US20080045725A1 - Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane - Google Patents
Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane Download PDFInfo
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- US20080045725A1 US20080045725A1 US11/740,667 US74066707A US2008045725A1 US 20080045725 A1 US20080045725 A1 US 20080045725A1 US 74066707 A US74066707 A US 74066707A US 2008045725 A1 US2008045725 A1 US 2008045725A1
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- NRZUWVRTLGNRLH-XJWMEUIESA-N C.ClC1=C(Cl)C=C([C@]23CCC[C@H]2C3)C=C1.ClC1=C(Cl)C=C([C@]23CNC[C@H]2C3)C=C1.ClC[C@@H]1CO1.N#CCC1=CC(Cl)=C(Cl)C=C1.N#C[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.N#C[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO Chemical compound C.ClC1=C(Cl)C=C([C@]23CCC[C@H]2C3)C=C1.ClC1=C(Cl)C=C([C@]23CNC[C@H]2C3)C=C1.ClC[C@@H]1CO1.N#CCC1=CC(Cl)=C(Cl)C=C1.N#C[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.N#C[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO NRZUWVRTLGNRLH-XJWMEUIESA-N 0.000 description 1
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- KGBJYNOTIRJUOY-IXUOVBOFSA-N ClC1=C(Cl)C=C([C@]23CNC[C@H]2C3)C=C1.ClC[C@@H]1CO1.N#CCC1=CC(Cl)=C(Cl)C=C1.N#C[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.N#C[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.O=S(Cl)Cl Chemical compound ClC1=C(Cl)C=C([C@]23CNC[C@H]2C3)C=C1.ClC[C@@H]1CO1.N#CCC1=CC(Cl)=C(Cl)C=C1.N#C[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.N#C[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CCl.NC[C@]1(C2=CC(Cl)=C(Cl)C=C2)C[C@@H]1CO.O=S(Cl)Cl KGBJYNOTIRJUOY-IXUOVBOFSA-N 0.000 description 1
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Classifications
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to processes for the preparation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
- These compounds are known to be useful for treating e.g., depression, anxiety disorders, eating disorders and urinary incontinence (see U.S. Pat. Nos. 6,372,919, 6,569,887 and 6,716,868).
- the subject invention provides a process for the preparation of (+) and ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane via a very simple, short and highly efficient synthesis.
- novel processes of this invention involves the asymmetric synthesis of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane.
- present invention provides novel processes for the preparation of a compound of the formula I:
- the present invention is directed to a process for preparing a compound of the formula I:
- the present invention is further directed to a process for preparing a compound of the formula I:
- the present invention is further directed to a process for preparing a compound of the formula Ib:
- the present invention is further directed to a process for preparing a compound of the formula Ib:
- the base may be selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide, potassium t-pentoxide, potassium amylate, lithium diisopropylamide (LDA), lithium tetramethylpiperidide (LiTMP), sec-butyllithium, or tert-butyllithium.
- NaHMDS sodium hexamethyldisilazide
- KHMDS potassium hexamethyldisilazide
- LiHMDS lithium hexamethyldisilazide
- the base is selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and lithium hexamethyldisilazide (LiHMDS). Further within this embodiment, the base is sodium hexamethyldisilazide (NaHMDS). Solvents for conducting the step of contacting 3,4-dichlorophenylacetonitrile and (S)-epichlorohydrin [or (S)-epichlorohydrin] in the presence of a base to give cyclopropyl compounds of the formula II [or IIb] comprise an organic solvent.
- the organic solvent comprises toluene, tetrahydrofuran (THF), diethyl ether, diglyme, dimethoxyethane (DME), or methyl t-butyl ether. Further within this embodiment, the organic solvent is tetrahydrofuran.
- the step of contacting 3,4-dichlorophenyl-acetonitrile and (S)-epichlorohydrin [or (S)-epichlorohydrin] in the presence of a base to give cyclopropyl compounds of the formula II [or IIb] is typically carried out at a temperature range of between about ⁇ 30 and about 25° C. Within this embodiment, the temperature range is less than about 0° C. Further within this embodiment, the temperature range is between about ⁇ 20 and about ⁇ 5° C.
- the step of reducing of the compounds of formula II [or IIb] with a reducing agent to give amino alcohol compounds of the formula III [or IIIb] the reducing agent may be selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride-borontrifluoride etherate, a dialkylborane, 9-borabicyclo[3.3.1]nonane (9-BBN), and lithium aluminum hydride (LAH).
- the reducing agent is borane dimethyl sulfide complex.
- Solvents for conducting the step of reducing of the compounds of formula II with a reducing agent to give amino alcohol compounds of the formula III [or IIIb] comprise an organic solvent.
- the organic solvent comprises toluene, tetrahydrofuran (THF), diethyl ether, diglyme, dimethoxyethane (DME), or methyl t-butyl ether. Further within this embodiment, the organic solvent is tetrahydrofuran.
- the step of reducing of the compounds of formula II [or IIb] with a reducing agent to give amino alcohol compounds of the formula III [or IIIb] is typically carried out at a temperature range of between about ⁇ 30 and about 25° C. Within this embodiment, the temperature range is less than about 0° C. Further within this embodiment, the temperature range is between about ⁇ 20 and about ⁇ 5° C.
- the step of chlorinating the compounds of formula III [or IIIb] with a chlorinating agent to give chloro compounds of the formula IV [or IVb] the chlorinating agent may be selected from thionyl chloride, SO 2 Cl 2 , and Ph 3 P/CCl 4 . Further within this embodiment, the chlorinating agent is thionyl chloride. Solvents for conducting the step of chlorinating the compounds of formula III [or IIIb] with a chlorinating agent to give chloro compounds of the formula IV [or IVb] comprise an organic solvent.
- the organic solvent comprises toluene, tetrahydrofuran (THF), diethyl ether, diglyme, dimethoxyethane (DME), methyl t-butyl ether, ethyl acetate, isopropyl acetate or N-methylpyrrolidinone. Further within this embodiment, the organic solvent comprises tetrahydrofuran, dimethoxyethane and isopropyl acetate.
- the step of chlorinating the compounds of formula III [or IIIb] with a chlorinating agent to give chloro compounds of the formula IV [or IVb] is typically carried out at a temperature range of between about 0 and about 40° C. Within this embodiment, the temperature range is less than about 0° C. Further within this embodiment, the temperature is about 25° C.
- the step of cyclodehydration of the compounds of the formula IV [or IVb] with a base to give the compound of formula [or Ib] may be selected from sodium hydroxide, potassium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, Et 3 N, i-Pr 2 NEt, DABCO, DBU, or other amine bases. Further within this embodiment, the base is sodium hydroxide. Solvents for conducting the step of cyclodehydration of the compounds of the formula IV [or IVb] with a base to give the compound of formula I [or Ib] comprise an aqueous solvent.
- the pH is typically at a range of between about 7-10. Within this embodiment, the pH is about 8-10. Further within this embodiment, the pH is about 8.5-9.5.
- the process steps are conducted sequentially without isolation of the intermediate compounds.
- the present invention is directed to a process for the preparation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as depicted below:
- the present invention is directed to a process for the preparation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as depicted below:
- the present invention is directed to a compound which is selected from the group consisting of:
- the present invention provides a heavy metal-free synthesis that is efficient and atom economic so that (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be prepared via a single through process without requiring isolation of any intermediates.
- the crude reaction mixture is reduced with borane dimethyl sulfide complex in one pot to afford the amino alcohol intermediates.
- the desired cis amino alcohol is directly cyclodehydrated to give (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]-hexane.
- the whole synthesis may be conducted as a single stage through process to allow direct isolation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl salt or ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl salt.
- Another aspect of this invention is directed to the foregoing processes wherein the (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable salt thereof, is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, greater than 95%, greater than 98%, greater than 99%, greater than 99.5% (enantiomeric excess) or greater than 99.9% (enantiomeric excess).
- Another aspect of this invention is directed to the foregoing processes wherein the ( ⁇ )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable salt thereof, is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, greater than 95%, greater than 98%, greater than 99%, greater than 99.5% (enantiomeric excess) or greater than 99.9% (enantiomeric excess).
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic or organic acids.
- Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Specific acids include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
- a specific acid is hydrochloric acid.
- the present process is surprisingly efficient, minimizing the production of side products, and increasing productivity and purity.
- the starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds.
- the skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
- i-PrOAc (18.5 L) and 5% dibasic sodium phosphate (18.5 L) were charged. The organic phase was then washed with saturated brine (18.5 L), azeotropically dried and solvent-switched to i-PrOAc (ca. 24.5 L) in vacuum.
- aqueous i-PrOAc was azeotropically concentrated in vacuum to ca. 24.5 L. Methylcyclohexane (17.5 L) was added dropwise over 2 h. The wet cake was displacement-washed with 7 L of 40% methylcyclohexane/1-PrOAc followed by a slurry wash (7 L, i-PrOAc) and a displacement wash (7 L, i-PrOAc). Typical isolated yield: 57-60% corrected with wt %: 87-99.5% (based on HCl salt).
- the wet cake was displacement-washed with 10 L of 30% i-PrOH in MeOBu-t followed by 2 ⁇ 7.5 L 10% i-PrOH in MeOBu-t (slurry wash, then displacement wash).
- the wet cake was suction dried under N 2 (10-50 RH %) at ambient temperature to give the hemihydrate HCl salt of (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3,10]hexane. Typical yield: 92%.
- reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above.
- specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Abstract
Description
- The present invention relates to processes for the preparation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof, and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof. These compounds are known to be useful for treating e.g., depression, anxiety disorders, eating disorders and urinary incontinence (see U.S. Pat. Nos. 6,372,919, 6,569,887 and 6,716,868).
- The general processes disclosed in the art for the preparation of racemic, (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane result in relatively low and inconsistent yields of the desired product (see e.g., U.S. Pat. Nos. 4,118,417, 4,131,611, 4,196,120, 4,231,935, 4,435,419, 6,372,919, 6,569,887, 6,716,868; Sorbera, et al., Drugs Future 2005, 30, 7; and Epstein, et al., J. Med. Chem., 1981, 24, 481). Some of such processes rely on the use of expensive reagents. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of (+) or (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in relatively high yield and enantiomeric purity. It will be appreciated that (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are useful therapeutic agents. As such, there is a need for the development of processes for the preparation of (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane which are readily amenable to scale-up, use cost-effective and readily available reagents, and which are therefore capable of practical application to large scale manufacture. Accordingly, the subject invention provides a process for the preparation of (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane via a very simple, short and highly efficient synthesis.
- The novel processes of this invention involves the asymmetric synthesis of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane. In particular, the present invention provides novel processes for the preparation of a compound of the formula I:
- or a pharmaceutically acceptable salt thereof,
-
- or a pharmaceutically acceptable salt thereof.
-
- or a pharmaceutically acceptable salt thereof, comprising:
-
-
-
-
- followed by cyclodehydration of the compounds of the formula IV with a base to give the compound of formula I, or a pharmaceutically acceptable salt thereof.
-
- or a pharmaceutically acceptable salt thereof, comprising:
-
- with a base to give the compound of formula I, or a pharmaceutically acceptable salt thereof.
-
- or a pharmaceutically acceptable salt thereof, comprising:
-
-
-
-
- followed by cyclodehydration of the compounds of the formula IVb with a base to give the compound of formula Ib, or a pharmaceutically acceptable salt thereof.
-
- or a pharmaceutically acceptable salt thereof, comprising:
-
- with a base to give the compound of formula Ib, or a pharmaceutically acceptable salt thereof.
- In an embodiment of the present invention the step of contacting 3,4-dichlorophenylacetonitrile and (S)-epichlorohydrin [or (R)-epichlorohydrin] in the presence of a base to give cyclopropyl compounds of the formula II [or IIb], the base may be selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide, potassium t-pentoxide, potassium amylate, lithium diisopropylamide (LDA), lithium tetramethylpiperidide (LiTMP), sec-butyllithium, or tert-butyllithium. Within this embodiment, the base is selected from sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and lithium hexamethyldisilazide (LiHMDS). Further within this embodiment, the base is sodium hexamethyldisilazide (NaHMDS). Solvents for conducting the step of contacting 3,4-dichlorophenylacetonitrile and (S)-epichlorohydrin [or (S)-epichlorohydrin] in the presence of a base to give cyclopropyl compounds of the formula II [or IIb] comprise an organic solvent. Within this embodiment, the organic solvent comprises toluene, tetrahydrofuran (THF), diethyl ether, diglyme, dimethoxyethane (DME), or methyl t-butyl ether. Further within this embodiment, the organic solvent is tetrahydrofuran. The step of contacting 3,4-dichlorophenyl-acetonitrile and (S)-epichlorohydrin [or (S)-epichlorohydrin] in the presence of a base to give cyclopropyl compounds of the formula II [or IIb] is typically carried out at a temperature range of between about −30 and about 25° C. Within this embodiment, the temperature range is less than about 0° C. Further within this embodiment, the temperature range is between about −20 and about −5° C.
- In an embodiment of the present invention the step of reducing of the compounds of formula II [or IIb] with a reducing agent to give amino alcohol compounds of the formula III [or IIIb], the reducing agent may be selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride-borontrifluoride etherate, a dialkylborane, 9-borabicyclo[3.3.1]nonane (9-BBN), and lithium aluminum hydride (LAH). Further within this embodiment, the reducing agent is borane dimethyl sulfide complex. Solvents for conducting the step of reducing of the compounds of formula II with a reducing agent to give amino alcohol compounds of the formula III [or IIIb] comprise an organic solvent. Within this embodiment, the organic solvent comprises toluene, tetrahydrofuran (THF), diethyl ether, diglyme, dimethoxyethane (DME), or methyl t-butyl ether. Further within this embodiment, the organic solvent is tetrahydrofuran. The step of reducing of the compounds of formula II [or IIb] with a reducing agent to give amino alcohol compounds of the formula III [or IIIb] is typically carried out at a temperature range of between about −30 and about 25° C. Within this embodiment, the temperature range is less than about 0° C. Further within this embodiment, the temperature range is between about −20 and about −5° C.
- In an embodiment of the present invention the step of chlorinating the compounds of formula III [or IIIb] with a chlorinating agent to give chloro compounds of the formula IV [or IVb], the chlorinating agent may be selected from thionyl chloride, SO2Cl2, and Ph3P/CCl4. Further within this embodiment, the chlorinating agent is thionyl chloride. Solvents for conducting the step of chlorinating the compounds of formula III [or IIIb] with a chlorinating agent to give chloro compounds of the formula IV [or IVb] comprise an organic solvent. Within this embodiment, the organic solvent comprises toluene, tetrahydrofuran (THF), diethyl ether, diglyme, dimethoxyethane (DME), methyl t-butyl ether, ethyl acetate, isopropyl acetate or N-methylpyrrolidinone. Further within this embodiment, the organic solvent comprises tetrahydrofuran, dimethoxyethane and isopropyl acetate. The step of chlorinating the compounds of formula III [or IIIb] with a chlorinating agent to give chloro compounds of the formula IV [or IVb] is typically carried out at a temperature range of between about 0 and about 40° C. Within this embodiment, the temperature range is less than about 0° C. Further within this embodiment, the temperature is about 25° C.
- In an embodiment of the present invention the step of cyclodehydration of the compounds of the formula IV [or IVb] with a base to give the compound of formula [or Ib], the base may be selected from sodium hydroxide, potassium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, Et3N, i-Pr2NEt, DABCO, DBU, or other amine bases. Further within this embodiment, the base is sodium hydroxide. Solvents for conducting the step of cyclodehydration of the compounds of the formula IV [or IVb] with a base to give the compound of formula I [or Ib] comprise an aqueous solvent. In the step of cyclodehydration of the compounds of the formula IV [or IVb] with a base to give the compound of formula I [or Ib], the pH is typically at a range of between about 7-10. Within this embodiment, the pH is about 8-10. Further within this embodiment, the pH is about 8.5-9.5.
- In an embodiment of the invention, the process steps are conducted sequentially without isolation of the intermediate compounds.
-
-
-
- or a salt thereof.
- The present invention provides a heavy metal-free synthesis that is efficient and atom economic so that (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be prepared via a single through process without requiring isolation of any intermediates. Starting from inexpensive, commercially available 3,4-dichlorophenylacetonitrile and (S)-epichlorohydrin (or (R)-epichlorohydrin), the key cyclopropane intermediate is constructed. Without further workup, the crude reaction mixture is reduced with borane dimethyl sulfide complex in one pot to afford the amino alcohol intermediates. The desired cis amino alcohol is directly cyclodehydrated to give (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]-hexane. The whole synthesis may be conducted as a single stage through process to allow direct isolation of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl salt or (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl salt.
- Another aspect of this invention is directed to the foregoing processes wherein the (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable salt thereof, is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, greater than 95%, greater than 98%, greater than 99%, greater than 99.5% (enantiomeric excess) or greater than 99.9% (enantiomeric excess).
- Another aspect of this invention is directed to the foregoing processes wherein the (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable salt thereof, is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, greater than 95%, greater than 98%, greater than 99%, greater than 99.5% (enantiomeric excess) or greater than 99.9% (enantiomeric excess).
- The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Specific acids include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. A specific acid is hydrochloric acid.
- The present process is surprisingly efficient, minimizing the production of side products, and increasing productivity and purity. The starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
- The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. Unless otherwise noted, all reactions were conducted under N2 atmosphere using standard air-free manipulation techniques. Solvents were purchased from Fisher Scientific Company and used without further purification. Commercial reagents were purchased either from Aldrich or Bayer and used without further purification. High performance liquid chromatography (HPLC) analysis was performed using Agilent Technology 1100 series instrument with ACE 5 C18 (240×4.6 mm I.D., 5 μm particle size) column. Proton nuclear magnetic resonance (1H NMR) spectra were measured on Bruker Avance-400 instrument (400 MHz). Carbon nuclear magnetic resonance (13C NMR) spectra were measured on Bruker Avance-400 instrument (100 MHz) with complete proton decoupling. Chemical shifts are reported in ppm downfield from tetramethylsilane (TMS).
- To a solution of 3,4-dichlorophenylacetonitrile (3.50 kg) and S-(+)-epichlorohydrin (2.22 kg) in THF (18.5 L) at −15° C. under atmosphere of N2 was added NaHMDS (16.5 L, 2M in THF) dropwise over 3 h. The reaction mixture was stirred for 3 h at −15° C., then, overnight at −5° C. BH3-Me2S (neat, 10M, 4.4 L) was added over 2 h. The reaction mixture was then gradually warmed to 40° C. over 3 h. After aging 1.5 h at 40° C., the reaction mixture was cooled to 20-25° C. and slowly quenched into a 2N HCl solution (27.7 L). The quenched mixture was then aged for 1 h at 40° C. Concentrated NH4OH (6.3 L) was added and the aqueous layer was discarded. i-PrOAc (18.5 L) and 5% dibasic sodium phosphate (18.5 L) were charged. The organic phase was then washed with saturated brine (18.5 L), azeotropically dried and solvent-switched to i-PrOAc (ca. 24.5 L) in vacuum.
- The above crude amino alcohol solution in i-PrOAc was slowly subsurface-added to a solution of SOCl2 (22.1 mol, 1.61 L) in i-PrOAc (17.5 L) at ambient temperature over 2 h. After aging additional 1-5 h, 5.0 N NaOH (16.4 L) was added over 1 h while the batch temperature was maintained at <30° C. with external cooling. The two-phase reaction mixture was stirred for 1 h at ambient temperature to allow pH to stabilize (usually to 8.5-9.0) with NaOH pH titration. The organic phase was washed with 40% aqueous i-PrOH (21 L) followed by water (10.5 L). Conc. HCl (1.69 L) was added. The aqueous i-PrOAc was azeotropically concentrated in vacuum to ca. 24.5 L. Methylcyclohexane (17.5 L) was added dropwise over 2 h. The wet cake was displacement-washed with 7 L of 40% methylcyclohexane/1-PrOAc followed by a slurry wash (7 L, i-PrOAc) and a displacement wash (7 L, i-PrOAc). Typical isolated yield: 57-60% corrected with wt %: 87-99.5% (based on HCl salt).
- (1R,5S)-(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3,10]hexane HCl salt (5.0 kg) was dissolved in i-PrOH (14.25 L) and water (0.75 L) at 55° C. Seeds (50 g) were added at 48-50° C. The batch was allowed to cool to ambient temperature (20° C.) over 2-4 h. MeOBu-t (37 L) was added dropwise over 2 h. After aging 1 h at 20° C., the batch was filtered. The wet cake was displacement-washed with 10 L of 30% i-PrOH in MeOBu-t followed by 2×7.5 L 10% i-PrOH in MeOBu-t (slurry wash, then displacement wash). The wet cake was suction dried under N2 (10-50 RH %) at ambient temperature to give the hemihydrate HCl salt of (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3,10]hexane. Typical yield: 92%. 1H-NMR (400 MHz, d4-MeOH): δ 7.52 (d, J=2.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.26 (dd, J=2.1, 8.4 Hz, 1H), 3.78 (d, J=11.4 Hz, 1H), 3.69 (dd, J=3.9, 11.3 Hz, 1H), 3.62 (dd, J=1.4, 11.3 Hz, 1H), 3.53 (d, J=11.4 Hz, 1H), 2.21 (m, 1H), 1.29 (t, J=7.5 Hz, 1H), 1.23 (dd, J=4.9, 6.5 Hz, 1H). 13C-NMR (100 MHz, d4-MeOH): δ 141.0, 133.7, 132.2, 132.0, 130.6, 128.4, 51.7, 49.1, 31.8, 24.9, 16.5. Anal. Calcd for C11H13Cl3NO0.5: C, 48.29; H, 4.79; N, 5.12; Cl, 38.88. Found: C, 48.35; H, 4.87; N, 5.07; 38.55.
- While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above. Likewise, the specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
Claims (13)
Priority Applications (27)
Application Number | Priority Date | Filing Date | Title |
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US11/740,667 US20080045725A1 (en) | 2006-04-28 | 2007-04-26 | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
EP07776380A EP2061318B1 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-) -1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
BRPI0710882-6A BRPI0710882A2 (en) | 2006-04-28 | 2007-04-27 | process for preparing a compound and compound |
KR1020087029108A KR101437038B1 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
MX2008013801A MX2008013801A (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3 -azabicyclo[3.1.0]hexane. |
RU2008146964/04A RU2008146964A (en) | 2006-04-28 | 2007-04-27 | METHOD FOR SYNTHESIS (+) AND (-) - 1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] HEXANE |
ES07776380T ES2387214T3 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-) - 1- (3,4-dichlorophenyl) -3-azabicyclo (3.1.0) hexane |
AT07776380T ATE550322T1 (en) | 2006-04-28 | 2007-04-27 | METHOD FOR THE SYNTHESIS OF (+)- AND (-)-1-(3, 4-DICHLORPHENYL)-3-AZABICYCLOÄ3.1.0ÜHEXANE |
AU2007288444A AU2007288444B8 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
CN200780015012XA CN101573034B (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-) -1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
JP2009521739A JP2010500972A (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane |
EP07835762A EP2012777A2 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
PCT/US2007/010288 WO2007127396A1 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-) -1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
PCT/US2007/011669 WO2008024143A2 (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
NZ572247A NZ572247A (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and intermediate compounds of the process |
CA2650658A CA2650658C (en) | 2006-04-28 | 2007-04-27 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
IL194750A IL194750A (en) | 2006-04-28 | 2008-10-22 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
HK09105289.0A HK1127899A1 (en) | 2006-04-28 | 2009-06-12 | Process for the synthesis of (+) and (-) -1-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane |
US12/782,705 US20100298574A1 (en) | 2006-04-28 | 2010-05-18 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US13/207,279 US20110295020A1 (en) | 2006-04-28 | 2011-08-10 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US13/366,211 US20120142940A1 (en) | 2006-04-28 | 2012-02-03 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicycle[3.1.0]Hexane |
US13/945,605 US9527813B2 (en) | 2006-04-28 | 2013-07-18 | Process for the synthesis of (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
JP2013181165A JP5802718B2 (en) | 2006-04-28 | 2013-09-02 | Process for the synthesis of (+) and (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane |
JP2015066151A JP5984988B2 (en) | 2006-04-28 | 2015-03-27 | Process for the synthesis of (+) and (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane |
JP2016104293A JP2016155863A (en) | 2006-04-28 | 2016-05-25 | Method for synthesizing (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US15/367,718 US20170233333A1 (en) | 2006-04-28 | 2016-12-02 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US15/820,959 US20180319738A1 (en) | 2006-04-28 | 2017-11-22 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
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US79609706P | 2006-04-28 | 2006-04-28 | |
US11/740,667 US20080045725A1 (en) | 2006-04-28 | 2007-04-26 | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
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US11/740,667 Abandoned US20080045725A1 (en) | 2006-04-28 | 2007-04-26 | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US12/782,705 Abandoned US20100298574A1 (en) | 2006-04-28 | 2010-05-18 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US13/207,279 Abandoned US20110295020A1 (en) | 2006-04-28 | 2011-08-10 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US13/366,211 Abandoned US20120142940A1 (en) | 2006-04-28 | 2012-02-03 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicycle[3.1.0]Hexane |
US13/945,605 Active US9527813B2 (en) | 2006-04-28 | 2013-07-18 | Process for the synthesis of (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US15/367,718 Abandoned US20170233333A1 (en) | 2006-04-28 | 2016-12-02 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US15/820,959 Abandoned US20180319738A1 (en) | 2006-04-28 | 2017-11-22 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
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US12/782,705 Abandoned US20100298574A1 (en) | 2006-04-28 | 2010-05-18 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US13/207,279 Abandoned US20110295020A1 (en) | 2006-04-28 | 2011-08-10 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US13/366,211 Abandoned US20120142940A1 (en) | 2006-04-28 | 2012-02-03 | Process For The Synthesis Of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicycle[3.1.0]Hexane |
US13/945,605 Active US9527813B2 (en) | 2006-04-28 | 2013-07-18 | Process for the synthesis of (+) and (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US15/367,718 Abandoned US20170233333A1 (en) | 2006-04-28 | 2016-12-02 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
US15/820,959 Abandoned US20180319738A1 (en) | 2006-04-28 | 2017-11-22 | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane |
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US (7) | US20080045725A1 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100204486A1 (en) * | 2006-04-28 | 2010-08-12 | Merck & Co., Inc. | Process for the Synthesis of (+)and (-)-1 Aryl-3-Azabicyclo(3.1.0) Hexanes |
WO2015070253A1 (en) * | 2013-11-11 | 2015-05-14 | Euthymics Bioscience, Inc. | Novel methods |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080045725A1 (en) * | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
CA3230068A1 (en) | 2021-08-31 | 2023-03-09 | Ethismos Research, Inc. | Methods of preventing and treating pain and associated symptoms |
Citations (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3892722A (en) * | 1973-06-14 | 1975-07-01 | Boris Davidovich Babitsky | Method for preparing stereoregular 1,4-transpolymers of 2-alkyl- butadienes-1,3 or stereoregular 1,4-transcopolymers of 2-alkylbutadienes-1,3 with butadiene-1,3 |
US4022652A (en) * | 1974-09-26 | 1977-05-10 | Tokyo Shibaura Electric Co., Ltd. | Method of growing multiple monocrystalline layers |
US4088652A (en) * | 1975-07-31 | 1978-05-09 | American Cyanamid Company | Acylazabicyclohexanes |
US4118393A (en) * | 1977-06-23 | 1978-10-03 | American Cyanamid Company | Phenyl azabicyclohexanones |
US4118417A (en) * | 1977-06-23 | 1978-10-03 | American Cyanamid Company | Process for resolving cis-1-substituted phenyl-1,2-cyclopropanedicarboxylic acids |
US4131611A (en) * | 1975-07-31 | 1978-12-26 | American Cyanamid Company | Azabicyclohexanes |
US4196120A (en) * | 1975-07-31 | 1980-04-01 | American Cyanamid Company | Azabicyclohexanes, method of use and preparation of the same |
US4231935A (en) * | 1975-07-31 | 1980-11-04 | American Cyanamid Company | 1-Phenyl-3-azabicyclo[3.1.0]hexanes |
US4336268A (en) * | 1980-01-29 | 1982-06-22 | Hoffmann-La Roche Inc. | Cyclohexene derivative analgesics |
US4435419A (en) * | 1981-07-01 | 1984-03-06 | American Cyanamid Company | Method of treating depression using azabicyclohexanes |
US4467102A (en) * | 1982-03-04 | 1984-08-21 | Ube Industries, Ltd. | Optically active propargyl alcohol derivative and a method for preparation of the same |
US4504657A (en) * | 1976-04-27 | 1985-03-12 | Bristol-Myers Company | Cephadroxil monohydrate |
US4521431A (en) * | 1980-10-01 | 1985-06-04 | Glaxo Group Limited | Aminoalkyl furan derivative |
US4591598A (en) * | 1983-07-06 | 1986-05-27 | Hoechst Aktiengesellschaft | Derivatives of 2-azabicyclo[3.1.0]hexane-3-carboxylic acid, and hypotensive use thereof |
US5039680A (en) * | 1987-07-11 | 1991-08-13 | Sandoz Ltd. | New use of 5HT-3 antagonists in preventing or reducing dependency on dependency-inducing agents |
US5075341A (en) * | 1989-12-01 | 1991-12-24 | The Mclean Hospital Corporation | Treatment for cocaine abuse |
US5130430A (en) * | 1990-10-31 | 1992-07-14 | Neurogen Corporation | 2-substituted imidazoquinoxaline diones, a new class of gaba brain receptor ligands |
US5198459A (en) * | 1987-07-11 | 1993-03-30 | Sandoz Ltd. | Use of 5HT-3 antagonists in preventing or reducing dependency on dependency-inducing agents |
US5232934A (en) * | 1992-07-17 | 1993-08-03 | Warner-Lambert Co. | Method for the treatment of psychomotor stimulant addiction |
US5488056A (en) * | 1994-10-31 | 1996-01-30 | Eli Lilly And Company | Method for treating anxiety |
US5556837A (en) * | 1994-08-01 | 1996-09-17 | Regeneron Pharmaceuticals Inc. | Methods for treating addictive disorders |
US5556838A (en) * | 1993-01-28 | 1996-09-17 | Virginia Commonwealth University | Inhibiting the development of tolerance to and/or dependence on an addictive substance |
US5574052A (en) * | 1986-03-17 | 1996-11-12 | Robert J. Schaap | Agonist-antagonist combination to reduce the use of nicotine and other drugs |
US5672360A (en) * | 1993-11-23 | 1997-09-30 | Purdue Pharma, L.P. | Method of treating pain by administering 24 hour oral opioid formulations |
US5762925A (en) * | 1994-11-03 | 1998-06-09 | Sagen; Jacqueline | Preventing opiate tolerance by cellular implantation |
US5911992A (en) * | 1997-06-12 | 1999-06-15 | A. Glenn Braswell | Method for controlling weight with hypericum perforatum and garcinia cambogia |
US5916920A (en) * | 1995-11-16 | 1999-06-29 | Eli Lilly And Company | 3-substituted Bicyclo 3.1.0!hexane-6-carboxylic acids |
US5969156A (en) * | 1995-07-17 | 1999-10-19 | Warner-Lambert Company | Crystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
US5985864A (en) * | 1996-06-07 | 1999-11-16 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
US6109269A (en) * | 1999-04-30 | 2000-08-29 | Medtronic, Inc. | Method of treating addiction by brain infusion |
US6121261A (en) * | 1997-11-19 | 2000-09-19 | Merck & Co., Inc. | Method for treating attention deficit disorder |
US6194000B1 (en) * | 1995-10-19 | 2001-02-27 | F.H. Faulding & Co., Limited | Analgesic immediate and controlled release pharmaceutical composition |
US6204284B1 (en) * | 1991-12-20 | 2001-03-20 | American Cyanamid Company | Use of 1-(substitutedphenyl)-3-azabicyclo[3.1.0]hexanes for the treatment of chemical dependencies |
US6245911B1 (en) * | 1997-12-05 | 2001-06-12 | Eisai Co., Ltd. | Donepezil polycrystals and process for producing the same |
US6245357B1 (en) * | 1998-03-06 | 2001-06-12 | Alza Corporation | Extended release dosage form |
US6268507B1 (en) * | 1997-05-14 | 2001-07-31 | Eli Lilly And Company | Hydantoin derivatives |
US20010034343A1 (en) * | 1995-12-20 | 2001-10-25 | Maynard George D. | Novel substituted 4-(1H-benzimidazol-2-yl) [1,4]diazepanes useful for the treatment of allergic diseases |
US6372919B1 (en) * | 2001-01-11 | 2002-04-16 | Dov Pharmaceutical, Inc. | (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as an anti-depressant agent |
US6569887B2 (en) * | 2001-08-24 | 2003-05-27 | Dov Pharmaceuticals Inc. | (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake |
US20040127541A1 (en) * | 2002-07-31 | 2004-07-01 | Janet Codd | Bicifadine formulation |
US6872718B1 (en) * | 1999-08-20 | 2005-03-29 | Takeda Chemical Industries, Ltd. | Tricyclic dihydrobenzofuran derivatives, process for the preparation thereof and agents |
US20050222146A1 (en) * | 2003-12-15 | 2005-10-06 | Fryer Andrew M | N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof |
US7094799B2 (en) * | 2002-11-08 | 2006-08-22 | Dov Pharmaceutical, Inc. | Polymorphs of bicifadine hydrochloride |
US20060223875A1 (en) * | 2005-03-08 | 2006-10-05 | Phil Skolnick | Methods and compositions for production, formulation and use of 1-aryl-3-azabicyclo[3.1.0]hexanes |
US20080122017A1 (en) * | 2006-11-24 | 2008-05-29 | Dongbu Hitek Co., Ltd. | Semiconductor device and fabricating method thereof |
US20080269348A1 (en) * | 2006-11-07 | 2008-10-30 | Phil Skolnick | Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use |
US20080293822A1 (en) * | 2006-11-07 | 2008-11-27 | Phil Skolnick | Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR72713B (en) | 1976-09-15 | 1983-12-01 | American Cyanamid Co | |
IL65843A (en) | 1977-08-11 | 1986-12-31 | American Cyanamid Co | Pharmaceutical compositions for the treatment of depression containing 3-aza-bicyclo(3.1.0)hexane derivatives and certain novel compounds of this type |
FI910897A (en) | 1990-02-28 | 1991-08-29 | Lilly Co Eli | FOERBAETTRINGAR ROERANDE (S) -NORFLUOXETIN. |
AU702594B2 (en) | 1995-10-13 | 1999-02-25 | Duphar International Research B.V. | Process for the preparation of enantiomerically pure imidazolyl compounds |
US20030013740A1 (en) | 1998-03-27 | 2003-01-16 | Martin P. Redmon | Stable dosage forms of fluoxetine and its enantiomers |
WO2000012464A1 (en) | 1998-08-31 | 2000-03-09 | Taisho Pharmaceutical Co., Ltd. | 6-fluorobicyclo[3. 1.0]hexane derivatives |
JP4194715B2 (en) | 1998-08-31 | 2008-12-10 | 大正製薬株式会社 | 6-Fluorobicyclo [3.1.0] hexane derivative |
JP2000159761A (en) | 1998-11-30 | 2000-06-13 | Yoshio Takeuchi | Fluorothalidomide |
JP4290265B2 (en) | 1999-03-02 | 2009-07-01 | 第一ファインケミカル株式会社 | Novel asymmetric ligand |
US20060173064A1 (en) | 2001-08-24 | 2006-08-03 | Lippa Arnold S | (-)-1-(3,4-Dichlorophenyl)-3-azabi cyclo[3.1.0]hexane, compositions thereof, and uses for treating alcohol-related disorders |
MXPA04005503A (en) | 2001-12-04 | 2004-12-06 | Schering Corp | N-aryl-n'-arylcycloalkyl-urea derivatives as mch antagonists for the treatment of obesity. |
US20080027119A1 (en) | 2002-07-31 | 2008-01-31 | Lippa Arnold S | Methods and compositions employing bicifadine for the treatment of acute pain, chronic pain, and symptoms of neuropathic disorders |
ATE451364T1 (en) | 2004-02-23 | 2009-12-15 | Glaxo Group Ltd | AZABICYCLOÄ3.1.0ÜHEXANE DERIVATIVES SUITABLE AS MODULATORS OF THE DOPAMINE D3 RECEPTOR |
EP1786417A4 (en) * | 2004-08-18 | 2009-05-20 | Dov Pharmaceutical Inc | Novel polymorphs of azabicyclohexane |
US20060100263A1 (en) | 2004-11-05 | 2006-05-11 | Anthony Basile | Antipyretic compositions and methods |
US20080009538A1 (en) | 2005-03-21 | 2008-01-10 | Phil Skolnick | Methods and compositions for the treatment of urinary incontinence |
GB0507602D0 (en) | 2005-04-14 | 2005-05-18 | Glaxo Group Ltd | Compounds |
RU2008107336A (en) * | 2005-07-27 | 2009-09-10 | Дов Фармасьютикал, Инк. (Us) | NEW 1-Aryl-3-Azabicyclo {3.1.0.} HEXANES: OBTAINING AND APPLICATION FOR TREATMENT OF PSYCHONEUROLOGICAL DISORDERS |
GB0517193D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Novel use |
GB0517191D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
US7799815B2 (en) | 2005-08-22 | 2010-09-21 | Glaxo Group Limited | Triazole derivatives as modulators of dopamine D3 receptors |
US20080045725A1 (en) * | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
EP2016053B1 (en) | 2006-04-28 | 2010-11-10 | Merck Sharp & Dohme Corp. | Process for the synthesis of (+) and (-)-1-aryl-3-azabicyclo[3.1.0]hexanes |
US8002193B2 (en) * | 2007-03-12 | 2011-08-23 | Visa U.S.A. Inc. | Payment card dynamically receiving power from external source |
-
2007
- 2007-04-26 US US11/740,667 patent/US20080045725A1/en not_active Abandoned
- 2007-04-27 CA CA2650658A patent/CA2650658C/en not_active Expired - Fee Related
- 2007-04-27 WO PCT/US2007/011669 patent/WO2008024143A2/en active Application Filing
- 2007-04-27 JP JP2009521739A patent/JP2010500972A/en not_active Withdrawn
- 2007-04-27 BR BRPI0710882-6A patent/BRPI0710882A2/en not_active IP Right Cessation
- 2007-04-27 EP EP07835762A patent/EP2012777A2/en active Pending
- 2007-04-27 CN CN200780015012XA patent/CN101573034B/en active Active
- 2007-04-27 ES ES07776380T patent/ES2387214T3/en active Active
- 2007-04-27 AT AT07776380T patent/ATE550322T1/en active
- 2007-04-27 EP EP07776380A patent/EP2061318B1/en not_active Not-in-force
- 2007-04-27 MX MX2008013801A patent/MX2008013801A/en active IP Right Grant
- 2007-04-27 NZ NZ572247A patent/NZ572247A/en not_active IP Right Cessation
- 2007-04-27 WO PCT/US2007/010288 patent/WO2007127396A1/en active Application Filing
- 2007-04-27 AU AU2007288444A patent/AU2007288444B8/en not_active Ceased
- 2007-04-27 RU RU2008146964/04A patent/RU2008146964A/en not_active Application Discontinuation
- 2007-04-27 KR KR1020087029108A patent/KR101437038B1/en not_active IP Right Cessation
-
2008
- 2008-10-22 IL IL194750A patent/IL194750A/en active IP Right Grant
-
2009
- 2009-06-12 HK HK09105289.0A patent/HK1127899A1/en not_active IP Right Cessation
-
2010
- 2010-05-18 US US12/782,705 patent/US20100298574A1/en not_active Abandoned
-
2011
- 2011-08-10 US US13/207,279 patent/US20110295020A1/en not_active Abandoned
-
2012
- 2012-02-03 US US13/366,211 patent/US20120142940A1/en not_active Abandoned
-
2013
- 2013-07-18 US US13/945,605 patent/US9527813B2/en active Active
- 2013-09-02 JP JP2013181165A patent/JP5802718B2/en not_active Expired - Fee Related
-
2015
- 2015-03-27 JP JP2015066151A patent/JP5984988B2/en active Active
-
2016
- 2016-05-25 JP JP2016104293A patent/JP2016155863A/en active Pending
- 2016-12-02 US US15/367,718 patent/US20170233333A1/en not_active Abandoned
-
2017
- 2017-11-22 US US15/820,959 patent/US20180319738A1/en not_active Abandoned
Patent Citations (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3892722A (en) * | 1973-06-14 | 1975-07-01 | Boris Davidovich Babitsky | Method for preparing stereoregular 1,4-transpolymers of 2-alkyl- butadienes-1,3 or stereoregular 1,4-transcopolymers of 2-alkylbutadienes-1,3 with butadiene-1,3 |
US4022652A (en) * | 1974-09-26 | 1977-05-10 | Tokyo Shibaura Electric Co., Ltd. | Method of growing multiple monocrystalline layers |
US4231935A (en) * | 1975-07-31 | 1980-11-04 | American Cyanamid Company | 1-Phenyl-3-azabicyclo[3.1.0]hexanes |
US4088652A (en) * | 1975-07-31 | 1978-05-09 | American Cyanamid Company | Acylazabicyclohexanes |
US4131611A (en) * | 1975-07-31 | 1978-12-26 | American Cyanamid Company | Azabicyclohexanes |
US4196120A (en) * | 1975-07-31 | 1980-04-01 | American Cyanamid Company | Azabicyclohexanes, method of use and preparation of the same |
US4504657A (en) * | 1976-04-27 | 1985-03-12 | Bristol-Myers Company | Cephadroxil monohydrate |
US4118393A (en) * | 1977-06-23 | 1978-10-03 | American Cyanamid Company | Phenyl azabicyclohexanones |
US4118417A (en) * | 1977-06-23 | 1978-10-03 | American Cyanamid Company | Process for resolving cis-1-substituted phenyl-1,2-cyclopropanedicarboxylic acids |
US4336268A (en) * | 1980-01-29 | 1982-06-22 | Hoffmann-La Roche Inc. | Cyclohexene derivative analgesics |
US4521431A (en) * | 1980-10-01 | 1985-06-04 | Glaxo Group Limited | Aminoalkyl furan derivative |
US4435419A (en) * | 1981-07-01 | 1984-03-06 | American Cyanamid Company | Method of treating depression using azabicyclohexanes |
US4467102A (en) * | 1982-03-04 | 1984-08-21 | Ube Industries, Ltd. | Optically active propargyl alcohol derivative and a method for preparation of the same |
US4591598A (en) * | 1983-07-06 | 1986-05-27 | Hoechst Aktiengesellschaft | Derivatives of 2-azabicyclo[3.1.0]hexane-3-carboxylic acid, and hypotensive use thereof |
US5574052A (en) * | 1986-03-17 | 1996-11-12 | Robert J. Schaap | Agonist-antagonist combination to reduce the use of nicotine and other drugs |
US5039680A (en) * | 1987-07-11 | 1991-08-13 | Sandoz Ltd. | New use of 5HT-3 antagonists in preventing or reducing dependency on dependency-inducing agents |
US5198459A (en) * | 1987-07-11 | 1993-03-30 | Sandoz Ltd. | Use of 5HT-3 antagonists in preventing or reducing dependency on dependency-inducing agents |
US5075341A (en) * | 1989-12-01 | 1991-12-24 | The Mclean Hospital Corporation | Treatment for cocaine abuse |
US5130430A (en) * | 1990-10-31 | 1992-07-14 | Neurogen Corporation | 2-substituted imidazoquinoxaline diones, a new class of gaba brain receptor ligands |
US6204284B1 (en) * | 1991-12-20 | 2001-03-20 | American Cyanamid Company | Use of 1-(substitutedphenyl)-3-azabicyclo[3.1.0]hexanes for the treatment of chemical dependencies |
US5232934A (en) * | 1992-07-17 | 1993-08-03 | Warner-Lambert Co. | Method for the treatment of psychomotor stimulant addiction |
US5556838A (en) * | 1993-01-28 | 1996-09-17 | Virginia Commonwealth University | Inhibiting the development of tolerance to and/or dependence on an addictive substance |
US5672360A (en) * | 1993-11-23 | 1997-09-30 | Purdue Pharma, L.P. | Method of treating pain by administering 24 hour oral opioid formulations |
US5556837A (en) * | 1994-08-01 | 1996-09-17 | Regeneron Pharmaceuticals Inc. | Methods for treating addictive disorders |
US5488056A (en) * | 1994-10-31 | 1996-01-30 | Eli Lilly And Company | Method for treating anxiety |
US5762925A (en) * | 1994-11-03 | 1998-06-09 | Sagen; Jacqueline | Preventing opiate tolerance by cellular implantation |
US5969156A (en) * | 1995-07-17 | 1999-10-19 | Warner-Lambert Company | Crystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
US6194000B1 (en) * | 1995-10-19 | 2001-02-27 | F.H. Faulding & Co., Limited | Analgesic immediate and controlled release pharmaceutical composition |
US5916920A (en) * | 1995-11-16 | 1999-06-29 | Eli Lilly And Company | 3-substituted Bicyclo 3.1.0!hexane-6-carboxylic acids |
US20010034343A1 (en) * | 1995-12-20 | 2001-10-25 | Maynard George D. | Novel substituted 4-(1H-benzimidazol-2-yl) [1,4]diazepanes useful for the treatment of allergic diseases |
US5985864A (en) * | 1996-06-07 | 1999-11-16 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
US6268507B1 (en) * | 1997-05-14 | 2001-07-31 | Eli Lilly And Company | Hydantoin derivatives |
US5911992A (en) * | 1997-06-12 | 1999-06-15 | A. Glenn Braswell | Method for controlling weight with hypericum perforatum and garcinia cambogia |
US6121261A (en) * | 1997-11-19 | 2000-09-19 | Merck & Co., Inc. | Method for treating attention deficit disorder |
US6245911B1 (en) * | 1997-12-05 | 2001-06-12 | Eisai Co., Ltd. | Donepezil polycrystals and process for producing the same |
US6245357B1 (en) * | 1998-03-06 | 2001-06-12 | Alza Corporation | Extended release dosage form |
US6109269A (en) * | 1999-04-30 | 2000-08-29 | Medtronic, Inc. | Method of treating addiction by brain infusion |
US6872718B1 (en) * | 1999-08-20 | 2005-03-29 | Takeda Chemical Industries, Ltd. | Tricyclic dihydrobenzofuran derivatives, process for the preparation thereof and agents |
US6372919B1 (en) * | 2001-01-11 | 2002-04-16 | Dov Pharmaceutical, Inc. | (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as an anti-depressant agent |
US7098229B2 (en) * | 2001-01-11 | 2006-08-29 | Dov Pharmaceutical, Inc. | (+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions and uses thereof |
US6716868B2 (en) * | 2001-08-24 | 2004-04-06 | Dov Pharmaceutical Inc | (-)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor |
US7041835B2 (en) * | 2001-08-24 | 2006-05-09 | Dor Pharmaceutical, Inc. | (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor |
US7081471B2 (en) * | 2001-08-24 | 2006-07-25 | Dov Pharmaceutical, Inc. | (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor |
US6569887B2 (en) * | 2001-08-24 | 2003-05-27 | Dov Pharmaceuticals Inc. | (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake |
US7098230B2 (en) * | 2001-08-24 | 2006-08-29 | Dov Pharmaceutical, Inc. | (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor |
US20040127541A1 (en) * | 2002-07-31 | 2004-07-01 | Janet Codd | Bicifadine formulation |
US7094799B2 (en) * | 2002-11-08 | 2006-08-22 | Dov Pharmaceutical, Inc. | Polymorphs of bicifadine hydrochloride |
US20050222146A1 (en) * | 2003-12-15 | 2005-10-06 | Fryer Andrew M | N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof |
US20060223875A1 (en) * | 2005-03-08 | 2006-10-05 | Phil Skolnick | Methods and compositions for production, formulation and use of 1-aryl-3-azabicyclo[3.1.0]hexanes |
US20080269348A1 (en) * | 2006-11-07 | 2008-10-30 | Phil Skolnick | Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use |
US20080293822A1 (en) * | 2006-11-07 | 2008-11-27 | Phil Skolnick | Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use |
US20080122017A1 (en) * | 2006-11-24 | 2008-05-29 | Dongbu Hitek Co., Ltd. | Semiconductor device and fabricating method thereof |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100204486A1 (en) * | 2006-04-28 | 2010-08-12 | Merck & Co., Inc. | Process for the Synthesis of (+)and (-)-1 Aryl-3-Azabicyclo(3.1.0) Hexanes |
WO2015070253A1 (en) * | 2013-11-11 | 2015-05-14 | Euthymics Bioscience, Inc. | Novel methods |
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