EP2280950A1 - Procédé de préparation de sulfamates d'hétéroaryle condensés avec un benzo et forme cristalline de n-((2s)-6-chloro-2,3-dihydro-l,4-benzodioxin- 2-yl) méthylsulfamide - Google Patents
Procédé de préparation de sulfamates d'hétéroaryle condensés avec un benzo et forme cristalline de n-((2s)-6-chloro-2,3-dihydro-l,4-benzodioxin- 2-yl) méthylsulfamideInfo
- Publication number
- EP2280950A1 EP2280950A1 EP08744381A EP08744381A EP2280950A1 EP 2280950 A1 EP2280950 A1 EP 2280950A1 EP 08744381 A EP08744381 A EP 08744381A EP 08744381 A EP08744381 A EP 08744381A EP 2280950 A1 EP2280950 A1 EP 2280950A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- group
- xii
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
- C07D321/02—Seven-membered rings
- C07D321/04—Seven-membered rings not condensed with other rings
- C07D321/08—1,4-Dioxepines; Hydrogenated 1,4-dioxepines
Definitions
- the present invention is directed to a process for the preparation of benzo-fused heteroaryl sulfamates, useful for the treatment of epilepsy and related disorders.
- Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.
- Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy.
- epilepsy is estimated at approximately 0.3 to 0.5 percent in different populations throughout the world, with the prevalence of epilepsy estimated at 5 to 10 people per 1000.
- An essential step in the evaluation and management of a patient with a seizure is to determine the type of seizure that has occurred.
- the main characteristic that distinguishes the different categories of seizures is whether the seizure activity is partial (synonymous with focal) or generalized.
- Partial seizures are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. If consciousness is fully preserved during the seizure, the clinical manifestations are considered relatively simple and the seizure is termed a simple-partial seizure. If consciousness is impaired, the seizure is termed a complex-partial seizure. An important additional subgroup comprises those seizures that begin as partial seizures and then spread diffusely throughout the cortex, which are known as partial seizures with secondary generalization.
- Generalized seizures involve diffuse regions of the brain simultaneously in a bilaterally symmetric fashion. Absence or petit mal seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. Atypical absence seizures typically include a longer duration in the lapse of consciousness, less abrupt onset and cessation, and more obvious motor signs that may include focal or lateralizing features.
- Generalized Tonic- clonic or grand mal seizures the main type of generalized seizures, are characterized by abrupt onset, without warning. The initial phase of the seizure is usually tonic contraction of muscles, impaired respiration, a marked enhancement of sympathetic tone leading to increased heart rate, blood pressure, and pupillary size.
- the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction.
- the periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min.
- the postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause sthdorous breathing and partial airway obstruction.
- Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1-2 s. Consciousness is briefly impaired, but there is usually no postictal confusion.
- Myoclonic seizures are characterized by a sudden and brief muscle contraction that may involve one part of the body or the entire body. (Harrison's Online, March 29, 2001 )
- the present invention is directed to processes for the preparation of compounds of formula (I)
- R 1 is selected from the group consisting of hydrogen and lower alkyl
- R 4 is selected from the group consisting of hydrogen and lower alkyl
- a is an integer from 1 to 2; is selected from the group consisting of
- each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro; provided that when ; or a pharmaceutically acceptable salt thereof.
- the present invention is directed to a process for the preparation of compounds of formula (IA)
- R 1 is hydrogen
- R 4 is selected from the group consisting of hydrogen and lower alkyl
- a is an integer from 1 to 2; is selected from the group consisting of
- each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
- the present invention is further directed to a process for the preparation of a compound of formula (IB)
- R 1 is selected from the group consisting of lower alkyl
- R 4 is selected from the group consisting of hydrogen and lower alkyl
- a is an integer from 1 to 2; is selected from the group consisting of
- each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
- the present invention is directed to a process for the preparation of a compound of formula (I-S)
- the present invention is further directed to a crystalline form of the compound of formula (I-S).
- the present invention is further directed to compounds of formula (XII)
- -C(O )OR 0 is a nitrogen protecting group and wherein a, R 4 and R 1 are as herein defined.
- -C(O)OR 0 is a nitrogen protecting group wherein R 0 is selected from the group consisting of Ci -4 alkyl (preferably t-butyl), benzyl, p-methoxybenzyl and 9-fluorenylmethyl.
- the compounds of formula (XII) are useful as intermediates in the synthesis of the compounds of formula (I).
- the present invention is further directed to a product prepared according to the process described herein.
- Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein.
- An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
- Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
- Exemplifying the invention are methods of treating epilepsy or a related disorder comprising administering to a subject in need thereof, a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
- Figure 1 illustrates a representative XRD Spectra for Crystalline Form of the Compound of Formula (I-S)
- R 1 , R 4 , a a nd are as herein defined.
- the compounds of formula (I) are useful in the treatment of epilepsy and related disorders.
- the present invention is directed to a process for the synthesis of compounds of formula (IA)
- R 1 is h ydrogen, and wherein R 4 , a and are as herein defined; and pharmaceutically acceptable salts thereof.
- the present invention is directed to a process for the preparation of compounds of formula (IB)
- R 1 is selected from the group consisting of lower alkyl
- R 4 , a and are as herein defined; and pharmaceutically acceptable salts thereof.
- the present invention is directed to a process for the synthesis of compounds of formula (IC)
- b and R 5 are as herein defined.
- b is an integer from 0 to 2; more preferably, b is an integer from 0 to 1 .
- R 5 is halogen, more preferably chloro.
- R 1 is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention, R 1 is hydrogen.
- -(CH 2 ) a - is selected from the group consisting of -CH 2 - and -CH 2 -CH 2 -.
- -(CH2) a - is -CH 2 -.
- R 4 is selected from the group consisting of hydrogen and methyl, preferably, R 4 is hydrogen.
- a is 1.
- b is an integer from 0 to 2.
- c is an integer from 0 to 2.
- b is an integer from 0 to 1 .
- c is an integer from 0 to 1.
- the sum of b and c is an integer form 0 to 2, preferably an integer from 0 to 1 .
- b is an integer from 0 to 2 and c is 0.
- a ring structure selected from the group consisting of 2-(chromanyl), 2-(6-chloro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(benzo[1 ,3]dioxolyl), 2-(5-chloro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(7-nitro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6,7-dichloro- 2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(2,3-dihydro-naphtho[2,3-b][1 ,4]dioxinyl) and 2-(7-chloro-benzo[1 ,3]dioxolyl).
- 2-(chromanyl) 2-(6-chloro-2,3-dihydro- benzo[1 ,4]
- a ring structure selected from the group consisting of 2- (5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-nitro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(2,3- dihydro-naphtho[2,3-b][1 ,4]dioxinyl).
- v — ⁇ is selected from the group consisting of 2-(2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(benzo[1 ,3]dioxolyl), 2- (3,4-dihydro-benzo[1 ,4]dioxepinyl), 2-(6-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6-fluoro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(chromanyl), 2-(5-fluoro-2,3- dihydro-benzo[1 ,4]dioxinyl), 2-(7-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6- chloro-benzo[1 ,3]dioxolyl), 2-(7-nitro-2,3-d
- benzo[1 ,4]dioxinyl In another embodiment of the present invention, is selected from the group consisting of 2-(2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7- methyl-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(6-bromo-2,3-dihydro- benzo[1 ,4]dioxinyl).
- R 3 is selected from the group consisting of halogen, lower alkyl, hydroxy substituted lower alkyl, -0-(lower alkyl), nitro, cyano, amino, lower alkylamino and di(lower alkyl)amino. In another embodiment of the present invention R 3 is selected from the group consisting of halogen and nitro. In another embodiment of the present invention R 3 is selected from the group consisting of chloro and nitro.
- R 5 is selected from the group consisting of (II) halogen and lower alkyl. In another embodiment of the present invention R 5 is selected from chloro, fluoro, bromo and methyl.
- (I) is other than wherein b is 1 and R 3 is selected from the group consisting of halogen, nitro, cyano, amino, lower alkyl, lower alkoxy and -C(0)0-(lower alkyl).
- R 3 is selected from the group consisting of halogen, nitro, cyano, amino, lower alkyl, lower alkoxy and -C(0)0-(lower alkyl).
- in the compound of formula (I) is other than
- the stereo-center on the compound of formula (I) is in the S-configuration. In another embodiment of the present invention, the stereo-center on the compound of formula (I) is in the R-configuration.
- the compound of formula (I) is present as an enantiomerically enriched mixture, wherein the % enantiomeric enrichment (%ee) is greater than about 75%, preferably greater than about 85%, more preferably greater than about 90%, more preferably greater than about 95%, most preferably greater than about 98%.
- the present invention is directed to one or more of the representative compounds of formula (I) as listed in Table 1 , below.
- Table 1 the column headed "stereo" defines the stereo-configuration at the carbon atom of the heterocycle attached at the starred bond. Where no designation is listed, the compound was prepared as a mixture of stereo- configurations. Where an “R” or “S” designation is listed, the stereo- configuration was based on the enantiomerically enriched starting material.
- R 1 , R 4 , R 5 , , etc. are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
- the present invention is further directed to compounds of formula (XII)
- -C(O )OR 0 is a nitrogen protecting group and wherein a, R 4 and R 1 are as herein defined.
- the present invention is directed to a compound of formula (XII-S) (XIi-S) wherein -C(O)OR 0 is a nitrogen protecting group.
- -C(O)OR 0 is a nitrogen protecting group wherein R 0 is selected from the group consisting of alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl.
- R 0 is selected from the group consisting of Ci -4 alkyl (preferably t-butyl), benzyl, p- methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl and 9-fluorenylmethyl. More preferably, R 0 is selected from the group consisting of Ci -4 alkyl (preferably t-butyl), benzyl, p-methoxybenzyl and 9-fluorenylmethyl. More preferably still, R 0 is selected from the group consisting of t-butyl, benzyl, p- methoxybenzyl and 9-fluorenylmethyl.
- halogen shall mean chlorine, bromine, fluorine and iodine.
- alkyl whether used alone or as part of a substituent group, includes straight and branched chains.
- alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
- lower when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
- alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
- aryl shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like, preferably phenyl.
- aralkyl shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like.
- aryl group such as phenyl, naphthyl and the like.
- cycloalkyl shall mean any stable monocyclic, bicyclic or polycyclic, saturated ring system, preferably a monocyclic or bicyclic saturated ring system, more preferably a monocyclic saturated ring system.
- Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
- the notation "*" shall denote the presence of a stereogenic center.
- the term “enantiomerically enriched” when used to describe a compound with one stereogenic center shall mean that one stereo-configuration of the compound is present in a greater amount than the opposite stereo-configuration of said compound.
- the desired enantiomer of said compound is present in an enantiomeric excess of at least about 75 percent ee, more preferably at least 85 percent ee, more preferably at least 90 percent ee, more preferably at least 95 percent ee, more preferably at least 98 percent ee, most preferably at least 99 percent ee.
- nitrogen protecting group shall mean any ester group which can act as a protecting group for a amine, amide, sulfamide or sulfanomide nitrogen. Suitable examples include, but are not limited to alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, and the like.
- the nitrogen protecting group may be of the formula - C(O)OR 0 , wherein R 0 is Ci -4 alkyl (preferably t-butyl), benzyl, p-methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl, 9-fluorenylmethyl, and the like, and wherein any of the R 0 groups may be further substituted.
- epilepsy and related disorders shall mean any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and / or tremors.
- Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, and the like), essential tremor, restless limb syndrome, and the like.
- epilepsy including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like
- seizures as a complication of a disease or condition such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epi
- the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome, more preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor.
- subject refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.
- therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
- reaction step(s) in the specification and claims are performed under suitable conditions (e.g. temperature, pressure, with appropriate solvents and/or reactants), according to known methods, to provide the desired product.
- suitable conditions shall mean a reaction step is performed under appropriate conditions (e.g. temperature, pressure, with appropriate solvents and/or reactants) according to known methods to provide the desired product.
- a reagent or reagent class/type/ e.g. base, solvent, etc.
- the individual reagents are independently selected for each reaction step and may be the same of different from each other.
- the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
- aprotic solvent shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
- leaving group shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
- nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
- the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
- the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
- the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
- some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
- some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
- these isomers may be separated by conventional techniques such as preparative chromatography.
- the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartahc acid followed by fractional crystallization and regeneration of the free base.
- an optically active acid such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartahc acid followed by fractional crystallization and regeneration of the free base.
- the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
- any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts. " Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable base (preferably a strong base) such as NaOH, KOH, NaH, chloline hydroxide, and the like.
- a pharmaceutically acceptable base preferably a strong base
- the present invention is directed to a process for the preparation of compounds of formula (I).
- Compounds of formula (IA) (compounds of formula (I) wherein R 1 is hydrogen) may be prepared as outlined in more detail in Scheme 1 , below.
- a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (Xl), wherein -C(O)OR 0 is a suitably selected nitrogen protecting group, for example, an alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, and the like, for example, wherein R 0 is Ci -4 alkyl (preferably t-butyl), benzyl, p-methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl, 9- fluorenylmethyl, and the like, and wherein any of the R 0 groups may be further substituted, a known compound or compound prepared by known methods; in the presence of an organic or inorganic base, wherein the organic or inorganic base is not reactive with the chloro group on the compound of formula (Xl), preferably, an organic base, more preferably a ter
- the compound of formula (XII) is de-protected according to known methods, to yield the corresponding compound of formula (IA). For example, by reacting the compound of formula (XII) with an acid or reacting the compound of formula (XII) with hydrogen or a source of hydrogen.
- the nitrogen protecting group (-C(O)OR 0 ) is BOC
- the compound of formula (XII) is de-protected by reacting with an acid such as TFA, HCI, and the like, preferably HCI; in an organic solvent such as THF, ethyl acetate, and the like.
- the nitrogen protecting group (-C(O)OR 0 ) is benzyl
- the compound of formula (XII) is de-protected by reacting with hydrogen or a source of hydrogen, such as hydrogen gas, in the present of a catalyst such as Pd/C, at a pressure in the range of from about 10 psi to about 60 psi, in an organic solvent such as ethanol, methanol, toluene acetic acid, and the like.
- the compound of formula (XII) is de-protected by reacting with a base such as an amine base such as piperidine, morpholine, and the like, in an organic solvent DMF, and the like.
- a base such as an amine base such as piperidine, morpholine, and the like
- Compounds of formula (IB) (compounds of formula (I) wherein R 1 is selected from the group consisting of lower alkyl) may be prepared according to the process as outlined in Scheme 2, below.
- a suitably substituted compound of formula (XII), prepared as in Scheme 1 above, is reacting with a suitably selected compound of formula (XV), an alkyl halide or alkyl sulfonate, wherein Q is a suitable leaving group such as Cl, Br, I, -0-SO 2 -CH 3 (mesylate) -0-SO 2 -CF 3 (triflate)-O-SO 2 - tolyl (tosylate), and the like; in the presence of an organic or inorganic base such as K 2 CO 3 , Na 2 CO 3 , NaOH, KOH, pyridine, DIPEA, TEA, and the like, preferably a tertiary amine base, more preferably pyridine; in an organic solvent such as THF, acetonithle, DMF, and the like; preferably at a temperature in the range of from about O 0 C to about 50 0 C; to yield the corresponding compound of formula (XVI).
- Q is a suitable leaving
- the compound of formula (XVI) is de-protected according to known methods, to yield the corresponding compound of formula (IB). For example, by reacting the compound of formula (XVI) with an acid or reacting the compound of formula (XVI) with hydrogen or a source of hydrogen.
- the nitrogen protecting group (-C(O)OR 0 ) is BOC
- the compound of formula (XVI) is de-protected by reacting with an acid such as TFA, HCI, and the like, preferably HCI; in an organic solvent such as THF, ethyl acetate, and the like.
- the nitrogen protecting group (-C(O)OR 0 ) is benzyl
- the compound of formula (XVI) is de-protected by reacting with hydrogen or a source of hydrogen, such as hydrogen gas, in the present of a catalyst such as Pd/C, at a pressure in the range of from about 10 psi to about 60 psi, in an organic solvent such as ethanol, methanol, toluene acetic acid, and the like.
- the compound of formula (XVI) is de-protected by reacting with a base such as an amine base such as piperidine, morpholine, and the like, in an organic solvent DMF, and the like.
- the compound of formula (I) is isolated according to known methods, for example by filtration, solvent evaporation, and the like.
- the compound of formula (I) is further purified according to known methods, for example by recrystallization from a suitable solvent such as water, toluene, and the like, preferably toluene.
- the present invention is directed to a process for the preparation of the compound of formula (I-S), as outlined in Scheme 3, below.
- a suitably substituted compound of formula (X-S), also known as C-(6-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-methylamine a known compound, wherein -C(O)OR 0 is a suitably selected nitrogen protecting group, for example, an alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, and the like, for example, wherein R 0 is Ci -4 alkyl (preferably t-butyl), benzyl, p- methoxybenzyl, phenylethyl, phenyl, naphthyl, cycloalkyl, 9-fluorenylmethyl, and the like, and wherein any of the R 0 groups may be further substituted, a known compound or compound prepared by known methods; in the presence of an organic or inorganic base, wherein the organic or inorganic base is not reactive with the chloro group on the compound of
- the compound of formula (XII-S) is de-protected according to known methods, to yield the corresponding compound of formula (I-S). For example, by reacting the compound of formula (XII-S) with an acid or reacting the compound of formula (XII-S) with hydrogen or a source of hydrogen.
- the nitrogen protecting group (-C(O)OR 0 ) is BOC
- the compound of formula (XII-S) is de-protected by reacting with an acid such as TFA, HCI, and the like, preferably HCI; in an organic solvent such as THF, ethyl acetate, and the like.
- the nitrogen protecting group (- C(O)OR 0 ) is benzyl
- the compound of formula (XII-S) is de-protected by reacting with hydrogen or a source of hydrogen, such as hydrogen gas, in the present of a catalyst such as Pd/C, at a pressure in the range of from about 10 psi to about 60 psi, in an organic solvent such as ethanol, methanol, toluene acetic acid, and the like.
- the nitrogen protecting group (- C(O)OR 0 ) is 9-fluorenylmethyl
- the compound of formula (XII-S) is de-protected by reacting with a base such as an amine base such as pipehdine, morpholine, and the like, in an organic solvent DMF, and the like.
- the compound of formula (I-S) is isolated according to known methods, for example by filtration.
- the compound of formula (I-S) is further purified according to known methods, for example by recrystallization from a suitable solvent such as water, toluene, and the like, preferably toluene.
- isocyanatidosulfuryl chloride a known compound
- t-butanol a known compound, wherein the t-butanol is preferably present in about 1 molar equivalent; neat or in an aprotic organic solvent such as, aceotnitrile, ethyl acetate, toluene, and the like, provided that the compound of formula (XIII) and the compound of formula (XIV) are at least partially soluble in the solvent and unreactive to the solvent, preferably neat or in acetonitrile; preferably, at a temperature in the range of from about 0° to about room temperature, morepreferably, at a temperature of about 0 0 C; to yield the corresponding compound of formula (Xl-S), also known as [(1 ,1 - dimethylethoxy)carbonyl]-sulfamoyl chloride.
- aprotic organic solvent such as, aceotnitrile, ethyl acetate, toluene
- the present invention is further directed to a crystalline form of the compound of formula (I-S).
- the crystalline form of the compound of formula (I-S) is further directed to a crystalline form of the compound of formula (I-S).
- the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks have a relative intensity of greater than or equal to about 10% relative intensity; preferably, wherein the peaks have a relative intensity of greater than or equal to about 25% relative intensity.
- the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks are defined by their position (°2 ⁇ ), d-spacing (A) and relative intensity (%).
- the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks are defined by their position (°2 ⁇ ) and d-spacing (A).
- a powder XRD spectra was measured for a representative sample of the crystalline form (I-SA) of the compound of formula (I-S), as shown in Figure 1 , with characteristic peaks as listed in Table 2 below.
- the PXRD spectra were measured using an X-Celerator detector, scanning form 3 to 35°2 ⁇ , at a step size of 0.0165°2 ⁇ , a time per step of 10.16 sec, an effective scan speed of 0.2067°/sec, instrument voltage of 45 kV and a current setting of 40 mA.
- the present invention further comprises pharmaceutical compositions containing one or more of the compounds prepared according to any of the processes described herein with a pharmaceutically acceptable carrier.
- Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
- Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
- the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
- injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
- compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
- any of the usual pharmaceutical media may be employed.
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
- injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
- compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1-1000 mg and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-100 mg/kg/day, or any range therein, more preferably from about 1.0-25.0 mg/kg/day, or any range therein.
- the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post- periodic dosing may be employed.
- compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
- a pharmaceutical carrier e.g.
- a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
- the method of treating epilepsy or a related disorder described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
- the pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg, of the compound, or any range therein, and may be constituted into any form suitable for the mode of administration selected.
- Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
- compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
- forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
- suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
- sterile suspensions and solutions are desired.
- Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
- a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
- Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
- compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
- Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of epilepsy or related disorders is required.
- the daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human per day.
- the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300.0 mg/kg of body weight per day, or any range therein.
- the range is from about 0.5 to about 100.0 mg/kg of body weight per day, or any range therein, more preferably, from about 1.0 to about 25.0 mg/kg of body weight per day, or any range therein.
- the compounds may be administered on a regimen of 1 to 4 times per day.
- Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
- synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
- Hypromellose also known as HPMC or Suspending hydroxypropylmethylcellulose
- an oral composition 100 mg of the compound of formula (I-S), prepared as in Example 7 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
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Abstract
La présente invention concerne un procédé de préparation de sulfamates d'hétéroaryle condensés avec un benzo, utiles pour le traitement de l'épilepsie et autres troubles associés selon la formule (IA) et un composé cristallin de formule (I-S). Un procédé de préparation d'un composé de formule (IA) est également décrit.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/US2008/058233 WO2009120191A1 (fr) | 2008-03-26 | 2008-03-26 | Procédé de préparation de sulfamates d'hétéroaryle condensés avec un benzo et forme cristalline de n-((2s)-6-chloro-2,3-dihydro-l,4-benzodioxin- 2-yl) méthylsulfamide |
Publications (1)
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EP2280950A1 true EP2280950A1 (fr) | 2011-02-09 |
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ID=40030223
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EP08744381A Withdrawn EP2280950A1 (fr) | 2008-03-26 | 2008-03-26 | Procédé de préparation de sulfamates d'hétéroaryle condensés avec un benzo et forme cristalline de n-((2s)-6-chloro-2,3-dihydro-l,4-benzodioxin- 2-yl) méthylsulfamide |
Country Status (14)
Country | Link |
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EP (1) | EP2280950A1 (fr) |
JP (1) | JP2011515464A (fr) |
KR (1) | KR20100126535A (fr) |
CN (1) | CN101981019A (fr) |
AU (1) | AU2008353491A1 (fr) |
BR (1) | BRPI0822454A2 (fr) |
CA (1) | CA2719624A1 (fr) |
CR (1) | CR11761A (fr) |
EA (1) | EA201071120A1 (fr) |
EC (1) | ECSP10010499A (fr) |
IL (1) | IL208222A0 (fr) |
MX (1) | MX2010010595A (fr) |
WO (1) | WO2009120191A1 (fr) |
ZA (1) | ZA201007611B (fr) |
Families Citing this family (9)
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MY147767A (en) | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
CN101754947A (zh) | 2005-05-20 | 2010-06-23 | 詹森药业有限公司 | 磺酰胺衍生物的制备方法 |
US8497298B2 (en) | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US8691867B2 (en) | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US8937096B2 (en) | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
TW200812573A (en) | 2006-05-19 | 2008-03-16 | Janssen Pharmaceutica Nv | Co-therapy for the treatment of epilepsy and related disorders |
EA018567B1 (ru) * | 2008-06-23 | 2013-08-30 | Янссен Фармацевтика Нв | Кристаллическая форма (2s)-(-)-n-(6-хлор-2,3-дигидробензо[1,4]диоксин-2-илметил)сульфамида |
US8815939B2 (en) | 2008-07-22 | 2014-08-26 | Janssen Pharmaceutica Nv | Substituted sulfamide derivatives |
CN107954906B (zh) * | 2017-11-24 | 2020-10-16 | 西北师范大学 | 一种芳基磺酰叔胺类化合物的合成方法 |
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US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
AR049646A1 (es) * | 2004-06-16 | 2006-08-23 | Janssen Pharmaceutica Nv | Derivados de sulfamato y sulfamida utiles para el tratamiento de la epilepsia y trastornos relacionados |
MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
WO2006023861A1 (fr) * | 2004-08-24 | 2006-03-02 | Janssen Pharmaceutica N.V. | Nouveaux composés polyaromatiques de type hétéroarylsulfamide pouvant être employés en tant qu'agents anticonvulsivants |
TW200738669A (en) * | 2006-02-22 | 2007-10-16 | Janssen Pharmaceutica Nv | Crystalline forms of N-(benzo[b]thien-3-ylmethyl)-sulfamide |
-
2008
- 2008-03-26 EP EP08744381A patent/EP2280950A1/fr not_active Withdrawn
- 2008-03-26 MX MX2010010595A patent/MX2010010595A/es unknown
- 2008-03-26 CA CA2719624A patent/CA2719624A1/fr not_active Abandoned
- 2008-03-26 EA EA201071120A patent/EA201071120A1/ru unknown
- 2008-03-26 AU AU2008353491A patent/AU2008353491A1/en not_active Abandoned
- 2008-03-26 KR KR1020107023447A patent/KR20100126535A/ko not_active Application Discontinuation
- 2008-03-26 JP JP2011501761A patent/JP2011515464A/ja not_active Withdrawn
- 2008-03-26 CN CN2008801285434A patent/CN101981019A/zh active Pending
- 2008-03-26 BR BRPI0822454-4A patent/BRPI0822454A2/pt not_active IP Right Cessation
- 2008-03-26 WO PCT/US2008/058233 patent/WO2009120191A1/fr active Application Filing
-
2010
- 2010-09-19 IL IL208222A patent/IL208222A0/en unknown
- 2010-09-24 EC EC2010010499A patent/ECSP10010499A/es unknown
- 2010-10-25 ZA ZA2010/07611A patent/ZA201007611B/en unknown
- 2010-10-26 CR CR11761A patent/CR11761A/es not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO2009120191A1 * |
Also Published As
Publication number | Publication date |
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IL208222A0 (en) | 2010-12-30 |
EA201071120A1 (ru) | 2011-06-30 |
BRPI0822454A2 (pt) | 2015-06-16 |
MX2010010595A (es) | 2010-10-25 |
ZA201007611B (en) | 2012-04-25 |
AU2008353491A1 (en) | 2009-10-01 |
WO2009120191A1 (fr) | 2009-10-01 |
JP2011515464A (ja) | 2011-05-19 |
CN101981019A (zh) | 2011-02-23 |
CA2719624A1 (fr) | 2009-10-01 |
ECSP10010499A (es) | 2010-10-30 |
KR20100126535A (ko) | 2010-12-01 |
CR11761A (es) | 2011-07-06 |
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