WO1999061441A1 - Polymorphs of crystalline (7s,9as)-7-[ 3-cyanophenoxy] methyl-2-(5- fluoropyrimidin-2- yl)-2,3,4,6,7,8,9a -octahydro-1h-pyrido[1,2-a] pyrazine- monohydrochloride and their pharmaceutical compositions - Google Patents
Polymorphs of crystalline (7s,9as)-7-[ 3-cyanophenoxy] methyl-2-(5- fluoropyrimidin-2- yl)-2,3,4,6,7,8,9a -octahydro-1h-pyrido[1,2-a] pyrazine- monohydrochloride and their pharmaceutical compositions Download PDFInfo
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- WO1999061441A1 WO1999061441A1 PCT/IB1999/000826 IB9900826W WO9961441A1 WO 1999061441 A1 WO1999061441 A1 WO 1999061441A1 IB 9900826 W IB9900826 W IB 9900826W WO 9961441 A1 WO9961441 A1 WO 9961441A1
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- monohydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention is directed to certain polymorphs of crystalline (7S,9aS)-7-[3-
- 2-a] pyrazine-monohydrochloride (hereafter the monohydrochloride) and their pharmaceutical compositions.
- the invention is also directed to methods of treating psychotic disorders and anxiety and depression in a mammal including humans. Treating is defined here as preventing and treating.
- U.S. Serial No. 08/315,470 filed on September 30, 1994 and 0 published as WO 96/10571 on April 11, 1996, which is incorporated by reference, discloses the amorphous monohydrochloride of the formula:
- the amorphous monohydrochloride is very hygroscopic and can pick up enough water to effect a conversion to a hydrate.
- the amorphous form of this monohydrochloride is 5 non-crystalline, demonstrates no lattice and does not have a distinct X-ray pattern.
- the amorphous monohydrochloride only demonstrates what is referred to as the amorphous hump and has no distinct d spacing.
- the present invention relates to two polymorphs of crystalline (7S,9aS)-7-[3- 0 cyanophenoxy]methyl-2-(5-fluoropyrimidin-2-yl)-2,3A6 ,8,9a-octahydro-1-H pyrido[1 ,2-a] pyrazine-monohydrochloride.
- the monohydrochloride is in crystalline Form A which is a stable nonhygroscopic polymorph.
- Form A's crystalline habits are either short rods or equant prisms.
- the rod shaped crystals of Form A are about 20 ⁇ to 35 ⁇ in size.
- Thermal conversion to Form A from amorphous forms of the monohydrochloride occurs between about 60° to 80°C, preferably about 68-69°C.
- Form A is characterized by the x-ray detraction pattern below.
- the monohydrochloride is in crystalline Form B wh ch is an anhydrous polymorph of microcrystalline or acicular aggregates.
- Form B is characterized by the x-ray diffraction pattern below.
- Form B melts and recrystallizes to form A between about 140° C and 160° C.
- the hydrate of the monochloride converts to Form B when dried at about 45°C.
- Another aspect of the invention relates to a pharmaceutical composition having antipsychotic activity which comprises at least one of the polymorphic Forms A or B of the monohydrochloride in an amount effective in the treatment of psychotic diseases and a pharmaceutically acceptable carrier.
- a method of treating psychotic diseases comprises administering to a subject in need of treatment an antipsychotic effective amount of either the A or B Form of the monohydrochloride, preferably Form A.
- Another aspect of the invention relates to a pharmaceutical composition having antidepressive activity which comprises at least one of the polymorphic forms A or B of the monohydochloride in an amount effective in the treatment of anxiety and depressive diseases and a pharmaceutically acceptable carrier.
- a method for treating depressive diseases comprises administering to a subject in need of treatment an antidepressive effective amount of either the A or B Form of the monohydrochloride, preferably Form A.
- a method of making crystalline polymorphic Form A comprises slurrying or refluxing amorphous forms of the monohydrochloride in about five to fifteen parts isopropyl alcohol and acetone. Refluxing the amorphous form in isopropyl ether in a five to one ratio also produces Form A.
- the refluxing is carried out between about 68 to 69°C in isopropyl ether. While crystalline rods are isolated from both acetone and isopropyl ether, only isopropyl ether produces the small size which may be advantageous.
- the slurrying is carried out under ambient conditions for about 1.5 to 72 hours or at reflux for two hours followed by a one hour ambient granulation in isopropyl alcohol or acetone. Large crystals of Form A with a rod like habit are grown from acetone solution by slow evaporation.
- a method of making crystalline polymorphic Form B comprises crystallizing the monohydrochloride in tetrahydrofuran/hexane, tetrahydrofuran or ethyl acetate and harvesting microcrystalline aggregates or acicular aggregates.
- Form A is a stable crystalline, nonhygroscopic polymorph which can exist in two distinct crystalline habits: short rods and equant prisms.
- Short rods are obtained by crystallization from either acetone or isopropyl ether.
- Equant prisms (octahedral when fully developed) are obtained by crystallization from isopropyl alcohol.
- Both crystalline habits of Form A have identical thermal behavior and the same X- ray diffraction patterns given herein above.
- the rod shaped crystals isolated from isopropyl ether are about 20 ⁇ to 35 ⁇ , obviating the need for milling. Exposing Form A to about 87% relative humidity reveals it to be nonhygroscopic, giving no detectable water.
- Form A from the monohydrochloride salt was accomplished by slurrying in either acetone or isopropyl alcohol under ambient conditions for about 1.5 to 72 hours. The product was collected by filtration. Refluxing of the monohydrochloride salt for two hours and ambient granulation for one hour gives the same results. The yield from isopropyl alcohol was about 86% and from acetone about 74% at a dilution of 15/1. Large crystals of Form A with a rod like habit were grown from the acetone solution by slow evaporation.
- Form B is an anhydrous polymorph. On isolation, Form B's distinct crystalline forms are microcrystalline aggregates or acicular aggregates. Form B can be isolated from tetrahydrofuran/hexane, tetrahydrofuran or ethyiacetate. Form B is not a hydrate but gains about 4 to 5% water when exposed to about 85 to 90% relative humidity. This appears to be a surface phenomenon since the crystalline lattice is not affected. Form B melts and recrystallizes to Form A between about 140° to 160° C.
- Dissolving Form A in methanol returned a methanolate which readily dried to a fairly stable pseudomorph. Bridging the pseudomorph in isopropyl alcohol yielded Form A. Bridging is a common term used in Chemical Microscopy and Crystallography for solution phase transformations, an experimental method often used to determine the lowest energy (most stable) crystalline form. Usually the crystalline forms are charged together in a variety of previously saturated solvents (saturated with the compound which provided the crystalline forms). After being slurred for a suitable period of time, the crystals are collected and examined to determine which crystalline form has prevailed. That crystalline form will be the lowest energy form under the experimental conditions.
- the amphorous form prepared from the monohydrochloride converts to Form A between about 60° and 80°C.
- heating the amphorous form in isopropyl ether to reflux at about 68°C to 69°C is sufficient to effect conversion.
- the thermal conversion does not work on either the hydrate or Form B as they both have conversion temperatures of about 150° C.
- Solubility is required to convert Form B to Form A.
- any solvent in which Form B has sufficient solubility will allow Form B to change to Form A. Slurrying any of the forms or a mixture of forms in water yields a barely crystalline unstable hydrate that loses its water under drying conditions, e.g., at 45°C in vacuo, and results in Form B.
- the A and B Forms of the monohydrochloride possess valuable and nonobvious properties. Since the Form A of the monohydrochloride is hygroscopically stable, formulation problems due to weight changes of the active ingredient during tabletting or capsulation operations are alleviated. Form B has similar advantages at below about 85% relative humidity.
- the effective dosage for the pharmaceutical composition of the monohydrochloride depends on the intended route of administration, the indicator, the indication to be treated, and other factors such as age and weight of the subject, in the following dosage ranges, the terms "mg A" refers to milligrams of the monohydrochloride.
- a recommended range for oral dosing is 5-300 mg A/day, preferably 40-200 mg A/day, more preferably 40-80 mg A/day, in single or divided doses.
- a recommended range for oral administration in oral forms such as pills or tablets is 2.5 mg A/day to 160 mg A/day and preferably 5-80 mgA/day.
- the stability of Form A, relative to all other forms is demonstrated by its lack of hygroscopic ' ity and lower energy bridging and thermal conversions.
- Form B's greater stability over the hydrate is demonstrated by the conversion of the hydrate to Form B under routine drying conditions.
- Example II Preparation of the Crystalline Monohydrochloride Form A A 20.23 gram portion of the free base of the monohydrochloride was suspended in 150 milliliters of isopropyl ether under ambient conditions. To the resulting thin white slurry, 4.02 grams of anhydrous hydrogen chloride was added while keeping the temperature below 50°C. This slurry was then used for the conversion to Form A by heating to reflux at about 68° to 69°C. The resulting particle size averaged between about 20 to 35 ⁇ . An x-ray configuration was obtained confirming that the compound is Form A of the monohydrochloride.
- Example II Preparation of the Crystalline Monohydrochloride Form A A A 20.23 gram portion of the free base of the monohydrochloride was suspended in 150 milliliters of isopropyl ether under ambient conditions. To the resulting thin white slurry, 4.02 grams of anhydrous hydrogen chloride was added while keeping the temperature below 50°C. This slurry was then used for the conversion to Form A by heating
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Abstract
Two crystalline polymorphic forms (7S,9aS)-7-[ 3-cyanophenoxy] methyl-2-( 5-fluoropyrimidin-2- yl)-2,3,4,6,7,8,9a -octahydro-1H-pyrido [1,2-a]pyrazine- monochloride (the monohydrochloride) are Form A and Form B. The pharmaceutical composition containing at least one of these polymorphs has advantageous stability for formulation to treat anxiety, depression and psychotic diseases such as affective psychosis, schizophrenia, and schizo-affective disorders. The administration of this pharmaceutical composition is oral by preferably by tablet or capsule. A method of making A and B Forms is also disclosed.
Description
POLYMORPHS OF CRYSTALLINE (7S,9AS)-7-(3-CYANOPHENOXY) METHYL-2-
(5-FLUOROPYRIMIDIN-2-YL)-2,3,4,6,7,8,9A -OCTAHYDRO-lH-PYRIDO(l,2-A)
PYRAZINE- MONOHYDROCHLORIDE AND THEIR PHARMACEUTICAL
COMPOSITIONS
Background of the Invention
This invention is directed to certain polymorphs of crystalline (7S,9aS)-7-[3-
5 cyanophenoxy]methyl-2-(5-fluoropyrimidin-2-yl)-2, 3, 4, 6, 7, 8, 9a-octahydro-1-H pyrido [1,
2-a] pyrazine-monohydrochloride (hereafter the monohydrochloride) and their pharmaceutical compositions. The invention is also directed to methods of treating psychotic disorders and anxiety and depression in a mammal including humans. Treating is defined here as preventing and treating. U.S. Serial No. 08/315,470, filed on September 30, 1994 and 0 published as WO 96/10571 on April 11, 1996, which is incorporated by reference, discloses the amorphous monohydrochloride of the formula:
The amorphous monohydrochloride is very hygroscopic and can pick up enough water to effect a conversion to a hydrate. The amorphous form of this monohydrochloride is 5 non-crystalline, demonstrates no lattice and does not have a distinct X-ray pattern. The amorphous monohydrochloride only demonstrates what is referred to as the amorphous hump and has no distinct d spacing.
Summary of the Invention The present invention relates to two polymorphs of crystalline (7S,9aS)-7-[3- 0 cyanophenoxy]methyl-2-(5-fluoropyrimidin-2-yl)-2,3A6 ,8,9a-octahydro-1-H pyrido[1 ,2-a] pyrazine-monohydrochloride. In one embodiment of the invention, the monohydrochloride is in crystalline Form A which is a stable nonhygroscopic polymorph. Form A's crystalline habits are either short rods or equant prisms. The rod shaped crystals of Form A are about 20 μ to 35 μ in size. Thermal conversion to Form A from amorphous forms of the
monohydrochloride occurs between about 60° to 80°C, preferably about 68-69°C. Form A is characterized by the x-ray detraction pattern below.
Form A
In another embodiment, the monohydrochloride is in crystalline Form B wh ch is an anhydrous polymorph of microcrystalline or acicular aggregates. Form B is characterized by the x-ray diffraction pattern below. Form B melts and recrystallizes to form A between about 140° C and 160° C. In another embodiment, the hydrate of the monochloride converts to Form B when dried at about 45°C.
Form B
A method of making crystalline polymorphic Form A comprises slurrying or refluxing amorphous forms of the monohydrochloride in about five to fifteen parts isopropyl alcohol and acetone. Refluxing the amorphous form in isopropyl ether in a five to one ratio also produces Form A. The refluxing is carried out between about 68 to 69°C in isopropyl ether. While crystalline rods are isolated from both acetone and isopropyl ether, only isopropyl ether produces the small size which may be advantageous. The slurrying is carried out under ambient conditions for about 1.5 to 72 hours or at reflux for two hours followed by a
one hour ambient granulation in isopropyl alcohol or acetone. Large crystals of Form A with a rod like habit are grown from acetone solution by slow evaporation.
A method of making crystalline polymorphic Form B comprises crystallizing the monohydrochloride in tetrahydrofuran/hexane, tetrahydrofuran or ethyl acetate and harvesting microcrystalline aggregates or acicular aggregates.
Detailed Description of the Invention Four distinct forms of the monohydrochloride exist. The four forms are Form A, Form B, the methanolate and the hydrate. Form A is a stable crystalline, nonhygroscopic polymorph which can exist in two distinct crystalline habits: short rods and equant prisms. Short rods are obtained by crystallization from either acetone or isopropyl ether. Equant prisms (octahedral when fully developed) are obtained by crystallization from isopropyl alcohol. Both crystalline habits of Form A have identical thermal behavior and the same X- ray diffraction patterns given herein above. The rod shaped crystals isolated from isopropyl ether are about 20μ to 35μ, obviating the need for milling. Exposing Form A to about 87% relative humidity reveals it to be nonhygroscopic, giving no detectable water.
Preparation of Form A from the monohydrochloride salt was accomplished by slurrying in either acetone or isopropyl alcohol under ambient conditions for about 1.5 to 72 hours. The product was collected by filtration. Refluxing of the monohydrochloride salt for two hours and ambient granulation for one hour gives the same results. The yield from isopropyl alcohol was about 86% and from acetone about 74% at a dilution of 15/1. Large crystals of Form A with a rod like habit were grown from the acetone solution by slow evaporation.
Form B is an anhydrous polymorph. On isolation, Form B's distinct crystalline forms are microcrystalline aggregates or acicular aggregates. Form B can be isolated from tetrahydrofuran/hexane, tetrahydrofuran or ethyiacetate. Form B is not a hydrate but gains about 4 to 5% water when exposed to about 85 to 90% relative humidity. This appears to be a surface phenomenon since the crystalline lattice is not affected. Form B melts and recrystallizes to Form A between about 140° to 160° C.
Dissolving Form A in methanol returned a methanolate which readily dried to a fairly stable pseudomorph. Bridging the pseudomorph in isopropyl alcohol yielded Form A. Bridging is a common term used in Chemical Microscopy and Crystallography for solution phase transformations, an experimental method often used to determine the lowest energy (most stable) crystalline form. Usually the crystalline forms are charged together in a variety of previously saturated solvents (saturated with the compound which provided the crystalline forms). After being slurred for a suitable period of time, the crystals are collected and
examined to determine which crystalline form has prevailed. That crystalline form will be the lowest energy form under the experimental conditions.
Bridging of Form A with Form B yielded Form A from isopropyl alcohol and acetone and returned the original mixture of forms from the following solvents; tetrahydrofuran ethyl acetate, cyclohexane, hexanes, acetonitrite and methyl ethyl ketone.
By stirring any of the less stable forms, for example, the B Form, hydrate or amorphous in isoprophyl alcohol at a dilution of about 5/1 to 15/1 parts solvent/solid, under ambient conditions, a conversion to Form A will result.
The amphorous form prepared from the monohydrochloride converts to Form A between about 60° and 80°C. Preferably, heating the amphorous form in isopropyl ether to reflux at about 68°C to 69°C is sufficient to effect conversion. The thermal conversion does not work on either the hydrate or Form B as they both have conversion temperatures of about 150° C. Solubility is required to convert Form B to Form A. For solubility, any solvent in which Form B has sufficient solubility will allow Form B to change to Form A. Slurrying any of the forms or a mixture of forms in water yields a barely crystalline unstable hydrate that loses its water under drying conditions, e.g., at 45°C in vacuo, and results in Form B.
The A and B Forms of the monohydrochloride possess valuable and nonobvious properties. Since the Form A of the monohydrochloride is hygroscopically stable, formulation problems due to weight changes of the active ingredient during tabletting or capsulation operations are alleviated. Form B has similar advantages at below about 85% relative humidity.
The effective dosage for the pharmaceutical composition of the monohydrochloride depends on the intended route of administration, the indicator, the indication to be treated, and other factors such as age and weight of the subject, in the following dosage ranges, the terms "mg A" refers to milligrams of the monohydrochloride. A recommended range for oral dosing is 5-300 mg A/day, preferably 40-200 mg A/day, more preferably 40-80 mg A/day, in single or divided doses. A recommended range for oral administration in oral forms such as pills or tablets is 2.5 mg A/day to 160 mg A/day and preferably 5-80 mgA/day. The stability of Form A, relative to all other forms is demonstrated by its lack of hygroscopic'ity and lower energy bridging and thermal conversions. Form B's greater stability over the hydrate is demonstrated by the conversion of the hydrate to Form B under routine drying conditions.
The following examples illustrate the methods and compounds of the present invention. It will be understood, however, that the invention is not limited to the specific Examples.
Example I Preparation of the Crystalline Monohydrochloride Form A A 20.23 gram portion of the free base of the monohydrochloride was suspended in 150 milliliters of isopropyl ether under ambient conditions. To the resulting thin white slurry, 4.02 grams of anhydrous hydrogen chloride was added while keeping the temperature below 50°C. This slurry was then used for the conversion to Form A by heating to reflux at about 68° to 69°C. The resulting particle size averaged between about 20 to 35μ. An x-ray configuration was obtained confirming that the compound is Form A of the monohydrochloride. Example II
Preparation of the Crystalline Monohydrochloride Form B A 5 gram portion of the amorphous monohydrochloride was suspended in 25 milliliters of tetrahydrofuran and left standing under ambient conditions for 72 hours. The resulting Form B was collected by filtration. An x-ray configuration was obtained confirming that the compound is Form B of the monohydrochloride.
Claims
We Claim 1. The crystalline forms of (7S, 9aS)-7-[3-cyanophenoxy] methyl-2-(5- fluoropyrimidin-2-yl) 2,3,4,6,7,8,9, 9a-octahydro-1-H pyrido [1,2-a] pyrazine monohydrochloride having the formula
(a) a stable nonhygroscopic Form A polymorph exhibiting the X-ray powder diffraction pattern
Peak 1 2 3 4 5 6 7 8
No. d 12.3 11.3 6.9 5.9 4.3 4.1 3.5 3.2 space
2. T lie monor lydrochlor ide polyπ lorph ace ordin. 3 tO claim 1 i wherein F crystalline habits are either short rods or equant prisms.
3. The monohydrochloride Form A polymorph according to Claim 2 wherein said short rods or equant prisms are about 20╬╝ to 35╬╝ in size.
4. The monohydrochloride polymorph Form A according to Claim 1 obtained from the amorphous form of the monohydrochloride by heating between about 60┬░ to 80┬░C.
5. The monohydrochloride polymorph Form A according to Claim 1 obtained by melting and recrystallizing Form B at between about 140┬░C and 160┬░C.
6. The monohydrochloride polymorph Form B according to Claim 1 wherein Form B is microcrystalline or has acicular aggregates.
7. The monohydrochloride polymorph Form B according to Claim 1 obtained by drying a hydrate of the monohydrochloride at about 45┬░C in vacuo.
8. A pharmaceutical composition having antipsychotic activity comprising at least one of the polymorphic Forms A or B according to Claim 1 , in an amount effective in the treatment of psychotic diseases and a pharmaceutically acceptable carrier.
9. A method of treating psychotic diseases which comprises administering to a subject in need of treatment an antipsychotic effective amount of the A Form of the compound of Claim 1.
10. A method of treating psychotic diseases which comprises administering to a subject in need of treatment an antipsychotic effective amount of the B Form of the compound of Claim 1.
11. A pharmaceutical composition having antidepressive activity comprising at least one of the polymorphic Forms A or B according to Claim 1 , in an amount effective in the treatment of anxiety and depressive diseases, and a pharmaceutically acceptable carrier.
12. A method of treating depressive diseases which comprises administering to a subject in need of treatment an antidepressive effective amount of Form A of the compound of Claim 1.
13. A method of treating depressive diseases which comprises administering to a subject in need of treatment an antidepressive effective amount of Form B of the compound of Claim 1.
14. The method of making crystalline polymorphic Form A of (7S, 9aS)-7[[3- cyanophenoxy]methyl-2-(5-fluoropyrimidin-2-yl)2,3,4,6,7,8,9,9a-octahydro-1-H pyrido [1 ,2- ajpyrazine monohydrochloride comprising: slurrying or refluxing amphorous forms of said monohydrochloride in about five to fifteen parts isopropyl alcohol or acetone to about one part of said monohydrochloride; and harvesting short rods of about 20╬╝ to 35╬╝ from acetone or isopropyl ether; or harvesting octaledral prisms from isopropyl alcohol
15. The method of claim 14 wherein the refluxing is carried out between about 60 to 80┬░C in isopropyl ether.
16. The method of claim 14 wherein the slurrying is carried out under ambient conditions for about 1.5 to 72 hours or reflux for two hours followed by one hour ambient granulation in isopropyl alcohol or acetone.
17. The method of clam 14, wherein large crystals of Form A with a rod like habit are grown from acetone solution by slow evaporation.
18. The method of making crystalline polymorphic Form B of (7S, 9aS)-7[3- cyanophenoxy]methyl-2-(5-fluoropy-rimidin-2-yl)2I3,4,6,7,8,9,9a-octahydro-1-H-pyrido[1I2- ajpyrazine mono-hydrochloride comprising: crystallizing said monohydrochloride in tetrahydrofuran/hexane, tetrahydrofuran or ethyl acetate and harvesting microcrystalline aggregates or acicular aggregates.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU35298/99A AU3529899A (en) | 1998-05-22 | 1999-05-07 | Polymorphs of crystalline (7s,9as)-7-[ 3-cyanophenoxy] methyl-2-(5- fluoropyrimidin-2- yl)-2,3,4,6,7,8,9a -octahydro-1h-pyrido[1,2-a] pyrazine- monohydrochloride and their pharmaceutical compositions |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8641298P | 1998-05-22 | 1998-05-22 | |
| US60/086,412 | 1998-05-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999061441A1 true WO1999061441A1 (en) | 1999-12-02 |
Family
ID=22198401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB1999/000826 WO1999061441A1 (en) | 1998-05-22 | 1999-05-07 | Polymorphs of crystalline (7s,9as)-7-[ 3-cyanophenoxy] methyl-2-(5- fluoropyrimidin-2- yl)-2,3,4,6,7,8,9a -octahydro-1h-pyrido[1,2-a] pyrazine- monohydrochloride and their pharmaceutical compositions |
Country Status (8)
| Country | Link |
|---|---|
| AP (1) | AP9901544A0 (en) |
| AU (1) | AU3529899A (en) |
| GT (1) | GT199900060A (en) |
| MA (1) | MA26632A1 (en) |
| PA (1) | PA8470901A1 (en) |
| TN (1) | TNSN99096A1 (en) |
| WO (1) | WO1999061441A1 (en) |
| ZA (1) | ZA993477B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996010571A1 (en) * | 1994-09-30 | 1996-04-11 | Pfizer Inc. | 2,7-SUBSTITUTED OCTAHYDRO-1H-PYRIDO[1,2-a]PYRAZINE DERIVATIVES |
-
1999
- 1999-04-23 GT GT199900060A patent/GT199900060A/en unknown
- 1999-04-27 PA PA19998470901A patent/PA8470901A1/en unknown
- 1999-05-07 WO PCT/IB1999/000826 patent/WO1999061441A1/en active Application Filing
- 1999-05-07 AU AU35298/99A patent/AU3529899A/en not_active Abandoned
- 1999-05-19 TN TNTNSN99096A patent/TNSN99096A1/en unknown
- 1999-05-19 MA MA25587A patent/MA26632A1/en unknown
- 1999-05-20 AP APAP/P/1999/001544A patent/AP9901544A0/en unknown
- 1999-05-21 ZA ZA9903477A patent/ZA993477B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996010571A1 (en) * | 1994-09-30 | 1996-04-11 | Pfizer Inc. | 2,7-SUBSTITUTED OCTAHYDRO-1H-PYRIDO[1,2-a]PYRAZINE DERIVATIVES |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| EP3610890A1 (en) | 2012-11-14 | 2020-02-19 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
| US10624875B2 (en) | 2012-11-14 | 2020-04-21 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3529899A (en) | 1999-12-13 |
| ZA993477B (en) | 2000-11-21 |
| GT199900060A (en) | 2000-10-14 |
| PA8470901A1 (en) | 2000-09-29 |
| TNSN99096A1 (en) | 2005-11-10 |
| AP9901544A0 (en) | 1999-06-30 |
| MA26632A1 (en) | 2004-12-20 |
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