θ of 4 to 35 ° and a step size of 0.03 °. 50 kilovolts (KV) and 40
Using a tube load of milliamperes (mA) to (tube load), and irradiated with copper (Cu) K _alpha radiation of wavelength lambda = 1.5046 Angstroms (Å) to the sample. Detection was determined using a Kevex solid state detector. The slit width was 1 mm for the divergence slit, 0.6 mm for the anti-scatter slit, and 0.1 mm for the detection slit.
The spacing between the columns represented by "d" is Angstroms. Typical relative intensities "I / I ₁ " were approximated to a full percent approximation. X-ray powder data as set forth herein may vary within an acceptable range depending on various factors such as, for example, the quality of the test material, the particular equipment used, the exact technique used, and the like. It will be understood by those skilled in the art.

A scanning calorimeter (DSC) was used to determine the melting range using a DSC 2910 from a TA instrument. Samples (2 to 5 mg) were added to a bent aluminum dish and heated from ambient temperature to 100 ° C. at a rate of 5 ° C./min under a nitrogen gas atmosphere. Also, the DSC data as set forth herein may vary within an acceptable range depending on various factors such as, for example, the quality of the test material, the particular equipment used, the exact technique used, etc. It will be understood by those skilled in the art.

The present invention has certain preferred embodiments. The invention aspects and features of the following situations listed below may be combined independently to form various preferred aspects of the invention. The embodiments of the invention listed below do not limit the scope of the invention in any way.

Some of the preferred features of the invention are as follows: Type I substantially without other types; benign prostatic hyperplasia, male pattern baldness, confluent acne, seborrhea Using type I to treat a condition selected from the group consisting of androgenetic alopecia, hirsutism and prostate cancer; formulating type I as a tablet; formulating type I as a capsule; Form I is formulated as a unit dose; Form I is formulated for injection; Form I is formulated for sustained release; Form I substantially without other forms is formulated as a tablet Form I substantially free of other forms is formulated for injection; Form I substantially free of other forms is formulated into a unit dosage form; substantially other forms Is formulated for fast dissolution. Type I formulations include Type I and any one or more of the following: sodium lauryl sulfate, microcrystalline cellulose, anhydrous lactose granules, colloidal silicon dioxide and / or magnesium stearate.

Type I samples are the subject of powder X-ray diffraction analysis. As a result of this analysis, the present invention
Form I is also provided using an iemens D5000 powder X-ray diffractometer and having the typical powder X-ray diffraction pattern shown below. [In the table, d is the surface spacing and I /
I ₁ indicates relative intensity]:

[Table 2]

FIG. 1 (FIG. 1) is an X-ray powder diffraction pattern overlay for Form I.
Some of the powder X-ray diffraction pattern peaks (at 2θ) are, for example, 10.31 ± 0.2, 10.7
Observed at 5 ± 0.2, 13.91 ± 0.2, 14.65 ± 0.2, 16.48 ± 0.2, 17.91 ± 0.2 and 22.5 ± 0.2. As a control, an X-ray powder diffraction pattern for the previously disclosed form of compound 1 is shown: Form A prepared by the procedure described in Example 64 of the '190 patent; prepared according to Example 68b of the' 190 patent. Type B; and J. Or. Chem., 61,
Form C produced according to the procedure described in 4450, 4454 (1996). CPS is a few / second.

Trans-(-)-(4aR, 10bR) -8-chloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (Compound 1) and its precursors can be prepared using procedures well known to those skilled in the art. For example, trans-(-)-(4aR, 10bR) -8-chloro-4-
A process for preparing methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one is disclosed in the '190 patent. Astleford, et al., J. Org.Chem., 61, 4450-4454 (19
96) (incorporated herein by reference).

For example, Form I can be obtained from Compound 1 by crystallizing from ethyl ether and hexane under specific conditions. Ethyl acetate and heptane; methyl t-
It is also possible to obtain Form I from Compound 1 by crystallization from butyl ether; methyl t-butyl ether and hexane; or ethyl acetate.

The following examples serve to illustrate the invention in more detail. The examples do not limit the scope of the invention in any way and should not be construed as such.

Example 1 Form I trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -Quinolin-3-one (viii) (2.0 grams), ethyl ether (20 ml) and hexane (20 ml) were heated to 40-42 ° C. until dissolved. The mixture was cooled to 5 ° C., stirred for about 90 minutes, then filtered and dried.

Compound 1 has useful 5α-reduction inhibitory activity. This activity has been demonstrated using established procedures, for example, as described in the '190 patent. It is clear that Form I Compound 1 provided in the present invention has similar receptor activity and the same therapeutic utility as Compound 1 described in the '190 patent. Thus, type I is useful for the treatment of benign prostatic hyperplasia, androgenetic baldness, crowding acne, seborrhea, androgenetic alopecia, hirsutism and prostate cancer, and metastatic prostate cancer.

The formulations of the present invention comprise from about 0.1% to about 95.0% by weight of Form I. Such formulations can be administered by a variety of routes including oral, rectal, topical, transdermal, buccal, subcutaneous, intravenous, intramuscular, and intranasal. Type I is effective as injection, oral and topical formulations. Type I may be formulated in a manner well known in the pharmaceutical art. For example, Remin
See gton's Pharmaceutical Sciences (16th edition 1980).

The preparation of the formulations for use in the present invention is typically prepared by mixing the active ingredient with excipients, diluting with excipients, or forming into capsules, sockets, paper or other containers. Enclose in a carrier. If an excipient is used as a diluent, it can act as a vehicle, carrier or vehicle for the active ingredient, to be a solid, semi-solid or liquid material. Thus the compound may contain tablets, pills, powders, troches, sockets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid solvents), for example up to 10% by weight of active compound It can be in the form of ointments, soft or hard gelatin capsules, suppositories, sterile injectable solutions and sterile powder packaging.

Some examples of preferred carriers, excipients and diluents include lactose, glucose,
Includes sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginic acid, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, alcohol, water, syrup and methylcellulose. Formulations may include: talc, magnesium stearate and natural oils as lubricants; wetting agents; emulsifying and suspending agents; methyl- and propylhydroxybenzoic acids as preservatives; sweeteners; it can. Using procedures known in the art, the active ingredients can be formulated for immediate release, maintenance, or sustained release after administration of the formulations of the present invention to a patient. For example, preferred immediate release formulations are described in U.S. Patent Nos. 5,079,018, 5,039,540, 4,305,502, 4,758,598 and 4,371,516, which are incorporated herein by reference.

Transdermal patches have been used to supply controlled amounts of Form I continuously or discontinuously. The construction and use of transdermal patches suitable for the delivery of pharmaceutically active substances is well known in the art. See, for example, US Pat. No. 5,023,252, issued Jun. 11, 1991, which is incorporated herein by reference. Such patches may be configured to deliver type I continuously, pulsatile or on demand.

For topical administration, the compounds of the invention may ideally be mixed with several excipients to give a sticky liquid or a cream-like product.

For oral administration, the compounds of the invention can ideally be mixed with carriers and diluents and can be shaped into tablets or enclosed in gelatin capsules.

Preferably, the active ingredient is formulated into unit dosages, each containing a dosage of about 0.05 to about 500 mg, generally about 1.0 to about 100 mg, more usually about 10 to about 50 mg. The term "unit dosage" refers to a unit of human patients and other mammals, each of which includes a predetermined quantity of active ingredient, together with suitable pharmaceutical excipients, calculated to produce the desired therapeutic effect. A physically discrete unit suitable for administration.

[0036] Type I is effective over a wide dosage range. For example, the daily dosage is
Generally, it will be administered in the range of about 0.01 to about 100 mg / kg (body weight), preferably in the range of about 0.01 to about 30 mg / kg, more preferably in the range of about 0.01 to about 10 mg / kg. For treatment of adult humans, a range of about 0.1 to about 5 mg / kg / day, in single or divided doses, is particularly preferred. However, the actual amount of compound to be administered will take into account relevant conditions, such as the condition to be treated, the choice of the route of administration, the actual compound to be administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms. It is not intended to limit the scope of the invention in any way, as determined by the physician and thus in the above dosage ranges. Dosage levels less than the lower limit of the above dosage range may be more appropriate. On the other hand, higher dosages can be administered without adverse side effects, but if such higher dosages are to be administered, one would need to first take each smaller dosage to administer throughout the day. Separate.

[0037] In order to describe the embodiment of the present invention in more detail, a pharmaceutical preparation example is shown below.
The production examples are for illustrative purposes only and do not limit the scope of the invention in any way. The formulations use Form I as the active ingredient.

Formulation Production Example 1 A hard gelatin capsule containing the following ingredients was formulated:

[Table 3] The above components were mixed, and 340 mg was filled into a hard gelatin capsule.

Formulation Production Example 2 A tablet was formulated using the following ingredients:

[Table 4] The compounds were mixed and 240 mg each were compressed into tablets.

Formulation Production Example 3 A dry powder inhalation formulation containing the following compounds was formulated:

[Table 5] The active mixture was mixed with lactose and the mixture was added to a dry powder inhaler.

Formulation Production Example 4 Tablets each containing 30 mg of the active ingredient were formulated as follows:

[Table 6] The active ingredient, starch and cellulose were passed through a # 20 mesh US sieve and mixed thoroughly. The resulting powder and the polyvinylpyrrolidone solution were mixed and then passed through a # 16 mesh US sieve. The granules thus produced were dried at 50-60 ° C and passed through a No. 16 mesh US sieve. Sodium carboxymethyl starch, magnesium stearate and talc, previously sieved through a # 30 mesh US sieve, were added to the granules, mixed, and compressed on a tablet machine to produce tablets weighing 120 mg each.

Formulation Production Example 5 Capsules each containing 40 mg of a drug were formulated as follows:

[Table 7] The active ingredient, cellulose, starch and magnesium stearate were mixed, passed through a No. 20 mesh US sieve, and 150 mg filled into hard gelatin capsules.

Pharmaceutical Preparation Example 6 Suppositories each containing 25 mg of active ingredient were formulated as follows:

[Table 8] The active ingredient was passed through a No. 60 mesh US sieve and suspended in saturated fatty acid glyceride that had previously been melted with minimal heat. Thereafter, the mixture was poured into a suppository mold having a nominal 2.0 g capacity and allowed to cool.

Formulation Production Example 7 Suspensions each containing 50 mg of drug per 5.0 ml of dosing were formulated as follows:

[Table 9] The drug, sucrose and xanthan gum were mixed, sifted through a # 10 mesh US sieve, and then mixed with the previously prepared microcrystalline cellulose solution and aqueous sodium carboxycellulose. The sodium benzoate, flavor and color were diluted with water and added to the mixture with stirring. Then enough water was added to produce the required amount.

Formulation Production Example 8 Capsules each containing 15 mg of a drug were formulated as follows:

[Table 10] The active ingredient, cellulose, starch and magnesium stearate were mixed, passed through a No. 20 mesh US sieve, and 425 mg filled into hard gelatin capsules.

Formulation Production Example 9 A topical formulation was formulated as follows:

[Table 11] The white soft paraffin was heated until it melted. The liquid paraffin and the emulsified wax were mixed and stirred until dissolved. The active ingredient was added and stirring continued until dispersed. Thereafter, the mixture was cooled until it became solid.

Formulation Production Example 10 Sublingual or buccal tablets each containing 10 mg of the active ingredient were formulated as follows:

[Table 12] Glycerol, water, sodium citrate, polyvinyl alcohol and polyvinyl pyrrolidone were mixed at about 90 ° C. with continuous stirring. Once the polymer had dissolved in the solution, the solution was cooled to about 50-55 ° C and the drug was slowly mixed. The homogeneous mixture was poured into a mold made of an inert metal to make a drug containing diffusing material with a thickness of about 2-4 mm. The diffuser was then cut into tablets of appropriate size.

Formulation Production Example 11 Tablets each containing 10 mg of active ingredient were formulated as follows:

[Table 13]

Formulation Production Example 12 Tablets each containing 50 mg of the active ingredient were formulated as follows:

[Table 14] Form I was formulated as a tablet using a direct compression method involving pre-mixing form I, sodium lauryl sulfate and a portion of the microcrystalline cellulose in a suitable container. Thereafter, a portion of the additional microcrystalline cellulose is mixed with the pre-mix, milled,
Pre-selection, sieving, or other equipment to assist in lump removal and powder dispersion. Additional microcrystalline cellulose, anhydrous lactose granules, colloidal dioxide and magnesium stearate were added and the tablets were compressed.

The type of formulation using type I administration is determined by the type of pharmacokinetic profile desired from the route of administration, and the condition of the patient.

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction pattern overlay for Form I. As a control, the powder X-ray crystal diffraction pattern for the previously disclosed form of compound 1 is shown.

[Explanation of Code] CPS is several / second.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/26 A61K 47/26 47/38 47/38 A61P 13/08 A61P 13/08 17/14 17 / 14 35/00 35/00 43/00 111 43/00 111 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K) E, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB , BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL , PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference) 4C034 CE03 4C076 AA01 AA22 AA37 AA49 AA53 BB01 BB11 CC17 CC18 CC27 DD29 DD34 DD38 DD41 DD43 DD46 DD57 DD67 EE06 EE13 EE31 EE33 EE38 EE51 GG01 GG14 GG41 4C086 AA01 AA02 AA03 MA02 MA28 MA03 MA03 MA05 MA28 ZA92 ZB26 ZC20

Claims (11)

[Claims] A compound of type I. 2. A crystalline form of trans-(-)-(4aR) -8-chloro-4-methyl characterized by having a powder X-ray diffraction pattern peak having a value of 2θ of 13.91 ± 0.2 °.
-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one. 3. A crystal form of trans-(-)-(4aR) -8-chloro-4-methyl-1, which has a powder spacing represented by d in the table and has the following powder X-ray diffraction pattern: 2,3,4,4a, 5,6,10
b-octahydrobenzo [f] quinolin-3-one. [Table 1] 4. The compound of claim 1, which is Form I substantially without other forms. 5. A pharmaceutical preparation comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically acceptable excipient. 6. The preparation according to claim 5, wherein the excipient is selected from lauryl sulfate, microcrystalline cellulose, anhydrous lactose granules, colloidal silicon dioxide and magnesium stearate. 7. A method for inhibiting 5α-reductase, comprising administering a compound according to claim 1 to a mammal in need of such treatment. 8. A method for treating benign prostatic hyperplasia, comprising administering a compound according to claim 1 to a mammal in need of such treatment. 9. A method of treating male pattern baldness, comprising administering a compound according to claim 1 to a mammal in need of such treatment. 10. A method for treating prostate cancer, comprising administering a compound according to claim 1 to a mammal in need of such treatment. 11. Trans-(-)-(4aR) -8- with ethyl ether and hexane
The method for producing a compound according to claim 1, comprising reacting chloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one. .