WO2000034246A1 - Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative - Google Patents
Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative Download PDFInfo
- Publication number
- WO2000034246A1 WO2000034246A1 PCT/US1999/026488 US9926488W WO0034246A1 WO 2000034246 A1 WO2000034246 A1 WO 2000034246A1 US 9926488 W US9926488 W US 9926488W WO 0034246 A1 WO0034246 A1 WO 0034246A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- methyl
- benzo
- octahydro
- quinolin
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
-
- 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.
- U.S. Patent No. 5,541,190, incorporated by reference herein 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) .
- DHT dihydrotestosterone
- 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.
- 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) .
- 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.
- 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.
- 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.
- 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 .
- 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.
- 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.
- Form or “form” refers to "crystalline form”.
- 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.
- 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.
- 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.
- DSC Differential scanning calorimetry
- 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.
- 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 :
- Figure 1 is an X-ray powder diffraction pattern overlay for Form IV.
- 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
- 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.
- 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
- 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) .
- 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.
- 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.
- Methyl t-butyl ether 130 L was added and the mixture stirred until all of the solids dissolved.
- 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) .
- 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 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.
- 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.
- 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.
- 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.
- 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 IV as the active ingredient.
- 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, 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 .
- 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.
- 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.
- 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: Ingredient Quantity
- 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.
- Sublingual or buccal tablets each containing
- 10 mg of active ingredient may be prepared as follows: Quantity
- 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.
- Formulation Preparation 11 Tablets each containing 10 mg of active ingredient, may be prepared as follows : Quantity
- Tablets each containing 50 mg of active ingredient, may be prepared as follows :
- 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.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000586694A JP2002531551A (en) | 1998-12-07 | 1999-11-10 | Crystal form of octahydrobenzo (F) quinolin-3-one derivative |
AU19109/00A AU1910900A (en) | 1998-12-07 | 1999-11-10 | Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative |
EP99962727A EP1135373A1 (en) | 1998-12-07 | 1999-11-10 | Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative |
CA002354021A CA2354021A1 (en) | 1998-12-07 | 1999-11-10 | Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11055898P | 1998-12-07 | 1998-12-07 | |
US60/110,558 | 1998-12-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000034246A1 true WO2000034246A1 (en) | 2000-06-15 |
Family
ID=22333674
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/026488 WO2000034246A1 (en) | 1998-12-07 | 1999-11-10 | Crystalline form of an octahydro-benzo(f)quinolin-3-one derivative |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1135373A1 (en) |
JP (1) | JP2002531551A (en) |
AU (1) | AU1910900A (en) |
CA (1) | CA2354021A1 (en) |
WO (1) | WO2000034246A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0532190A2 (en) * | 1991-08-21 | 1993-03-17 | Eli Lilly And Company | Benzo f quinolinones as 5-alpha-reductase inhibitors |
EP0591583A1 (en) * | 1991-08-21 | 1994-04-13 | Eli Lilly And Company | Benzo (f) quinolinones as 5-alpha-reductase inhibitors |
-
1999
- 1999-11-10 EP EP99962727A patent/EP1135373A1/en not_active Withdrawn
- 1999-11-10 AU AU19109/00A patent/AU1910900A/en not_active Abandoned
- 1999-11-10 JP JP2000586694A patent/JP2002531551A/en not_active Withdrawn
- 1999-11-10 WO PCT/US1999/026488 patent/WO2000034246A1/en not_active Application Discontinuation
- 1999-11-10 CA CA002354021A patent/CA2354021A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0532190A2 (en) * | 1991-08-21 | 1993-03-17 | Eli Lilly And Company | Benzo f quinolinones as 5-alpha-reductase inhibitors |
EP0591583A1 (en) * | 1991-08-21 | 1994-04-13 | Eli Lilly And Company | Benzo (f) quinolinones as 5-alpha-reductase inhibitors |
US5541190A (en) * | 1991-08-21 | 1996-07-30 | Eli Lilly And Company | Benzo(F)quinolinones |
Non-Patent Citations (3)
Title |
---|
B.A. ASTLEFORD ET AL.: "Resolution of delta-lactams provides access to nonracemic benzoquinolinones: the synthesis of LY300502 and LY300503", JOURNAL OF ORGANIC CHEMISTRY., vol. 61, no. 13, 28 June 1996 (1996-06-28), EASTON US, pages 4450 - 4454, XP002136311 * |
BIOORG. MED. CHEM. LETT., vol. 4, no. 11, 1994, pages 1365 - 1368 * |
CHEMICAL ABSTRACTS, vol. 121, no. 11, 12 September 1994, Columbus, Ohio, US; abstract no. 133926, A.D. ABELL ET AL.: "Preparative chiral HPLC separation of all possible stereoisomers of LY191704 and LY26611 and their in vitro inhibition of human types 1 and 2 steroid 5alpha-reductases" XP002136312 * |
Also Published As
Publication number | Publication date |
---|---|
JP2002531551A (en) | 2002-09-24 |
CA2354021A1 (en) | 2000-06-15 |
EP1135373A1 (en) | 2001-09-26 |
AU1910900A (en) | 2000-06-26 |
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