JP2002531551A - Crystal form of octahydrobenzo (F) quinolin-3-one derivative - 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 5a-reductase. It has been disclosed. 5a-Reductase mediates the conversion of testosterone to the more potent androgen 5a-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 benzo [f] quinolinone derivative is useful for treating a disease in which inhibition of 5a-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 II") 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 crystalline forms ("Form I" and "Form III"). A further different crystal form ("V form") 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 II is difficult to crystallize and is often observed as a mixture. Such mixtures are metastable and transform into other forms of the solid state. Different crystal forms ("I
Mixtures of "Types" and "Type III") for various reasons, such as exhibiting different solubilities for different types, and often making it more difficult to accurately adjust the effective dose of the compound. It is not attractive to formulate and commercially develop.In addition, this mixture is metastable and difficult to formulate consistently.Form V, for example, is difficult to crystallize and often Form V is also known to be inconvenient because it is recognized 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 IV"). Type IV has been found to have many unexpected and beneficial properties. For example, Form IV has the advantage of being chemically, thermodynamically and physically stable. Type IV is also easily reproducible and has various advantages, for example, in terms of formulation.

The present invention provides Form 1 of Compound 1. The present invention further provides Form IV substantially without other forms.

Another embodiment of the present invention is directed to inhibiting 5a-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 IV to treat E. coli.

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

[0011] In addition, the present invention provides trans- by crystallization from ether-based or alkane-based solvents, or mixtures thereof, such as diethyl ether, methyl t-butyl ether, heptane, or methyl t-butyl ether / heptane. (-)-(4aR) -8-
Provided is a method for producing Form IV, comprising obtaining Form IV from chloro-4-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one. Form IV was further crystallized using methyl t-butyl ether / heptane to give 6-chloro-1,2,3,4-tetrahydro-2R- (methylamino) -1R-naphthalenepropionic acid methyl ester: 2R, 3R-
It can also be prepared from bis [(4-methylbenzoyloxy) butannic acid.

As used herein, “form” means “crystalline form”.

The term “substantially free of other forms” refers to Form IV 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 1 of Form IV as a pharmaceutical formulation, “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 milliamps (mA), the sample was irradiated with copper (Cu) Ka radiation at _a wavelength l = 1.5046 Angstroms (Å). 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, denoted by d ", is Angstroms. The typical relative intensity" I / I ₁ "was approximated to a full percent approximation. The powder X-ray data as shown herein is Those skilled in the art will appreciate that various factors can vary within an acceptable range, eg, the quality of the test material, the particular equipment used, the exact technique used, etc.

A scanning calorimeter (DSC) was used to determine the melting range using a DSC 2910 from a TA instrument. The sample (2 to 5 mg) was 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 IV substantially without other types; benign prostatic hyperplasia, male pattern baldness, confluent acne, seborrhea Using type IV to treat a condition selected from the group consisting of androgenetic alopecia, hirsutism and prostate cancer; formulating type IV as a tablet; formulating type IV as a capsule; Form IV is formulated as a unit dose; Form IV is formulated for injection; Form IV is formulated for sustained release; Form IV substantially without other forms is formulated as a tablet Form IV substantially free of other forms is formulated for injection; Form IV substantially free of other forms is formulated into a unit dosage form; substantially other forms Is formulated for fast dissolution. Type IV formulations include Type IV and any one or more of the following: sodium lauryl sulfate, microcrystalline cellulose, anhydrous lactose granules, colloidal silicon dioxide and / or magnesium stearate.

Type IV samples are the subject of powder X-ray diffraction analysis. As a result of this analysis, 18.82 ± 0.2
The present invention also provides Form IV characterized by displaying a powder X-ray diffraction pattern with peaks at ° and 9.41 ± 0.2 °. Further, the present invention relates to Siemens D5000 powder X
Using a line diffractometer, provide Form IV characterized by a typical powder X-ray diffraction pattern as follows. [In the table, d is the axial distance and I / I ₁ the relative intensity]
:

[Table 2]

FIG. 1 (FIG. 1) is an X-ray powder diffraction pattern overlay for Form IV. As controls, the previously disclosed forms of Compound 1 are shown: Form II prepared by the procedure described in Example 64 of the '190 Patent; Form I and Form III prepared according to Example 68b of the' 190 Patent Mixture; and Form V prepared according to the procedure described in J. Org. Chem., 61, 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 IV converts compound 1 to diethyl ether (Example 1 below), methyl t-butyl ether (Example 2 below), heptane (Examples 3 and 4), or methyl t-butyl ether / heptane ( It can be obtained from the following Examples 5, 6, and 7) by crystallization under certain conditions. Form IV can also be neutralized and then crystallized from methyl t-butyl ether / heptane (Example 8 below) to give 6-chloro-1,
2,3,4-tetrahydro-2R- (methylamino) -1R-naphthalenepropionic acid methyl ester: 2R, 3R-bis [(4-methylbenzoyloxy] butanniic acid (vii) can be obtained.

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 IV trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -Quinolin-3-one (viii) (2.0 grams) and diethyl ether (16m
l) was heated to 34-36 ° C for 3-5 minutes. The mixture was cooled to ambient temperature and stirred for about 1 hour. After cooling to 5 ° C. and stirring for about 90 minutes, the product was filtered and dried.

Example 2 Type IV. Trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinolin-3-one (viii ) (2.0 grams) and methyl t-butyl ether (16 ml) were heated to 34 ° C. and the reaction was added to trans-(−)-(4aR, 10bR) -4-methyl-8-
Chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinolin-3-one (viii, IV
(Type) 0.0203 grams were added as nuclei. After cooling the mixture to ambient temperature,
Stirred for about 1 hour. After cooling to 5 ° C. and stirring for about 90 minutes, the product was filtered and dried.

Example 3 Type IV. Trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinolin-3-one (viii ) (2.0 g) and heptane (16 ml) at 94 ° C
Heated. The reaction was cooled to 76 ° C. and Form IV (0.006 grams) was added as a nucleus. The mixture was cooled to 34 ° C. and again trans-(−)-(4aR, 10bR) -4-methyl
-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinolin-3-one (viii,
(Type IV) (0.006 grams) was added as a nucleus. The reaction was cooled slowly to ambient temperature and stirred for about 1 hour. Cooled to 5 ° C., stirred for about 90 minutes, filtered and dried the product.

Example 4 Type IV. Trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinolin-3-one (viii ) (2.07 grams) and heptane (15 ml)
Heated to 51 ° C. The reaction was stirred for 30 minutes and cooled to ambient temperature. The reaction mixture was stirred for 1 hour and cooled to 5 ° C. Heptane chilled mixture
(25 ml) and dried in vacuo at 28 ° C.

Example 5 Type IV. Trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinolin-3-one (viii ) (3 grams) and methyl t-butyl ether
(12 ml) was heated to 45 ° C. in a flask. The reaction was stirred vigorously for 30 minutes. Heptane (12 ml) was added and the reaction was again stirred vigorously for 30 minutes. Trans-(-)-(4aR, 10
bR) -4-Methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -quinoline-
3-one (viii) (0.09 grams) was added as a nucleus. The slurry containing the nuclei was transferred to a reaction vessel and rinsed with heptane (5 ml). After cooling the reaction to ambient temperature,
Stirred for hours. After the reaction mixture was cooled to 5 ° C., it was stirred for about 90 minutes. The slurry was filtered and vacuum dried at 22 ° C.

Example 6 Trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] Form IV -Quinolin-3-one (viii) (58.65 grams) and methyl tert-butyl ether (245 ml) were heated in a flask to 52 ° C. The reaction was stirred vigorously for 30 minutes. Heptane (240 ml) was added and the reaction was again stirred vigorously. Type IV (1.2 grams) was added as a core. The slurry containing the nuclei was transferred to a reaction vessel and cooled to ambient temperature. Then the reaction was stirred for 1 hour. After the reaction mixture was cooled to 5 ° C., it was stirred for about 90 minutes. The slurry was filtered and vacuum dried at 28 ° C.

Example 7 Form IV trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] -Quinolin-3-one (viii) in methyl t-butyl ether (25-30 solvent L / k
g). The solution was treated with anhydrous magnesium sulfate (1.4 kg / kg product) for about 1 hour.
Dry for hours, filter, and wash with enough methyl t-butyl ether. A water content of less than 0.5% is preferred to prevent the formation of unwanted hydrates. The resulting solution was distilled at atmospheric pressure to 8-10 times the amount of existing product. Although not necessary, heptane (8-10 times the amount of the product) IV
Crystallization preferably starts with the nucleus of the type (2% of expected product) product. Desirably, the crystallization temperature is maintained at 40-50 ° C during the addition. The resulting slurry was cooled to 0-5 ° C by standard methods and stirred for at least 1 hour. Thereafter, the product was filtered, washed with cold heptane and dried in a vacuum oven or a filter / dryer at 45-50 ° C.

Example 8 Trans-(-)-(4aR, 10bR) -4-methyl-8-chloro-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] Form IV -Quinolin-3-one (viii, 15.0 kg, 60.2 mol) was dissolved in methanol (15 L), methane sulfonate (11.6 kg, 120.7 mol) was added, and the temperature was maintained at about 15-25 ° C.
The mixture was diluted with water (7.5 L) and heated to about 75-85 ° C. for approximately 24 hours. The transition of the reaction was analyzed by HPLC (3.9 × 150 mm water C-18; 50:50 acetonitrile: 0.5%
Water-soluble ammonium acetate; 1.0 mL / min; 220 nm). When compound viii was less than approximately 2%, the reaction mixture was cooled to about 50 ° C. and additional methanol (330 L) was added. Heating was continued to about 45-55 ° C and the reaction was monitored by HPLC until the amount of amino acids was less than 4%. The solution is cooled to about 10-30 ° C and R, R-(-)
-Ni-p-toluoyltartaric acid (24.1 kg, 59.6 mol) was added. The mixture was filtered to remove any trace lumps and the filter was rinsed with methanol (50 L).

The combined filtration and rinsing is cooled to approximately 5 ° C. and the temperature of the reaction mixture is lowered below 10 ° C. while slowly adding an aqueous slurry of sodium bicarbonate (10.1 kg, 120.2 mol in 50 L). Kept. The sodium bicarbonate slurry was washed with water (25L). Thereafter, the solution was slowly warmed at about 40-50 ° C. until all solids were dissolved. The clear solution was slowly cooled to about 20 ° C. and stirred for approximately 4 hours. The unwanted diastereomerate was filtered, washed with methanol (130 L) and dried. The methanol filtrate and the wash were washed under vacuum at about 30 ° C. and 6-chloro-1,2,3,4-tetrahydro-2R- (methylamino) -1R-naphthalenepropionic acid methyl ester: 2R, 3R-bis [(4-Methylbenzoyloxy) butanic acid (vii) was concentrated to about 2 mL / g.

Stir vigorously and slowly add methylene chloride (150 L) at approximately 20 ° C.
Stirring was continued for about 1 hour. The slurry was cooled to about 0 ° C. and stirred for an additional 4 hours. The desired compound (vii) was filtered, washed with methylene chloride (100 L) and dried. 6-Chloro-1,2,3,4-tetrahydro-2R- (methylamino) -1R-naphthalenepropionic acid methyl ester: 2R, 3R-bis [(4-methylbenzoyloxy] butanic acid (vii) (17.0 kg , 24.8 mol) slurry, water (120 L) and ammonium hydroxide
(9.3 kg of a 44% by weight solution) HPLC analysis of the mixture (3.9 x 150 mm water C-18; 50
: 50 acetonitrile: 0.5% water-soluble ammonium acetate; 0.5 mL / min; 220 nm)
Stirred at about 20 ° C. until (vii) was exhausted. Methyl t-butyl ether (13
0 L) was added and the mixture was stirred until all of the solid was dissolved. The poorly water-soluble ammonia phase was separated, a mixture of water (10 L) and ammonium hydroxide (910 kg of a 44% by weight solution) was added, and the two-phase system was stirred for about 1 hour.

The aqueous ammonia layer was separated and the methyl t-butyl ether phase was washed with water (65L).
Separate the aqueous layer and remove about 1 kg of anhydrous magnesium sulfate (8.9 kg) to remove water from the organic layer.
Slurry for hours. Then, magnesium sulfate was filtered and methyl t-butyl ether was added.
(40 L). Then, the compound IV is dried at about 55-60 ° C.
Distillation was carried out under normal pressure to equal 1.5 ml / gr volume. To the resulting concentrated solution was added a slurry of Form IV nucleated crystals (0.14 kg) in heptane (20 L), keeping the temperature at 50-55 ° C. The slurry was rinsed with heptane (10 L). Thereafter, the resulting slurry product was slowly cooled to about 5 ° C. and stirred for about 2 hours. Thereafter, the slurry was filtered and the solid was rinsed with heptane at 0-10 ° C (40 L) and dried. Form IV (90.5%) was obtained as a white solid.

Compound 1 has useful 5a-reduction inhibitory activity. This activity has been demonstrated using established procedures, for example, as described in the '190 patent. It is clear that the compound IV of the type IV provided in the present invention has the same receptor activity and the same therapeutic effect as the compound 1 described in the '190 patent. Therefore, type IV is benign prostatic hyperplasia,
Androgenetic baldness, tribal acne, seborrhea, androgenetic alopecia, hirsutism and prostate cancer,
And it is useful for the treatment of metastatic prostate cancer.

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

The formulations used in the present invention are usually prepared by mixing the active ingredients 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 provide controlled or continuous supply of a controlled amount of Form IV. 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 IV 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 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. Form IV was formulated as a tablet, most preferably using a direct compression method involving pre-mixing of a portion of sodium lauryl sulfate and microcrystalline cellulose in a suitable container. The premix was then mixed with additional microcrystalline cellulose fraction and subjected to milling, preselection, 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 appropriately.

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" is intended to include a predetermined amount of active ingredient, together with suitable pharmaceutical excipients, calculated to produce the desired therapeutic effect,
A physically separated unit suitable for unit administration to human patients and other mammals.

Type IV 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.

[0047] In order to describe the embodiment of the present invention in more detail, an example of preparation of a pharmaceutical preparation is shown below.
The production examples are for illustrative purposes only and do not limit the scope of the invention in any way. The formulation uses Form IV 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 the 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 the 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 the 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 the active ingredient were formulated as follows:

[Table 13]

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

[Table 14] Form IV was formulated as tablets using a direct compression method involving pre-mixing Form IV, 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 IV 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 IV. As a control, the previously disclosed version 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 // C07M 7:00 C07M 7:00 9:00 9:00 (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, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU) , TJ, TM), AE, AL, A M, 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, ZW (72) Inventor Bruce Edward Parker United States 46077 Sailors Street, Zions Ondville, Indiana 1595 (72) Inventor David Brian Shaw United States 46239 Indianapolis, Indiana East Prospect Street, 11835 (72) Inventor Paul James Syroys, Indianapolis, Indiana, 46236 Indianapolis, Bayridge Circle West 11103 (72) Inventor Ovidio Vargas, United States 46033 Carmel, Indiana, Foster・ Drive No. 4628 (72) Inventor Leland Otto Weigel Cherry Hill Court, Indianapolis, Indiana 46254 United States 4927 F term (reference) 4C034 CE03 4C076 AA01 AA16 AA36 AA53 AA93 BB01 BB02 BB22 BB29 CC29 DD24 DD29 DD37 DD41 DD67 EE31 FF04 4C086 AA01 AA03 AA04 BC28 GA15 MA01 MA05 NA03 NA10 ZA81 ZA92 ZB26 ZC20

Claims (12)

[Claims] A compound of type IV. 2. A crystalline form of trans-(-)-(4aR) -8 characterized by having X-ray powder diffraction pattern peaks having 2θ values of 18.82 ± 0.2 ° and 9.41 ± 0.2 °.
-Chloro-4-methyl-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 according to claim 1, which is Form IV 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 of inhibiting 5a-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. A solvent selected from diethyl ether, methyl t-butyl ether, heptane or a mixture of methyl t-butyl ether and heptane, and trans-(-)-(4aR) -8-chloro-4-methyl-1 , 2,3,4,4a, 5,6,10b-octahydrobenzo [f]
The method for producing a compound according to claim 1, comprising reacting with quinolin-3-one. 12. A mixture of methyl t-butyl ether and heptane with 6-chloro-1,2,3
The compound of claim 1, comprising reacting 2,4-tetrahydro-2R- (methylamino) -1R-naphthalenepropionic acid methyl ester with 2R, 3R-bis [(4-methylbenzoyloxy] butanedioic acid. Manufacturing method.