CA2354022A1 - Crystalline form of benzoquinoline-3-one derivatve as inhibitor of 5-alpha reductase - Google Patents
Crystalline form of benzoquinoline-3-one derivatve as inhibitor of 5-alpha reductase Download PDFInfo
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- CA2354022A1 CA2354022A1 CA002354022A CA2354022A CA2354022A1 CA 2354022 A1 CA2354022 A1 CA 2354022A1 CA 002354022 A CA002354022 A CA 002354022A CA 2354022 A CA2354022 A CA 2354022A CA 2354022 A1 CA2354022 A1 CA 2354022A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
WO 00/34245 PCT/US99/2b809 PIiARMACEUTICAL AGENT
The present invention relates to a pharmaceutical agent. More particularly, this invention relates to a novel crystalline form of an octahydro-ben:?o[f]quinolin-3-one derivative, to pharmaceutical formul<~tions 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 5oc--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 condit~.ons 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 trani~ (-)-(4aR)-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., 6Z, 4450 (1996 WO 00!34245 PCT/US99126809 It has been found that a specific crystalline form, ("Form A") 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 (represented as "Form B") was disclosed in Example 6$b of the '190 Patent. It has also been found that still a different crystalline form ("Form C") was disclosed at J.Org.Chem., 6.2; 4450, 4454 (1996) .
The prior art forms have all been found to have a variety of pharmaceutical development disadvantages. For example, Form A is difficult to crystallize and is often observed in mixtures of other forms. These mixtures are metastable and convert to other forms in the solid state.
The mixture of different crystalline forms ("Form B") 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, E~tc. In addition, this mixture has exhibited metastability and has been difficult to manufacture consistently. Form C has also been found to have disadvantages, for example, Form C has been difficult to crystallize in pure form 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 I").
Form I has been found to have a number of unexpected and advantageous properties. For example, Form I provides various stability and manufacturing advantages.
The present invention provides Form T of Compound 1. The invention further provides Form I
substantially free of any other form or forms.
In another embodiment of the invention, there is provided a method for using Form I for inhibiting the enzyme 5a-reductase, as well as for treating benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutisrn and prostatic cancer.
The present invention also provides a pharmaceutical formulation comprising Form I as an active ingredient, associated with one or more pharmaceutically acceptable excipients.
In addition, the present invention provides processes for preparing Form I comprising obtaining Form I
from traps-(-)-(4aR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one by crystallization from an ether or alkane solvent or a mixture thereof, e.g. ethyl ether, diethyl ether, methyl f-butyl ether, heptane, hexane or methyl t-butyl ether/heptane.
As used herein, unless otherwise stated, "Form" or "form" refers to "crystalline form".
The term "substantially frere of any other form or forms" shall refer to Form I, 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 forma It is especially preferred that "substantially free of other forms" shall refer to less than about 1% of any other form.
When Form I 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 team "mammal" includes, but is not limited to, a human.
The term "treating" as used herein includes prophylaxis of the named condition oo amelioration or elimination of the condition once it has been established.
There are various analytical techniques available for identifying and characterizing d_Lfferent 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 dif#:raction 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° 28 with a 0.03 degree step size. Samples were irradiated with copper (Cu) Kph radiation of wavelength 71,=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 _5_ 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 "T/I1" 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 calo:rimetry (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 ~_ndependently 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 I which is substantially free of: any other form or forms;
Form I 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;
The present invention relates to a pharmaceutical agent. More particularly, this invention relates to a novel crystalline form of an octahydro-ben:?o[f]quinolin-3-one derivative, to pharmaceutical formul<~tions 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 5oc--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 condit~.ons 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 trani~ (-)-(4aR)-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., 6Z, 4450 (1996 WO 00!34245 PCT/US99126809 It has been found that a specific crystalline form, ("Form A") 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 (represented as "Form B") was disclosed in Example 6$b of the '190 Patent. It has also been found that still a different crystalline form ("Form C") was disclosed at J.Org.Chem., 6.2; 4450, 4454 (1996) .
The prior art forms have all been found to have a variety of pharmaceutical development disadvantages. For example, Form A is difficult to crystallize and is often observed in mixtures of other forms. These mixtures are metastable and convert to other forms in the solid state.
The mixture of different crystalline forms ("Form B") 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, E~tc. In addition, this mixture has exhibited metastability and has been difficult to manufacture consistently. Form C has also been found to have disadvantages, for example, Form C has been difficult to crystallize in pure form 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 I").
Form I has been found to have a number of unexpected and advantageous properties. For example, Form I provides various stability and manufacturing advantages.
The present invention provides Form T of Compound 1. The invention further provides Form I
substantially free of any other form or forms.
In another embodiment of the invention, there is provided a method for using Form I for inhibiting the enzyme 5a-reductase, as well as for treating benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutisrn and prostatic cancer.
The present invention also provides a pharmaceutical formulation comprising Form I as an active ingredient, associated with one or more pharmaceutically acceptable excipients.
In addition, the present invention provides processes for preparing Form I comprising obtaining Form I
from traps-(-)-(4aR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one by crystallization from an ether or alkane solvent or a mixture thereof, e.g. ethyl ether, diethyl ether, methyl f-butyl ether, heptane, hexane or methyl t-butyl ether/heptane.
As used herein, unless otherwise stated, "Form" or "form" refers to "crystalline form".
The term "substantially frere of any other form or forms" shall refer to Form I, 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 forma It is especially preferred that "substantially free of other forms" shall refer to less than about 1% of any other form.
When Form I 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 team "mammal" includes, but is not limited to, a human.
The term "treating" as used herein includes prophylaxis of the named condition oo amelioration or elimination of the condition once it has been established.
There are various analytical techniques available for identifying and characterizing d_Lfferent 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 dif#:raction 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° 28 with a 0.03 degree step size. Samples were irradiated with copper (Cu) Kph radiation of wavelength 71,=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 _5_ 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 "T/I1" 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 calo:rimetry (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 ~_ndependently 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 I which is substantially free of: any other form or forms;
Form I 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 I is formulated as a tablet;
Form I is formulated 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 free of any other form or forms is formulated as a tablet;
Form I, substantially free of any other form or forms is formulated for injection;
Form I, substantially free of any other form or forms is formulated in a unit dosage form;
Form I, substantially free of any other form or forms is formulated for rapid dissolution;
The Form I formulation comprises Forrn I and any one or more 25 of the following: sodium lauryl sulfate, microcrystalline cellulose, lactose anhydrous granular, colloidal silicon dioxide and/or magnesium stearate.
A sample of Form I has been subject to X-ray powder diffraction analysi s. As.a result of this analysis, the present invention also provides Form I 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/I1 represents the relative intensities:
d I/Il 16.81 g 8.57 27 8.22 11 5.36 100 6.04 28 5.37 35 5.15 33 4.74 26 _7_ 4.27 g 3.95 37 3.79 10 3.73 31 3.66 26 3.50 14 3.21 1p 3.03 7 2.98 9 Figure 1 (Fig. 1) is an X--.ray powder diffraction pattern overlay for Form I. Some of the peaks in the X-ray powder diffraction pattern (at value:> of 28) are observed at, for example, 10.31 ~ 0.2, 10.75 -~_ 0.2, 13.91 ~ 0.2, 14.65 ~ 0.2, 16.48 ~ 0.2, 17.91 ~ 0.2 and 22.5 ~ 0.2. By way of comparison, the x-ray powder diffraction patterns for the previously disclosed forms of Compound I are provided:
Form A, prepared by the procedures described in Example 64 of the '190 Patent; Form B, prepared according to Example 68b of the '190 Patent; and Form C, ~>repared according to the procedure at J. Or. Chem., 6Z, 49:50, 4454 (1996). CPS is counts/second.
Traps-(-)-(4aR,10bR)-8-Chloro-4-methyl-1,2,3,4,4a,S,6,10b-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 traps-(-)-(4aR,10bR)-8-chloro-4-methyl-1,2,3,4,4a,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.
_g_ Form I may be obtained, fo:r example, from Compound 1 by crystallization under certain conditions from ethyl ether and hexane. It is also possib:Le to obtain Form I from Compound 1 by crystallization from ei~hyl acetate and heptane; methyl ~-butyl ether; methy:L t-butyl ether and hexane; or ethyl acetate.
The following Example further illustrates the present invention. The Example is not intended to be limiting to the scope of the invention in any respect and should not be so construed.
Form I.
trans-(-)-(4aR,10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydro-benzo[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 then cooled to 5 °C and stirred for about 90 minutes, and then was filtered and dried.
Compound 1 has useful 5oc-reductase inhibitory activity.
This activity has been demonstrated using well-established procedures, for example, as described in the '190 Patent.
Compound 1, Form I, provided by the ~rresent 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 I 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 I.
These formulations can be administered by a variety of routes including oral, rectal, topical, transdermal, buccally, subcutaneous, intravenous, intramuscular, and intranasal. Form I is effective as an injectable, oral and topical formulation. Form I 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 o~: 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 c;an 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 ac°tive 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 empi~oying 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 I in controlled amounts.
The construction and use of transder~mal 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 T.
For topical administration, the compound of this invention ideally can be admixed witJh 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.
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 physica:Lly 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 I 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 bod~r 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, they 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 I 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 225.0 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 Lactose g5 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/tablety 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.
WO 00/34245 PCT/US99I2b809 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 ingredients) 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 paurf:d into a suppository mold of nominal 2.0 g capacity and a~.lowed 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 (110) 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.
WO 00!34245 PCT/US99/2b809 Formulation Preparation 10 Sublingual or buccal tablets, each containing mg of active ingredient, may be prepared as follows:
Quantity 5 Ingredient Per Tablet Active Ingredient 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg 10 Polyvinyl AICOhoI 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 i~he 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 mixi~ure 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.&0 mg Colloidal Silicon Dioxide ~ 1.60 mg WO 00/34245 PCTIUS99/2b809 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.OO mg Colloidal Silicon Dioxide 4.00 mg Magnesium Stearate 3.00 mg Total 500.0 mg Form I is formulated as a tablet by a direct compression method comprising premixing Form I, 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 I may be dictated by the type of pharmacokinetic profile desired from 'the route of administration and the state of the patient.
Form I is formulated 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 free of any other form or forms is formulated as a tablet;
Form I, substantially free of any other form or forms is formulated for injection;
Form I, substantially free of any other form or forms is formulated in a unit dosage form;
Form I, substantially free of any other form or forms is formulated for rapid dissolution;
The Form I formulation comprises Forrn I and any one or more 25 of the following: sodium lauryl sulfate, microcrystalline cellulose, lactose anhydrous granular, colloidal silicon dioxide and/or magnesium stearate.
A sample of Form I has been subject to X-ray powder diffraction analysi s. As.a result of this analysis, the present invention also provides Form I 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/I1 represents the relative intensities:
d I/Il 16.81 g 8.57 27 8.22 11 5.36 100 6.04 28 5.37 35 5.15 33 4.74 26 _7_ 4.27 g 3.95 37 3.79 10 3.73 31 3.66 26 3.50 14 3.21 1p 3.03 7 2.98 9 Figure 1 (Fig. 1) is an X--.ray powder diffraction pattern overlay for Form I. Some of the peaks in the X-ray powder diffraction pattern (at value:> of 28) are observed at, for example, 10.31 ~ 0.2, 10.75 -~_ 0.2, 13.91 ~ 0.2, 14.65 ~ 0.2, 16.48 ~ 0.2, 17.91 ~ 0.2 and 22.5 ~ 0.2. By way of comparison, the x-ray powder diffraction patterns for the previously disclosed forms of Compound I are provided:
Form A, prepared by the procedures described in Example 64 of the '190 Patent; Form B, prepared according to Example 68b of the '190 Patent; and Form C, ~>repared according to the procedure at J. Or. Chem., 6Z, 49:50, 4454 (1996). CPS is counts/second.
Traps-(-)-(4aR,10bR)-8-Chloro-4-methyl-1,2,3,4,4a,S,6,10b-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 traps-(-)-(4aR,10bR)-8-chloro-4-methyl-1,2,3,4,4a,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.
_g_ Form I may be obtained, fo:r example, from Compound 1 by crystallization under certain conditions from ethyl ether and hexane. It is also possib:Le to obtain Form I from Compound 1 by crystallization from ei~hyl acetate and heptane; methyl ~-butyl ether; methy:L t-butyl ether and hexane; or ethyl acetate.
The following Example further illustrates the present invention. The Example is not intended to be limiting to the scope of the invention in any respect and should not be so construed.
Form I.
trans-(-)-(4aR,10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydro-benzo[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 then cooled to 5 °C and stirred for about 90 minutes, and then was filtered and dried.
Compound 1 has useful 5oc-reductase inhibitory activity.
This activity has been demonstrated using well-established procedures, for example, as described in the '190 Patent.
Compound 1, Form I, provided by the ~rresent 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 I 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 I.
These formulations can be administered by a variety of routes including oral, rectal, topical, transdermal, buccally, subcutaneous, intravenous, intramuscular, and intranasal. Form I is effective as an injectable, oral and topical formulation. Form I 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 o~: 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 c;an 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 ac°tive 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 empi~oying 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 I in controlled amounts.
The construction and use of transder~mal 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 T.
For topical administration, the compound of this invention ideally can be admixed witJh 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.
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 physica:Lly 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 I 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 bod~r 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, they 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 I 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 225.0 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 Lactose g5 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/tablety 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.
WO 00/34245 PCT/US99I2b809 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 ingredients) 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 paurf:d into a suppository mold of nominal 2.0 g capacity and a~.lowed 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 (110) 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.
WO 00!34245 PCT/US99/2b809 Formulation Preparation 10 Sublingual or buccal tablets, each containing mg of active ingredient, may be prepared as follows:
Quantity 5 Ingredient Per Tablet Active Ingredient 10.0 mg Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg 10 Polyvinyl AICOhoI 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 i~he 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 mixi~ure 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.&0 mg Colloidal Silicon Dioxide ~ 1.60 mg WO 00/34245 PCTIUS99/2b809 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.OO mg Colloidal Silicon Dioxide 4.00 mg Magnesium Stearate 3.00 mg Total 500.0 mg Form I is formulated as a tablet by a direct compression method comprising premixing Form I, 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 I 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 I of Compound 1.
2. A crystalline form of trans-(-)-(4aR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one characterized by having a peak in the X-ray powder diffraction pattern at values of 2.theta. of 13.91~ 0.2°.
3. A crystalline form of trans-(-)-(4aR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one having an X-ray powder diffraction pattern as follows, wherein d represents the interplanar spacing:
d 16.81 8.57 8.22 6.36 6.04 5.37 5.15 4.74 4.27 3.95 3.79 3.73 3.66 3.50 3.21 3.03 2.98 4. The compound of Claim 1, wherein the Form I
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 5.alpha.-reductase comprising administering to a mammal in need of such treatment the compound of claim 2.
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.
21. A process of preparing the compound of Claim 1 comprising reacting trans-(-)-(4aR)-8-chloro-4-methyl-2,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one with ethyl ether and hexane.
1. Form I of Compound 1.
2. A crystalline form of trans-(-)-(4aR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one characterized by having a peak in the X-ray powder diffraction pattern at values of 2.theta. of 13.91~ 0.2°.
3. A crystalline form of trans-(-)-(4aR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one having an X-ray powder diffraction pattern as follows, wherein d represents the interplanar spacing:
d 16.81 8.57 8.22 6.36 6.04 5.37 5.15 4.74 4.27 3.95 3.79 3.73 3.66 3.50 3.21 3.03 2.98 4. The compound of Claim 1, wherein the Form I
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 5.alpha.-reductase comprising administering to a mammal in need of such treatment the compound of claim 2.
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.
21. A process of preparing the compound of Claim 1 comprising reacting trans-(-)-(4aR)-8-chloro-4-methyl-2,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one with ethyl ether and hexane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11124398P | 1998-12-07 | 1998-12-07 | |
| US60/111,243 | 1998-12-07 | ||
| PCT/US1999/026809 WO2000034245A2 (en) | 1998-12-07 | 1999-11-10 | Crystalline form of benzoquinoline-3-one derivatve as inhibitor of 5-alpha reductase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2354022A1 true CA2354022A1 (en) | 2000-06-15 |
Family
ID=22337361
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002354022A Abandoned CA2354022A1 (en) | 1998-12-07 | 1999-11-10 | Crystalline form of benzoquinoline-3-one derivatve as inhibitor of 5-alpha reductase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1149080A2 (en) |
| JP (1) | JP2002531550A (en) |
| AU (1) | AU3099600A (en) |
| CA (1) | CA2354022A1 (en) |
| WO (1) | WO2000034245A2 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0591583B1 (en) * | 1991-08-21 | 2001-12-19 | Eli Lilly And Company | Benzo (f) quinolinones as 5-alpha-reductase inhibitors |
| US5239075A (en) * | 1991-08-21 | 1993-08-24 | Eli Lilly And Company | Process for the preparation of benzo (f) quinolinones |
-
1999
- 1999-11-10 WO PCT/US1999/026809 patent/WO2000034245A2/en not_active Application Discontinuation
- 1999-11-10 JP JP2000586693A patent/JP2002531550A/en not_active Withdrawn
- 1999-11-10 CA CA002354022A patent/CA2354022A1/en not_active Abandoned
- 1999-11-10 AU AU30996/00A patent/AU3099600A/en not_active Abandoned
- 1999-11-10 EP EP99964980A patent/EP1149080A2/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002531550A (en) | 2002-09-24 |
| WO2000034245A3 (en) | 2001-01-18 |
| AU3099600A (en) | 2000-06-26 |
| EP1149080A2 (en) | 2001-10-31 |
| WO2000034245A2 (en) | 2000-06-15 |
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