EP1149080A2 - Forme cristalline de derive de benzoquinolin-3-one en tant qu'inhibitrice de 5-alpha-reductase - Google Patents

Forme cristalline de derive de benzoquinolin-3-one en tant qu'inhibitrice de 5-alpha-reductase

Info

Publication number
EP1149080A2
EP1149080A2 EP99964980A EP99964980A EP1149080A2 EP 1149080 A2 EP1149080 A2 EP 1149080A2 EP 99964980 A EP99964980 A EP 99964980A EP 99964980 A EP99964980 A EP 99964980A EP 1149080 A2 EP1149080 A2 EP 1149080A2
Authority
EP
European Patent Office
Prior art keywords
compound
benzo
methyl
active ingredient
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99964980A
Other languages
German (de)
English (en)
Inventor
Leland Otto Weigel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1149080A2 publication Critical patent/EP1149080A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • 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.
  • 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, lOb-octahydro-benzo [f] quinolin-3-one ("Compound 1”) .
  • Compound 1 is described in Examples 64 and 68b of the '190 Patent and also at " . Org . Chem. , 61 , 4450 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 68b of the '190 Patent. It has also been found that still a different crystalline form (“Form C”) was disclosed at J. Org. Chem . , 61 , 4450, 4454 (1996).
  • 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.
  • Form B 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, etc.
  • 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.
  • Form I yet another crystalline form.
  • Form I has been found to have a number of unexpected and advantageous properties.
  • Form I provides various stability and manufacturing advantages.
  • the present invention provides Form I of
  • Compound 1 The invention further provides Form I substantially free of any other form or forms .
  • a method for using Form I for inhibiting the enzyme 5 -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 I as an active ingredient, associated with one or more pharmaceutically acceptable excipients.
  • the present invention provides processes for preparing Form I comprising obtaining Form I from trans- ( - ) - ( AaR) -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. ethyl ether, diethyl ether, methyl t-butyl ether, heptane, hexane or methyl t-butyl ether/heptane .
  • an ether or alkane solvent or a mixture thereof e.g. ethyl ether, diethyl ether, methyl t-butyl ether, heptane, hexane or methyl t-butyl ether/heptane .
  • Form or “form” refers to "crystalline form”.
  • substantially free 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 form. It is especially preferred that "substantially free of other forms” shall refer to less than about 1% of any other form.
  • 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.
  • mammal shall refer to the Mammalia class of higher vertebrates.
  • mammal includes, but is not limited to, a human.
  • treating includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
  • 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.
  • DSC differential scanning calorimetry
  • 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° 2 ⁇ with a
  • DSC Differential scanning calorimetry
  • 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 Form I and any one or more of the following: sodium lauryl sulfate, microcrystalline cellulose, lactose anhydrous granular, colloidal silicon dioxide and/or magnesium stearate.
  • Form I A sample of Form I has been subject to X-ray powder diffraction 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/Ii represents the relative intensities:
  • Figure 1 is an X-ray powder diffraction pattern overlay for Form I. Some of the peaks in the X-ray powder diffraction pattern (at values of 2 ⁇ ) are observed at, for example, 10.31 ⁇ 0.2, 10.75 ⁇ 0.2, 13.91 ⁇ 0.2,
  • 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
  • Form C prepared according to the procedure at J. Or. Chem. , 61, 4450, 4454 (1996).
  • CPS is counts/second.
  • Form I may be obtained, for example, from Compound 1 by crystallization under certain conditions from ethyl ether and hexane. It is also possible to obtain Form I from Compound 1 by crystallization from ethyl acetate and heptane; methyl t-butyl ether; methyl t-butyl ether and hexane; or ethyl acetate.
  • 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 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 .
  • 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.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • 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.
  • 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.
  • 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.
  • 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 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 I.
  • 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.
  • 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 g, usually about 1.0 to about 100 mg, more usually about 10 to about 50 mg, of the active ingredient.
  • 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 I may be effective over a wide dosage range.
  • 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.
  • the range of about 0.1 to about 5 mg/kg/day, in single or divided dose is especially preferred.
  • 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.
  • 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 .
  • 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.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • a tablet formula is prepared using the ingredients below:
  • 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:
  • 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)
  • 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.
  • Quantity Ingredient (mg/capsule)
  • 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.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • 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.
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 C.
  • 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.
  • Tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • Formulation Preparation 12 Tablets, each containing 50 mg of active ingredient, may be prepared as follows:
  • 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 phar acokinetic profile desired from the route of administration and the state of the patient.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des agents pharmaceutiques. Plus particulièrement, cette invention concerne une nouvelle forme cristalline d'un dérivé d'octahydro-benzo[f]quinoline-3-one, des formulations pharmaceutiques contenant cette forme cristalline en tant que principe actif ainsi que ses méthodes d'utilisation et processus de préparation.
EP99964980A 1998-12-07 1999-11-10 Forme cristalline de derive de benzoquinolin-3-one en tant qu'inhibitrice de 5-alpha-reductase Withdrawn EP1149080A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11124398P 1998-12-07 1998-12-07
US111243P 1998-12-07
PCT/US1999/026809 WO2000034245A2 (fr) 1998-12-07 1999-11-10 Agent pharmaceutique

Publications (1)

Publication Number Publication Date
EP1149080A2 true EP1149080A2 (fr) 2001-10-31

Family

ID=22337361

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99964980A Withdrawn EP1149080A2 (fr) 1998-12-07 1999-11-10 Forme cristalline de derive de benzoquinolin-3-one en tant qu'inhibitrice de 5-alpha-reductase

Country Status (5)

Country Link
EP (1) EP1149080A2 (fr)
JP (1) JP2002531550A (fr)
AU (1) AU3099600A (fr)
CA (1) CA2354022A1 (fr)
WO (1) WO2000034245A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5239075A (en) * 1991-08-21 1993-08-24 Eli Lilly And Company Process for the preparation of benzo (f) quinolinones
ES2169026T3 (es) * 1991-08-21 2002-07-01 Lilly Co Eli Benzo(f)quinolinonas como inhibidores de 5-alfa-reductasa.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0034245A2 *

Also Published As

Publication number Publication date
WO2000034245A3 (fr) 2001-01-18
JP2002531550A (ja) 2002-09-24
AU3099600A (en) 2000-06-26
WO2000034245A2 (fr) 2000-06-15
CA2354022A1 (fr) 2000-06-15

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