EP1135373A1

EP1135373A1 - Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative

Info

Publication number: EP1135373A1
Application number: EP99962727A
Authority: EP
Inventors: Kevin Lee Haehl; Bruce Edward Parker; David Bryan Shaw; Paul James Sirois; Ovidio Vargas; Leland Otto Weigel
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1998-12-07
Filing date: 1999-11-10
Publication date: 2001-09-26
Also published as: WO2000034246A1; AU1910900A; CA2354021A1; JP2002531551A

Abstract

The present invention relates to pharmaceutical agents. More particularly, this invention relates to a novel crystalline form of an octahydro-benzo[f]quinolin-3-one derivative, to pharmaceutical formulations containing this crystalline form as an active ingredient, and to methods of using and processes for preparing the same.

Description

CRYSTALLINE FORM OF AN OCTAHYDRO-BENZO(F)QUINOLIN-3-ONE DERIVATIVE

The present invention relates to a pharmaceutical agent. More particularly, this invention relates to a novel crystalline form of an octahydro-benzo [f] quinolin-3-one derivative, to pharmaceutical formulations containing this crystalline form as an active ingredient, and to methods of using and preparing the same.

U.S. Patent No. 5,541,190, incorporated by reference herein (hereinafter '190 Patent), discloses certain benzo [ f] quinolinone derivatives which are potent 5a- reductase inhibitors. The enzyme 5a-reductase mediates the conversion of testosterone to the more potent androgen 5a- dihydrotestosterone (DHT) . It is generally known that certain undesirable physiological conditions such as benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancer, are androgen mediated conditions dependent on DHT. Thus, the benzo [f] quinolinone derivatives are useful in the treatment of diseases in which inhibition of the enzyme 5a- reductase is desired.

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

It has been found that a specific crystalline form, ("Form II") was prepared by the procedures described in Example 64 of the '190 Patent. In addition, it has been found that a mixture of different crystalline forms ("Form I" and "Form III") was disclosed in Example 68b of the '190 Patent. It has also been found that still a different crystalline form ("Form V") was disclosed at J. Org. Chem . , 61 , 4450, 4454 (1996) .

The prior art forms have all been found to have a variety of pharmaceutical development disadvantages. For example, Form II is difficult to crystallize and is often observed in mixtures. These mixtures are metastable and convert to other forms in the solid state. The mixture of different crystalline forms ("Form I" and "Form III") is unattractive to formulate and commercially develop for various reasons, e.g., different dissolution rates for the different forms, the effective dose of the compound is often more difficult to properly control, etc. In addition, this mixture has exhibited metastability and has been difficult to manufacture consistently. Form V has also been found to have disadvantages, for example, Form V has been difficult to crystallize and is often observed in metastable mixtures.

Data from clinical and non-clinical studies continue to indicate that Compound 1 is effective in treating and preventing certain androgen mediated conditions. There has therefore been a need to find a pharmaceutically acceptable crystalline form of Compound 1, capable of reproducible manufacture as well as possessing chemical, thermodynamic and physical stability. Unexpectedly, it has been found that Compound 1 can be obtained in yet another crystalline form ("Form IV") . Form IV has been found to have a number of unexpected and advantageous properties. For example, Form IV provides chemical, thermodynamic and physical stability advantages. Form IV is also readily reproducible and provides various advantages, e.g. manufacturing advantages.

The present invention provides Form IV of Compound 1. The invention further provides Form IV substantially free of any other form or forms.

In another embodiment of the invention, there is provided a method for using Form IV for inhibiting the enzyme 5a-reductase, as well as for treating benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancer.

The present invention also provides a pharmaceutical formulation comprising Form IV as an active ingredient, associated with one or more pharmaceutically acceptable excipients .

In addition, the present invention provides processes for preparing Form IV comprising obtaining Form IV from trans- (-) - (4aJ) -8-chloro-4-methyl-l, 2 , 3, 4, 4a, 5, 6, 10b- octahydro-benzo [f] quinolin-3-one by crystallization from an ether or alkane solvent or a mixture thereof, e.g. diethyl ether, methyl t-butyl ether, heptane, or methyl t -butyl ether/heptane. Form IV can also be prepared from 6-chloro- 1,2,3, 4-tetrahydro-2i?- (methylamino) -li?-naphthalenepropanoic acid methyl ester : 2R, 3J?-bis [ (4-methylbenzoyloxy] butandioic acid by crystallization with methyl t-butyl ether/heptane.

As used herein, "Form" or "form" refers to "crystalline form".

The term "substantially free of any other form or forms" shall refer to Form IV, associated with less than about 20% by weight of any other form; and preferably it shall refer to less than about 10% of any other form; more preferably less than about 5% of any other form and even more preferably less than 2% of any other crystalline form. It is especially preferred that "substantially free of other forms" shall refer to less than about 1% of any other form. When Form IV of Compound 1 is formulated as a pharmaceutical formulation, "formulated substantially free of any other form or forms" shall refer to less than about 20% of any of the other forms. It is preferred that the term shall refer to less than about 10% of any of the other forms in the formulation. It is even more preferred that the term shall refer to less than about 5% of any of the other forms in the formulation. The detection limits for the undesired form in a formulation shall vary depending on the content of the form and the amount of excipient used in the formulation.

The term "mammal" shall refer to the Mammalia class of higher vertebrates. The term "mammal" includes, but is not limited to, a human.

The term "treating" as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.

There are various analytical techniques available for identifying and characterizing different crystalline forms of drug substances, e.g., X-ray powder diffraction, differential scanning calorimetry (DSC) , solid state NMR and infrared spectrum. The most widely used technique is X-ray powder diffraction. Each different crystalline form of a drug substance produces a powder diffraction pattern that uniquely identifies a crystalline form, somewhat analogous to the way a fingerprint uniquely identifies an individual.

X-ray powder diffraction data were collected using a Siemens D5000 X-ray diffractometer from 4 to 35° 2θ with a 0.03 degree step size. Samples were irradiated with copper (Cu) K_a of wavelength 1=1.5046 Angstroms (A) with a tube load of 50 Kilovolts (KV) and 40 milliamps (mA) . Detection was determined by use of a Kevex solid state detector. Slit sizes were 1 mm for the divergence slit, 0.6 mm for the antiscatter slit, and 0.1 mm for the detector slit. The interplanar spacings in the column marked "d" are in

Angstroms. The typical relative intensities "I/Ii" are rounded to the nearest whole percent. One skilled in the art will appreciate that X-ray powder data, such as the data presented herein, may vary within acceptable ranges depending on various factors, such as, the quality of the sample tested, specific equipment employed, the exact techniques used, etc.

Differential scanning calorimetry (DSC) was used to determine the melting ranges using a DSC 2910 by TA Instruments. The sample (2 to 5 mg) was added to a crimped aluminum pan and heated from ambient to 100 C at a rate of 5 C/min. in a nitrogen atmosphere. One skilled in the art will also appreciate that DSC data, such as the data presented herein, may vary within acceptable ranges depending on various factors, such as, the quality of the sample tested, specific equipment and techniques employed, etc.

Certain preferred aspects of this invention exist. The following conditions, invention embodiments and characteristics listed below may be independently combined to produce a variety of preferred aspects of this invention. The following list of embodiments of this invention is not intended to limit the scope of this invention in any way.

Some preferred characteristics of this invention include the following:

Form IV which is substantially free of any other form or forms ;

Form IV is used for treating a condition selected from the group consisting of benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancer; Form IV is formulated as a tablet; Form IV is formulated 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 free of any other form or forms is formulated as a tablet; Form IV, substantially free of any other form or forms is formulated for injection;

Form IV, substantially free of any other form or forms is formulated in a unit dosage form; Form IV, substantially free of any other form or forms is formulated for rapid dissolution;

The Form IV formulation comprises Form IV and any one or more of the following: sodium lauryl sulfate, microcrystalline cellulose, lactose anhydrous granular, colloidal silicon dioxide and/or magnesium stearate. A sample of Form IV has been subject to X-ray powder diffraction analysis. As a result of this analysis, the present invention also provides Form IV characterized by displaying an X-ray powder diffraction pattern having peaks at 18.82± 0.2° and 9.41± 0.2°. The present invention further provides Form IV characterized by having a typical x-ray powder diffraction pattern as follows, using a Siemens D5000 x-ray powder diffractometer wherein d represents the interplanar spacing and I/Ii represents the relative intensities :

d ι/iι

18 . 82 67

9 . 41 100

7 . 64 27 6.73 73

6.55 11

5.93 17

5.61 58

5.25 15

5.13 42

4.72 12

4.51 31

4.20 37

3.95 46

3.89 45

3.66 30

3.51 18

Figure 1 (Fig. 1) is an X-ray powder diffraction pattern overlay for Form IV. By way of comparison, the previously disclosed forms of Compound I are provided: Form II, prepared by the procedures described in Example 64 of the '190 Patent; the mixture of Form I and Form III, prepared according to Example 68b of the '190 Patent; and Form V, prepared according to the procedure at J. Org. Chem. , 61 , 4450, 4454 (1996). CPS is counts/second.

Trans- (-)- (4ai?,10b2?) -8-Chloro-4-methyl- 1,2, 3, 4, 4a, 5,6, lOb-octahydro-benzo [f] quinolin-3-one (Compound 1) and precursors thereof, are prepared using procedures known to those of ordinary skill in the art. For example, the '190 Patent discloses a process for preparing trans- (-) - (4ai?, lObl?) -8-chloro-4-methyl-l , 2 , 3 , 4, 4a, 5, 6, 10b- octahydro-benzo [f] quinolin-3-one. See also : Astleford, et al., J. Org. Chem. , 61 , 4450-4454 (1996), incorporated by reference herein. Form IV may be obtained, for example, from

Compound 1 by crystallization under certain conditions from diethyl ether (following EXAMPLE 1), methyl t-butyl ether (following EXAMPLE 2), heptane (EXAMPLES 3 AND 4), or methyl t-butyl ether/heptane (following EXAMPLES 5, 6, and 7). Form IV can also be obtained from 6-chloro-l , 2 , 3 , 4- tetrahydro-2i?- (methylamino) -li?-naphthalenepropanoic acid methyl ester : 2R, 3i?-bis [ (4-methylbenzoyloxy] butandioic acid (vii) by neutralization and subsequent crystallization from methyl t-butyl ether/heptane (following EXAMPLE 8) .

The following Examples further illustrate the present invention. The Examples are not intended to be limiting to the scope of the invention in any respect and should not be so construed.

EXAMPLE 1 Form IV. trans- (-) - (4ai?,10bJ?) -4-methyl-8-chloro-l , 2 , 3 , 4 , 4a, 5, 6,10b- octahydro-benzo [f] -quinolin-3-one (viii) (2.0 grams) and diethyl ether (16 ml) were heated to 34-36 C for 3-5 minutes. The mixture was allowed to cool to ambient temperature and was then stirred for about one hour. The product was then cooled to 5 C and stirred for about 90 minutes, and then was filtered and dried.

EXAMPLE 2 Form IV. trans- (-) - (4aJ?, lObJ?) -4-methyl-8-chloro-l, 2 , 3 , 4, 4a, 5, 6, 10b- octahydro-benzo [f] -quinolin-3-one (viii) (2.0 grams) and methyl t-butyl ether (16 ml) were heated to 34 °C and the reaction was seeded with 0.0203 grams of trans- (-)- (4aϋ, lObJ?) -4-methyl-8-chloro-l ,2,3,4, 4a, 5, 6, lOb-octahydro- benzo [f] -quinolin-3-one (viii, Form IV). The mixture was allowed to cool to ambient and then stirred for about one hour. The product was cooled to 5 °C and stirred for about 90 minutes, and then was filtered and dried. EXAMPLE 3 Form IV. trans- (-) - (4a.R,10b.R) -4-methyl-8-chloro-l , 2 , 3 , 4 , 4a, 5, 6,10b- octahydro-benzo [f] -quinolin-3-one (viii) (2.0 grams) and heptane (16 ml) were heated to 94 C. The reaction was allowed to cool to 76 C and was seeded with Form IV (0.006 grams) . The mixture was allowed to cool to 34 C and was again seeded with trans- (-) - (4aJ?,10bi?) -4-methyl-8-chloro-l, 2 , 3 , 4, 4a, 5, 6, 10b- octahydro-benzo [f] -quinolin-3-one (viii, Form IV) (0.006 grams) . The reaction was slowly cooled to ambient and then stirred for about one hour. The product was cooled to 5 C, stirred for about 90 minutes, filtered and dried.

EXAMPLE 4 Form IV. trans- (-) - (4aJ?,10bi?) -4-methyl-8-chloro-l, 2 , 3 , 4, 4a, 5, 6,10b- octahydro-benzo [f] -quinolin-3-one (viii) (2.07 grams) and heptane (15 ml) were heated to 45-51 °C . The reaction was stirred for 30 minutes and allowed to cool to ambient. The reaction mixture was stirred for 1 hour and allowed to cool to 5 C. The mixture was washed with cold heptane (25 ml) and dried in vacuum at 28 C.

EXAMPLE 5 Form IV. trans- { - ) - ( 4aR, lObR) -4-methyl-8-chloro-l, 2 , 3 , 4, 4a, 5, 6,10b- octahydro-benzo [ f] -quinolin-3-one (viii) (3 grams) and methyl t-butyl ether (12 ml) were heated in a flask to

45 C. The reaction was agitated for 30 minutes. Heptane (12ml) was added and the reaction was again agitated for 30 minutes . trans- (-) - ( 4aR, lObi?) -4-methyl-8-chloro- 1,2, 3, 4, 4a, 5, 6, lOb-octahydro-benzo [f] -quinolin-3-one (viii) (0.09 grams) was added as a seed. The seeded slurry was transferred to a reaction vessel and rinsed with heptane (5ml) . The reaction was allowed to cool to ambient and then stirred for 1 hour. The reaction mixture was cooled to 5 C and then stirred for around 90 minutes. The slurry was filtered and dried in vacuum at 22 °C.

EXAMPLE 6 Form IV. trans- (-) - (4ai=?, lObJ?) -4-methyl-8-chloro-l , 2 , 3 , 4 , 4a, 5 , 6, 10b- octahydro-benzo [f] -quinolin-3-one (viii) (58.65 grams) and methyl t-butyl ether (245 ml) were heated in a flask to 52 C. The reaction was agitated for 30 minutes. Heptane (240 ml) was added and the reaction was again agitated. Form IV (1.2 grams) was added as a seed. The seeded slurry was transferred to a reaction vessel and allowed to cool to ambient. The reaction was then stirred for 1 hour. The reaction mixture was cooled to 5 C and was then stirred for around 90 minutes. The slurry was filtered and dried in vacuum at 28 °C .

EXAMPLE 7 Form IV trans- (-) -(4ai?,10bfl) -4-methyl-8-chloro-l, 2 , 3 , 4, 4a, 5, 6,10b- octahydro-benzo [f] -quinolin-3-one (viii) is dissolved in methyl t-butyl ether (25-30 L solvent/kg) . The solution is dried with anhydrous magnesium sulfate (1.4 kg/kg product) for about 1 hour, filtered and washed with sufficient methyl t-butyl ether. A moisture content of less than 0.5% is desirable to prevent the formation of undesired hydrated forms. The resulting solution is atmospherically distilled to 8-10 volumes, relative to the amount of product present. Although not required, crystallization is preferably initiated by seeding the product with Form IV (2% relative to expected product yield) in heptane (8-10 volumes relative to product) . The crystallization temperature is preferably maintained between 40-50 C during the addition. The resulting slurry is cooled to 0-5 °C by standard methods and stirred for at least 1 hour. The product is then filtered and washed with cold heptane and dried in a vacuum oven or filter/dryer at 45-50 C.

EXAMPLE 8 Form IV. trans- (-) - (4ai=J, lObi?) -4-methyl-8-chloro-l , 2 , 3 , 4, 4a, 5, 6,10b- octahydro-benzo [f] -quinolin-3-one (viii, 15.0 kg, 60.2 mol) was dissolved in methanol (15 L) and methane sulfonic acid

(11.6 kg, 120.7 mol) was added, keeping the temperature 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 course of the reaction was monitored by HPLC (3.9 x 150 mm Waters C-18; 50:50 Acetonitrile : 0.5% aqueous ammonium acetate; 1.0 mL/min; 220 run) . When compound viii decreased to less than approximately 2%, the reaction mixture was cooled to about 50 °C and additional methanol (330 L) was added. Heating was continued at about 45-55 C and the reaction monitored by HPLC until the amount of the amino acid was less than 4%. The solution was cooled to about 10- 30 °C and J?,JR- (-) -Di-p-toluoyl tartaric acid (24.1 kg,

59.6 mol) was added. The mixture was filtered to remove any trace amount of solids and the filter rinsed with methanol (50 L) . The combined filtrate and rinse were cooled to approximately 5 C and an aqueous slurry of sodium bicarbonate (10.1 kg, 120.2 mol in 50 L) was slowly added while keeping the temperature of the reaction mixture at less than 10 C. The sodium bicarbonate slurry was washed in with water (25 L) . The solution was then slowly warmed to 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 undesired diastereomeric salt was filtered, washed with methanol (130 L) and dried. The methanol filtrate and wash were concentrated under vacuum at about 30 C to about 2 mL/g of 6-chloro-l, 2 , 3 , 4- tetrah.ydro-2.R- (methylamino) -li?-naphthalenepropanoic acid methyl ester : 2R, 3J?-bis [ (4-methylbenzoyloxy] butandioic acid (vii) . With good agitation, methylene chloride (150 L) was slowly added at approximately 20 C and stirring 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. A slurry of 6-chloro-l, 2 , 3 , 4-tetrahydro- 2R- (methylamino) -lJJ-naphthalenepropanoic acid methyl ester : 2R, 3.R-bis [ (4-methylbenzoyloxy] butandioic acid (vii) (17.0 kg, 24.8 mol), water (120 L) and ammonium hydroxide (9.3 kg of 44 weight % solution) was stirred at about 20 C until HPLC analysis (3.9 x 150 mm Waters C-18; 50:50 acetonitrile : 0.5% aqueous ammonium acetate; 0.5 mL/min; 220 nm) of the mixture showed that compound (vii) had been consumed. Methyl t-butyl ether (130 L) was added and the mixture stirred until all of the solids dissolved. The lower aqueous ammonia phase was separated, and a mixture of water (10 L) and ammonium hydroxide (910 kg of a 44 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 washed with water (65 L) . The aqueous layer was separated and the organic phase was slurried with anhydrous magnesium sulfate (8.9 kg) for about 1 hour to remove water. The magnesium sulfate was then filtered and washed with methyl t-butyl ether (40 L) . The dried organic solution was then atmospherically distilled at about 55-60 °C to achieve a volume equivalent to approximately 1.5 ml/gr compound VI. To the resulting concentrated solution was slowly added a slurry of Form IV seed crystals (0.14 kg) in heptane (20 L) , while maintaining a temperature of 50-55 °C . The slurry was rinsed with heptane (10 L) . The resulting product slurry was then slowly cooled to about 5 °C and stirred for about 2 hours . The slurry was then filtered and the solid rinsed with 0-10 °C heptane (40 L) and dried. Form IV (90.5%) was obtained as a white solid.

Compound 1 has useful 5a-reductase inhibitory activity. This activity has been demonstrated using well-established procedures, for example, as described in the '190 Patent. Compound 1, Form IV, provided by the present invention appears to have the same profile of receptor activity and the same therapeutic uses as Compound 1 described in the '190 patent. Therefore, Form IV is useful for the treatment of benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancer, and the metastasis of prostatic cancer.

The formulations of the present invention contain from about 0.1% by weight to about 95.0% by weight of Form IV. These formulations can be administered by a variety of routes including oral, rectal, topical, transdermal, buccally, subcutaneous, intravenous, intramuscular, and intranasal. Form IV is effective as an injectable, oral and topical formulation. Form IV may be formulated in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, (16th ed. 1980) .

In making the formulations employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient . Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, alcohol, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The formulations of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. For example, one such preferred quick release formulation is described in U.S. Patent Nos . 5,079,018, 5,039,540, 4,305,502, 4,758,598, and 4,371,516, hereby incorporated by reference.

Transdermal patches may be used to provide continuous or discontinuous infusion of Form IV in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is known in the art. See, e.g. , U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of Form IV.

For topical administration, the compound of this invention ideally can be admixed with any variety of excipients in order to form a viscous liquid or cream-like preparation.

For oral administration, the compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules. Most preferably, Form IV is formulated as a tablet by a direct compression method comprising premixing Form IV, sodium lauryl sulfate and a portion of macrocrystalline cellulose in a suitable container. The premix is then combined with an additional portion of microcrystalline cellulose and passed through a co-mill, screen, sieve, or other piece of equipment which will remove agglomerates and assist in powder dispersion. Additional microcrystalline cellulose, lactose anhydrous granular, colloidal dioxide and magnesium stearate are added and the tablet is appropriately compressed.

The formulations are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 500 mg, usually about 1.0 to about 100 mg, more usually about 10 to about 50 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

Form IV may be effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 100 mg/kg of body weight, preferably within the range of about 0.01 to about 30 mg/kg, more preferably within the range of about 0.01 to about 10 mg/kg. In the treatment of adult humans, the range of about 0.1 to about 5 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day . In order to more fully illustrate the operation of the present invention, the following formulation examples are provided. The examples are illustrative only, and are not intended to limit the scope of the invention in any manner. The formulations employ Form IV as the active ingredient.

Formulation Preparation 1 Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule)

Active Ingredient 100.0

Starch 235.0

Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. Formulation Preparation 2

A tablet formula is prepared using the ingredients below:

Quantity

Ingredient (mg/tablet )

Active Ingredient 100.0

Cellulose, microcrystalline 125.0

Colloidal silicon dioxide 10.0

Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing 240 mg .

Formulation Preparation 3 A dry powder inhaler formulation is prepared containing the following components:

Ingredient Weight %

Active Ingredient 5

Lactose 95

The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

Formulation Preparation 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows :

Quantity Ingredient (mg/tablet)

Active Ingredient 30.0 mg Starch 45.0 mg

Microcrystalline cellulose 35.0 mg

Polyvinylpyrrolidone

(as 10% solution in water) 4.0 mg

Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg

Talc 1.0 mg

Total ^• 120 mg

The active ingredient, starch and cellulose are passed through a No . 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60 C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No . 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.

Formulation Preparation 5 Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule)

Active Ingredient 40.0 mg

Starch 109.0 mg

Magnesium stearate 1.0 mg

Total 150.0 mg

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities .

Formulation Preparation 6 Suppositories, each containing 25 mg of active ingredient are made as follows:

Ingredient Amount Active Ingredient 25 mg

Saturated fatty acid glycerides to 2,000 mg

The active ingredient (s ) is passed through a No . 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Preparation 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:

Ingredient Amount Active Ingredient 50.0 mg

Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%)

Microcrystalline cellulose (89%) 50.0 mg

Sucrose 1.75 g Sodium benzoate 10.0 mg

Flavor and Color q.v.

Purified water to 5.0 ml

The medicament, sucrose and xanthan gum are blended, passed through a No . 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

Formulation Preparation 8 Capsules, each containing 15 mg of medicament, are made as follows : Quantity

Ingredient (mg/capsule)

Active Ingredient 15.0 mg

Starch 407.0 mg Magnesium stearate 3.0 mg

Total 425.0 mg

The active ingredient (s) , cellulose, starch, and magnesium stearate are blended, passed through a No . 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities .

Formulation Preparation 9 A topical formulation may be prepared as follows: Ingredient Quantity

Active Ingredient 1-10 g

Emulsifying Wax 30 g

Liquid Paraffin 20 g

White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.

Formulation Preparation 10

Sublingual or buccal tablets, each containing

10 mg of active ingredient, may be prepared as follows: Quantity

Ingredient Per Tablet

Active Ingredient 10.0 mg

Glycerol 210.5 mg

Water 143.0 mg Sodium Citrate 4.5 mg

Polyvinyl Alcohol 26.5 mg

Polyvinylpyrrolidone 15.5 mg

Total 410.0 mg

The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 °C. When the polymers have gone into solution, the solution is cooled to about 50-55 °C and the medicament is slowly admixed. The homogeneous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.

Formulation Preparation 11 Tablets, each containing 10 mg of active ingredient, may be prepared as follows : Quantity

Ingredient Per Tablet

Active Ingredient 10.0 mg

Microcrystalline Cellulose 111.36 mg

Lactose Anhydrous Granular 74.24 mg Sodium Lauryl Sulfate 1.60 mg

Colloidal Silicon Dioxide 1.60 mg

Magnesium Stearate 1.20 mg

Total 200.0 mg

Formulation Preparation 12

Tablets, each containing 50 mg of active ingredient, may be prepared as follows :

Quantity Ingredient Per Tablet Active Ingredient 50.0 mg

Microcrystalline Cellulose 263.40 mg

Lactose Anhydrous Granular 175.60 mg

Sodium Lauryl Sulfate 4.00 mg Colloidal Silicon Dioxide 4.00 mg

Magnesium Stearate 3.00 mg

Total 500.0 mg

Form IV is formulated as a tablet by a direct compression method comprising premixing Form IV, sodium lauryl sulfate and a portion of microcrystalline cellulose in a suitable container. The premix is then combined with an additional portion of microcrystalline cellulose and passed through a co-mill, screen, sieve, or other piece of equipment which will remove agglomerates and assist in powder dispersion. Additional microcrystalline cellulose, lactose anhydrous granular, colloidal silicon dioxide and magnesium stearate are added and the tablet is compressed. The type of formulation employed for the administration of Form IV may be dictated by the type of pharmacokinetic profile desired from the route of administration and the state of the patient.

Claims

We claim :

1. Form IV of Compound 1.

2. A crystalline form of trans- ( - ) - (4ai?) -8- chloro-4-methyl-l,2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo [f] quinolin-3-one characterized by peaks in the X-ray powder diffraction pattern at values of 2Θ of 18.82± 0.2° and 9.41+ 0.2°.

3. A crystalline form of trans- ( -) - (4ai?) -8- chloro-4-methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydro- benzo [f] quinolin-3-one having an X-ray powder diffraction pattern as follows, wherein d represents the interplanar spacing:

d

18.82

9.41

7.64

6.73 6.55

5.93

5.61

5.25

5.13 4.72

4.51

4.20

3.95

3.89 3.66

3.51.

4. The compound of Claim 1, wherein the Form IV is substantially free of any other form or forms.

5. A pharmaceutical formulation comprising a therapeutically effective amount of a compound as described in Claim 1 in combination with a pharmaceutically acceptable excipient .

6. The formulation of Claim 5 wherein the excipients are selected from lauryl sulfate, microcrystalline cellulose, lactose anhydrous granular, colloidal silicon dioxide and magnesium stearate.

7. A method of inhibiting the enzyme 5a- reductase comprising administering to a mammal in need of such treatment the compound of claim 1.

8. A method of treating benign prostatic hyperplasia comprising administering to a mammal in need of such treatment the compound of claim 1.

9. A method of treating male pattern baldness comprising administering to a mammal in need of such treatment the compound of claim 1.

10. A method of treating prostatic cancer comprising administering to a mammal in need of such treatment the compound of claim 1.

11. A process of preparing the compound of Claim 1 comprising reacting trans- (-)- (4aJ?) -8-chloro-4- methyl-1, 2,3,4, 4a, 5,6, lOb-octahydro-benzo [f] quinolin-3-one with a solvent selected from diethyl ether, methyl t-butyl ether, heptane, or a combination of methyl t-butyl ether and heptane .

12. A process of preparing the compound of Claim 1 comprising reacting 6-chloro-l, 2 , 3 , 4-tetrah.ydro-2.R-

(methylamino) -lJ?-naphthalenepropanoic acid methyl ester : 2R, 3.R-bis [ (4-methylbenzoyloxy] butandioic acid with methyl t-butyl ether and heptane.