KR20100126536A - Processes for the preparation of benzo-fused dioxin derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of benzo-fused heteroaryl derivatives useful for the treatment of epilepsy and related disorders. The invention also relates to a process for the preparation of intermediates in the synthesis of benzo-fused heteroaryl derivatives.

Description

PROCESSES FOR THE PREPARATION OF BENZO-FUSED DIOXIN DERIVATIVES}

The present invention relates to a process for the preparation of benzo-fused heteroaryl derivatives useful for the treatment of epilepsy and related disorders. The invention also relates to a process for the preparation of intermediates in the synthesis of benzo-fused heteroaryl derivatives.

Epilepsy refers to the symptoms of a person who has seizures that recur because of a chronic underlying process. Because of the many causes and forms of epilepsy, epilepsy refers to a clinical phenomenon rather than the presence of a disease. If epilepsy is defined as two or more unexplained seizures, the incidence of epilepsy is estimated to be approximately 0.3 to 0.5 percent in other communities throughout the world, and the prevalence of epilepsy is estimated to be 5 to 10 people per 1000 people.

An essential step in the evaluation and management of seizure patients is to determine the type of seizures that have occurred. The main characteristic that distinguishes different categories of seizures is whether the seizure activity is partial (synonymous with focal) or generalized seizure.

Partial seizures are seizures in which seizure activity is confined to discrete regions of the cerebral cortex. If consciousness is fully maintained during seizures, clinical findings are considered fairly simple, and seizures are called simple-partial seizures. If consciousness is lost, the seizure is called a compound-partial seizure. An important additional subgroup includes seizures that begin with partial seizures and then spread and spread throughout the cortex, which is known as partial seizures with secondary prevalence.

A generalized seizure involves diffuse areas of the brain at the same time in a symmetrical manner. Absence or petit mal seizure is characterized by a sudden, brief loss of consciousness, without loss of postural control. Atypical syncope seizures typically include more pronounced motor symptoms that may include longer periods of loss of consciousness, less sudden onset and discontinuation, and focus or deflection patterns. A major type of generalized seizure, generalized tonic-clonic seizure or grand mal seizure, is characterized by sudden onset without warning. The initial state of seizures is usually a marked increase in sympathetic nervous system that causes muscle tonic contraction, shortness of breath, heart rate, blood pressure and pupil size increase. After 10 to 20 seconds, the seizure state of seizures typically develops into a myoclonic state produced by overlapping muscle relaxation periods in tension muscle contractions. The relaxation period gradually increases until the end of the seizure state, which typically lasts up to one minute. The post-seizure condition is characterized by hyperresorption, which can cause irresponsiveness, muscle relaxation and grunting breathing and partial airway obstruction. Armless seizures are characterized by a sudden loss of postural muscle tension lasting 1 to 2 seconds. Consciousness is temporarily lost, but usually there is no confusion after the seizure. Myoclonic seizure is characterized by a sudden brief muscle contraction that may involve part or all of the body. (harrisonsonline.com, March 29, 2001)

McComsey, D. et al. In US 2006/0041008 A1 published February 23, 2006 and McComsey, D. et al. In US Patent Publication 2005/0282887 A1 published December 22, 2005 are formulas of The compounds of (I) and their use in the treatment of epilepsy and related disorders are disclosed. McComsey, D. et al. In US 2006/0041008 A1 and McComsey, D. et al. In US 2005/0282887 A1 are formulas that include reacting sulfamide with suitably substituted amines ( Further disclosed are methods for preparing the compounds of I).

In the method (s) disclosed by McComsey D. et al., Compounds of formula (I), wherein R ¹ and R ² are each hydrogen, describe the use of sulfamoyl chloride (Cl-SO ₂ -NH ₂ ) as a reagent, which reagent Is not suitable for large scale / commercial manufacturing. However, there is a need for methods suitable for the preparation of large scale materials and / or commercial preparation of compounds of formula (I).

가

및

로 이루어진 군으로부터 선택되는 화학식 (X)의 화합물을 보호하여; Pg¹이 알콜 보호기인 화학식 (XI)의 상응하는 화합물을 생성하고;The present invention

end

And

Protecting a compound of formula (X) selected from the group consisting of: To yield the corresponding compound of formula (XI) wherein Pg ¹ is an alcohol protecting group;

The compound of formula (XI) in the presence of an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII);

The compound of formula (XII) in an organic solvent, in a mixture of organic solvents, or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII);

The compound of formula (XIII) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XIV);

Deprotecting the compound of formula (XIV); To yield the corresponding compound of formula (XV);

The compound of formula (XV) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (V);

By reacting a compound of formula (V); To a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising producing the corresponding compound of formula (I):

Where

은

로 이루어진 군으로부터 선택되며;

silver

It is selected from the group consisting of;

Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;

Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro;

R ⁴ is selected from the group consisting of hydrogen and lower alkyl;

R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl.

The present invention also provides protection of a compound of formula (X); To yield the corresponding compound of formula (XI) wherein Pg ¹ is an alcohol protecting group;

The compound of formula (XI) in the presence of an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII);

The compound of formula (XII) in an organic solvent, in a mixture of organic solvents, or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII);

The compound of formula (XIII) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XIV);

Deprotecting the compound of formula (XIV); To yield the corresponding compound of formula (XV);

The compound of formula (XV) in an organic solvent; By reaction with an organic or inorganic base; To a process for the preparation of a compound of formula (V) comprising producing the corresponding compound of formula (V):

Where

는

및

로 이루어진 군으로부터 선택되고;

Is

And

≪ / RTI >

Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;

Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro.

In one embodiment, the present invention is directed to protecting a compound of formula (XS); To yield the corresponding compound of formula (XI-S) wherein Pg ¹ is an alcohol protecting group;

The compound of formula (XI-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII-S);

The compound of formula (XII-S) in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII-S);

The compound of formula (XIII-S) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XIV-S);

Deprotecting the compound of formula (XIV-S); To yield the corresponding compound of formula (XV-S);

The compound of formula (XV-S) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (V-S);

By reacting a compound of formula (V-S); A compound of formula (IS) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IS) also comprises N-[[(2S) -6 -Chloro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl] -sulphamide).

In another embodiment, the present invention provides protection of a compound of formula (XS); To yield the corresponding compound of formula (XI-S) wherein Pg ¹ is an alcohol protecting group;

The compound of formula (XI-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII-S);

The compound of formula (XII-S) in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII-S);

The compound of formula (XIII-S) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XIV-S);

Deprotecting the compound of formula (XIV-S); To yield the corresponding compound of formula (XV-S);

The compound of formula (XV-S) in an organic solvent; By reaction with an organic or inorganic base; Formula (also known as (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl)- (S) -methanol, comprising producing the corresponding compound of formula (VS) To a process for the preparation of the compound of VS):

가

및

로 이루어진 군으로부터 선택되며; Q가 -C(O)-(C_{1 - 4}알킬)로 이루어진 군으로부터 선택되는 화학식 (XVI)의 화합물을 무기 염기의 존재 하에; 약 실온보다 높은 온도에서; 유기 용매 중에서; 에폭시-메틸렌의 공급원과 반응시켜; 화학식 (XVII)의 상응하는 화합물을 생성하고;The invention also

end

And

It is selected from the group consisting of; Q is -C (O) - of a compound of formula (XVI) is selected from the group consisting of _- (C _{1 4} alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XVII);

The compound of formula (XVII) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII);

The compound of formula (XVIII) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (V);

By reacting a compound of formula (V); To a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising producing the corresponding compound of formula (I):

Where

은

및

로 이루어진 군으로부터 선택되고;

silver

And

≪ / RTI >

Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;

Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro;

R ⁴ is selected from the group consisting of hydrogen and lower alkyl;

R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl.

The invention also Q is -C (O) - of a compound of formula (XVI) is selected from the group consisting of _- (C _{1 4} alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XVII);

The compound of formula (XVII) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII);

The compound of formula (XVIII) in an organic solvent; By reaction with an organic or inorganic base; A process for the preparation of a compound of formula (V), comprising producing the corresponding compound of formula (V):

Where

는

및

로 이루어진 군으로부터 선택되고;

Is

And

≪ / RTI >

Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;

Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro.

In one embodiment, the present invention Q is -C (O) - of a compound of formula (XVI-S) is selected from the group consisting of _- (C _{1 4} alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XVII-S);

The compound of formula (XVII-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII-S);

The compound of formula (XVIII-S) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (V-S);

By reacting a compound of formula (V-S); A compound of formula (IS) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IS) also comprises N-[[(2S) -6 -Chloro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl] -sulphamide).

In another embodiment, the present invention provides a compound of formula (XVI-S) wherein Q is selected from the group consisting of -C (O)-(C _1-4 alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XVII-S);

The compound of formula (XVII-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII-S);

The compound of formula (XVIII-S) in an organic solvent; By reaction with an organic or inorganic base; Formula (also known as (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl)- (S) -methanol, comprising producing the corresponding compound of formula (VS) To a process for the preparation of the compound of VS):

The invention also relates to the crystalline form of the compound of formula (I-S):

[Formula I-S]

.

.

In one embodiment, the present invention relates to crystalline forms (I-SA) as defined below. In another embodiment, the present invention relates to crystalline form (I-SB) as defined below.

The invention also relates to products produced according to any of the methods described herein.

An example of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a product prepared according to any of the crystalline forms described herein or any method described herein. Exemplary of the invention is a pharmaceutical composition prepared by mixing any crystalline form described herein or a product prepared according to any method described herein and a pharmaceutically acceptable carrier. An example of the present invention is a process for the preparation of a pharmaceutical composition comprising mixing any crystalline form described herein or a product prepared according to any of the methods described herein and a pharmaceutically acceptable carrier.

Exemplary of the invention is a method of treating epilepsy or related disorders comprising administering a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above to a subject in need thereof.

Brief description of the drawings

<Figure 1>

1 shows representative XRD spectra for representative samples of crystalline form (I-SA) (labeled b and c) and crystalline form (I-SB) (labeled a).

The present invention relates to a process for the preparation of compounds of formula (I):

[Formula I]

은 본 명세서에서 정의된 바와 같다. 본 발명의 화합물은 간질 및 관련 장애의 치료에 유용하다.Wherein R ¹ , R ² , R ⁴ and

Is as defined herein. Compounds of the invention are useful for the treatment of epilepsy and related disorders.

The invention also relates to a process for the preparation of a compound of formula (V) which may be represented herein by one of the following formulas:

Compounds of formula (V) are useful as intermediates in the synthesis of compounds of formula (I).

In one embodiment, the invention relates to a process for the preparation of a compound of formula (I-S) or a pharmaceutically acceptable salt thereof:

[Formula I-S]

In another embodiment, the present invention relates to a process for the preparation of a compound of formula (V-S):

[Formula V-S]

In one embodiment, the present invention relates to a method for synthesizing a compound of formula (I-A) and a pharmaceutically acceptable salt thereof:

[Formula I-A]

Wherein b and R ⁵ are as defined herein. Preferably, b is an integer from 0 to 2; More preferably, b is an integer of 0-1. Preferably, R ⁵ is halogen, more preferably R ⁵ is chloro.

In one embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ¹ and R ² are each hydrogen or R ¹ and R ² are each methyl.

In one embodiment of the invention, R ⁴ is selected from the group consisting of hydrogen and methyl, preferably R ⁴ is hydrogen.

In one embodiment of the present invention, b is an integer of 0 to 2. In another embodiment of the invention, c is an integer from 0 to 2. In another embodiment of the invention, b is an integer from 0 to 1. In another embodiment of the invention, c is an integer from 0 to 1. In another embodiment of the invention, the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1. In another embodiment of the invention, b is an integer from 0 to 2 and c is 0.

In one embodiment of the invention, R ⁵ is selected from the group consisting of halogen and lower alkyl. In another embodiment of the invention, R ⁵ is selected from chloro, fluoro, bromo and methyl.

은

및

로 이루어진 군으로부터 선택되는 고리 구조이다. 본 발명의 또다른 실시형태에 있어서,In one embodiment of the present invention,

silver

And

It is a ring structure selected from the group consisting of. In another embodiment of the present invention,

은

로 이루어진 군으로부터 선택된다.

silver

Choose from a group consisting of:

은 2-(6-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(5-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-니트로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6,7-다이클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐) 및 2-(2,3-다이하이드로-나프토[2,3-b][1,4]다이옥시닐)로 이루어진 군으로부터 선택되는 고리 구조이다. 본 발명의 또다른 실시형태에 있어서,

은 2-(5-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-니트로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6,7-다이클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐) 및 2-(2,3-다이하이드로-나프토[2,3-b][1,4]다이옥시닐)로 이루어진 군으로부터 선택되는 고리 구조이다.In one embodiment of the present invention,

Silver 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxyl), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxyl) , 2- (7-nitro-2,3-dihydro-benzo [1,4] dioxyyl), 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] di Oxynyl) and 2- (2,3-dihydro-naphtho [2,3-b] [1,4] dioxylyl). In another embodiment of the present invention,

Silver 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxyl), 2- (7-nitro-2,3-dihydro-benzo [1,4] dioxyl) , 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxyyl) and 2- (2,3-dihydro-naphtho [2,3-b] [1 , 4] dioxyyl)).

은 2-(2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6-플루오로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(5-플루오로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-니트로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-메틸-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(5-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6-브로모-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6,7-다이클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(8-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐) 및 2-(2,3-다이하이드로-나프토[2,3-b][1,4]다이옥시닐)로 이루어진 군으로부터 선택된다.In one embodiment of the present invention,

Silver 2- (2,3-dihydro-benzo [1,4] dioxyyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxyl), 2- ( 6-fluoro-2,3-dihydro-benzo [1,4] dioxyyl), 2- (5-fluoro-2,3-dihydro-benzo [1,4] dioxyyl), 2 -(7-chloro-2,3-dihydro-benzo [1,4] dioxyl), 2- (7-nitro-2,3-dihydro-benzo [1,4] dioxyl), 2 -(7-methyl-2,3-dihydro-benzo [1,4] dioxyyl), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxyyl), 2 -(6-bromo-2,3-dihydro-benzo [1,4] dioxyyl), 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxy Yl), 2- (8-chloro-2,3-dihydro-benzo [1,4] dioxyyl) and 2- (2,3-dihydro-naphtho [2,3-b] [1, 4] dioxylyl).

은 2-(2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-메틸-2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(6-브로모-2,3-다이하이드로-벤조[1,4]다이옥시닐) 및 2-(6,7-다이클로로-2,3-다이하이드로-벤조[1,4]다이옥시닐)로 이루어진 군으로부터 선택된다. 본 발명의 또다른 실시형태에 있어서,

은 2-(2,3-다이하이드로-벤조[1,4]다이옥시닐), 2-(7-메틸-2,3-다이하이드로-벤조[1,4]다이옥시닐) 및 2-(6-브로모-2,3-다이하이드로-벤조[1,4]다이옥시닐)로 이루어진 군으로부터 선택된다.In another embodiment of the present invention,

Silver 2- (2,3-dihydro-benzo [1,4] dioxyyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxyl), 2- ( 7-chloro-2,3-dihydro-benzo [1,4] dioxyyl), 2- (7-methyl-2,3-dihydro-benzo [1,4] dioxyyl), 2- ( 6-bromo-2,3-dihydro-benzo [1,4] dioxyl) and 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxyl) It is selected from the group consisting of. In another embodiment of the present invention,

Silver 2- (2,3-dihydro-benzo [1,4] dioxyyl), 2- (7-methyl-2,3-dihydro-benzo [1,4] dioxyyl) and 2- ( 6-bromo-2,3-dihydro-benzo [1,4] dioxylyl).

In one embodiment of the invention, the stereogenic center on the compound of formula (I) is an S-configuration. In another embodiment of the invention, the stereogenic center on the compound of formula (I) is R-configuration.

In one embodiment of the invention, the compound of formula (I) is present in 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%, even more preferably greater than about 98%, most preferably greater than about 98%.

Representative compounds of the invention are as listed in Tables 1 and 2 below. In Tables 1 and 2 below, the "stereo" at the beginning of the vertical row is defined as the steric arrangement at the carbon atom of the heterocycle attached to the starred bond. If nomenclature is stated, the compound is prepared in a mixture of steric configurations. If the "R" or "S" nomenclature is described, the conformation is based on the enantiomerically enriched starting material.

In a further embodiment of the present invention, substituents selected for one or more variables defined herein (ie, R ¹ , R ² , R ⁴ , b and R ^5, etc.) are selected from the complete list defined herein. Included are embodiments that are independently selected to be any individual substituent or any subset of substituents.

Unless otherwise indicated, the term "halogen" as used herein will mean chlorine, bromine, fluorine and iodine.

Unless indicated otherwise, the term "alkyl" as used herein, whether used alone or as part of a substituent, includes straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise indicated, "lower" used with alkyl means a carbon chain composition of 1 to 4 carbon atoms.

Unless otherwise indicated, "alkoxy" as used herein will represent the oxygen ether radicals of the straight or branched chain alkyl groups described above. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.

The symbol "*" as used herein will indicate the presence of a stereogenic center.

Unless otherwise indicated, the term “enantiomerically rich” as used herein, when used to describe a compound having one stereogenic center, means that one stereo-array of the compound is the opposite stereotype of the compound. It will mean that it is present in greater amounts than the array. Preferably, when the compound is said to be enantiomerically rich, the preferred enantiomer of the compound is at least about 75% ee, more preferably at least 85% ee, more preferably at least 90% ee, more preferably Is in an enantiomeric excess of at least 95% ee, even more preferably at least 98% ee, most preferably at least 99% ee.

Abbreviations used in the present specification, particularly in schemes and examples, are as follows:

Unless otherwise indicated, the terms “epilepsy and related disorders” or “epilepsy or related disorders” as used herein refer to a subject (preferably an adult human, child or infant) experiencing one or more seizures and / or tremors. It will mean any disorder. Suitable examples include epilepsy (including but not limited to topical-related epilepsy, systemic epilepsy, epilepsy with both systemic and local epilepsy), epilepsy as a complication of a disease or condition (eg encephalopathy, phenylketonuria, pediatric Goche disease, Lundborg progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, epilepsy associated with drug use or withdrawal, alcohol use or withdrawal, sleep deprivation), tremor, restless limb syndrome, etc. It is not limited to this. Preferably, the disorder is selected from epilepsy (regardless of type, root cause or origin), tremor or limb anxiety syndrome, more preferably the disorder is epilepsy (regardless of type, root cause or origin) or tremor .

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the subject of a treatment, observation, or experiment, or has been the subject of a treatment, observation, or experiment.

As used herein, the term “therapeutically effective amount” means biological or in a tissue system, animal or human pursued by a researcher, veterinarian, medical doctor or other clinician, including alleviating the symptoms of the disease or disorder being treated. The amount of active compound or medicament that results in a medical response.

The term "composition" as used herein is intended to include not only products comprising a particular amount of a particular component, but also any product resulting directly or indirectly from a combination of a particular amount of a particular component.

Those skilled in the art will appreciate that the reaction step (s) within the description and claims, in accordance with known methods, are carried out under appropriate conditions (such as temperature, pressure, appropriate solvents and / or reactants) to provide the desired product, unless stated otherwise. It will be recognized that it is performed under. The term "appropriate conditions" will mean that the reaction step is carried out under appropriate conditions (such as temperature, pressure, suitable solvents and / or reactants) according to known methods in order to provide the desired product.

Those skilled in the art will appreciate that within the description and claims set forth herein, if a reagent or reagent classification / type / (eg, base, solvent, etc.) is described in more than one step of the process, the individual reagents may be reacted with each reaction. It will be appreciated that the steps may be selected independently and may be the same or different from each other. For example, if two steps of the process refer to an organic or inorganic base as a reagent, 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.

To provide a more accurate description, some of the quantitative expressions given herein are not limited to the term "about." Whether the term "about" is used explicitly or not, it is meant that all amounts given herein are actually referring to a given value, and also for any given value reasonably inferred based on conventional techniques in the art. It is understood that it is meant to refer to an approximation, including approximations due to experimental and / or measurement conditions for such a given value.

As used herein, unless otherwise indicated, the term “aprotic solvent” shall mean any solvent that does not produce protons. Suitable examples include, but are not limited to, DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.

As used herein, unless otherwise indicated, the term "leaving group" shall mean a charged or uncharged atom or group that is released during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise indicated, the term "nitrogen protecting group" means a group that can be attached to a nitrogen atom and easily removed after the reaction to protect the nitrogen atom from participating in the reaction. something to do. Suitable nitrogen protecting groups include groups of the carbamate—formula —C (O) OR where R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH ₂ ═CH—CH ₂ —, and the like. ; Amides-groups of the formula -C (O) -R, wherein R is for example methyl, phenyl, trifluoromethyl and the like; N-sulfonyl derivatives-formula -SO ₂ -R "(where R" is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl -, 2,3,6-trimethyl-4-methoxybenzene, etc.), but is not limited thereto. Other suitable nitrogen protecting groups can be found in textbooks such as TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Unless otherwise indicated, the term "alcohol protecting group" as used herein may be attached to the oxygen of the hydroxyl group (OH) to protect it from participating in the reaction, and may be readily removed after the reaction. It will mean a group that can. Suitable alcohol protecting groups include but are not limited to t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, ethoxyethyl, THP, SEM, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, allyl, and the like. Does not. Other suitable alcohol protecting groups are described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is hereby incorporated by reference in its entirety.

If the compounds according to the invention have at least one chiral center, they can therefore exist as enantiomers. If the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the present invention. Preferably, when the compound is present as an enantiomer, the enantiomer is present in an enantiomeric excess of at least about 75%, more preferably the enantiomer is at least about 85% enantiomeric excess, more preferably about At least 90% enantiomeric excess, more preferably at least about 95% enantiomeric excess, even more preferably at least about 98% enantiomeric excess, most preferably at least about 99% enantiomeric excess. Similarly, when the compound is present as a diastereomer, the diastereomer is at least about 75% diastereomeric excess, more preferably at least about 85% diastereomeric excess, more preferably at least about 90% There is a diastereomeric excess, more preferably at least about 95% of the diastereomeric excess, more preferably at least about 98% of the diastereomeric excess, most preferably at least about 99% of the diastereomeric excess. .

In addition, some of the crystalline forms for the compounds of the present invention may exist as polymorphs, and such forms are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates (ie, hydrates) with water, or solvates with common organic solvents, which solvates are also intended to be within the scope of the present invention.

Those skilled in the art will recognize that the reaction step of the present invention may be carried out in a variety of solvents or solvent systems, which reaction may also be carried out in a mixture of suitable solvents or solvent systems.

If the process for the preparation of the compounds according to the invention results in a mixture of stereoisomers, 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 by enantiomer specific synthesis or by cleavage. Compounds may be prepared using standard techniques, for example optically active acids such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid. The formation of the salts used and the formation of diastereomeric pairs by fractional crystallization and regeneration of the free base can then be broken down into their constituent enantiomers. The compounds may also be cleaved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of chiral aids. Alternatively, the compound can be partitioned using a chiral HPLC column.

In any of the methods of preparing the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This is described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; And in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, by means of conventional protecting groups. The protecting group can be removed in a convenient subsequent step using methods known in the art.

For use in medicine, salts of the compounds of the present invention refer to nontoxic "pharmaceutically acceptable salts". However, other salts may be useful for the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable base (preferably a strong base), such as NaOH, KOH, NaH, choline hydroxide, etc. Acid addition salts are included.

The present invention relates to a process for the preparation of compounds of formula (V) as described in more detail in Scheme 1 below.

Scheme 1

Thus, known compounds or compounds prepared by known methods,

로 이루어진 군으로부터 선택되는 화학식 (X)의 적절하게 치환된 화합물은 바람직하게는 약 1 몰 당량 이상의 양, 더욱 바람직하게는 과량으로 존재하는 유기 또는 무기 염기, 이를 테면 K₂CO₃, Na₂CO₃, Cs₂CO₃, 테트라메틸구아니딘, TEA 등의 존재 하에; 바람직하게는 K₂CO₃의 존재 하에; 약 실온보다 높은 온도, 바람직하게는 약 40℃ 내지 약 100℃ 범위의 온도, 더욱 바람직하게는 약 60℃ 내지 약 80℃ 범위의 온도, 가장 바람직하게는 약 60℃의 온도에서; 유기 용매, 이를 테면 DMF, THF, N-메틸피롤리돈 등 중에서; 벤질 브로마이드, 알릴 브로마이드, 2-(트라이메틸실릴)에톡시메틸 클로라이드 (SEM-Cl), t-부틸-다이페닐실릴 클로라이드, 메톡시 또는 니트로-치환된 벤질 브로마이드 (예컨대, 4-니트로-벤질 브로마이드, 4-메톡시벤질 브로마이드 등), 1-(C_1-4알콕시)메틸 할라이드 또는 1-(C_1-4알콕시)에틸 할라이드 (여기에서, 할라이드는 Cl, Br 또는 I (예컨대 MOM-Cl, 에톡시에틸클로라이드 등)이다) 등과 같은 적절한 보호제 (즉, 이후의 반응 조건, 예컨대 가수분해, 산화 하에서 안정한 보호제)와의 반응에 의하여 보호되어; Pg¹이 상응하는 알콜 보호기인 화학식 (XI)의 상응하는 화합물을 생성한다. 예를 들어, 보호제가 벤질 브로마이드인 경우, Pg¹은 벤질이며; 보호제가 알릴 브로마이드인 경우, Pg¹은 알릴이고; 보호제가 MOM-Cl인 경우, Pg¹은 메톡시 메틸 에테르 (MOM)이다. 당업자는 부가적 보호기 및 상기 보호기의 도입방법이 예컨대 본 명세서에 그 전체가 참고로 인용되는 문헌[T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991]에 기술된 바와 같이 해당 분야에 공지임을 인식할 것이다.end

Suitably substituted compounds of formula (X) selected from the group consisting of are preferably organic or inorganic bases present in an amount of at least about 1 molar equivalent, more preferably in excess, such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , tetramethylguanidine, TEA and the like; Preferably in the presence of K ₂ CO ₃ ; At a temperature above about room temperature, preferably in the range of about 40 ° C. to about 100 ° C., more preferably in the range of about 60 ° C. to about 80 ° C., and most preferably at a temperature of about 60 ° C .; In an organic solvent such as DMF, THF, N-methylpyrrolidone and the like; Benzyl bromide, allyl bromide, 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), t-butyl-diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromide (eg 4-nitro-benzyl bromide , 4-methoxybenzyl bromide and the like), 1- (C _1-4 alkoxy) methyl halide or 1- (C _1-4 alkoxy) ethyl halide (where the halide is Cl, Br or I (eg MOM-Cl, Protected by reaction with a suitable protecting agent (ie, a protecting agent that is stable under subsequent reaction conditions such as hydrolysis, oxidation); To yield the corresponding compound of formula (XI), wherein Pg ¹ is the corresponding alcohol protecting group. For example, when the protective agent is benzyl bromide, Pg ¹ is benzyl; When the protective agent is allyl bromide, Pg ¹ is allyl; If the protective agent is MOM-Cl, Pg ¹ is methoxy methyl ether (MOM). Those skilled in the art will appreciate that additional protecting groups and methods of introducing such protecting groups are described, for example, in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is hereby incorporated by reference in its entirety. It will be appreciated that this is well known in the art.

The compound of formula (XI) can be used in an organic solvent such as DCE, DCM, chloroform, acetonitrile, NMP and the like, preferably DCM; Preferably at about room temperature; Appropriately selected oxidizing agents, such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate, etc., which are present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents, preferably m- In response to CPBA; To yield the corresponding compound of formula (XII).

The compound of formula (XII) is in an organic solvent or mixture thereof, such as methanol, ethanol, propanol, a mixture of THF and alcohol, or the like, or in a mixture of one or more organic solvents and water; Preferably in alcohol, more preferably in methanol; Preferably at a temperature in the range from about room temperature to about reflux temperature, more preferably at about room temperature; Preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 2 to about 3 molar equivalents, such as NaOCH ₃ , Kt-butoxide, sodium carbonate , Potassium bicarbonate, and the like, preferably by reaction with NaOCH ₃ ; To yield the corresponding compound of formula (XIII).

The compound of formula (XIII) is preferably an inorganic base present in an amount of at least about 1 molar equivalent, more preferably in excess, such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc. Preferably in the presence of K ₂ CO ₃ ; At a temperature above about room temperature, preferably at a temperature ranging from about room temperature to about 100 ° C., more preferably at a temperature in a range from about 40 ° C. to about 60 ° C., most preferably at a temperature of about 40 ° C .; In an organic solvent such as DMF, THF, N-methylpyrrolidinone, etc., preferably DMF; preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in a range from about 1 to about 2 molar equivalents Epoxy-methylene (ie, present in an amount ranging from about 1.1 to about 1.5 molar equivalents)

)의 공급원, 이를 테면 글리시딜-m-노실레이트, 글리시딜-토실레이트, 에피클로로하이드린, 에피브로모하이드린 등, 바람직하게는 글리시딜-m-노실레이트 또는 글리시딜-토실레이트, 바람직하게는 에폭시-메틸렌의 거울상이성체적으로 풍부한 공급원, 더욱 바람직하게는 (R)-글리시딜-m-노실레이트 또는 (R)-글리시딜-토실레이트와 반응하여; 화학식 (XIV)의 상응하는 화합물을 생성한다.

), Such as glycidyl- m -nosylate, glycidyl-tosylate, epichlorohydrin, epibromohydrin and the like, preferably glycidyl- m -nosylate or glycidyl- Reacting with an enantiomerically rich source of tosylate, preferably an epoxy-methylene, more preferably with (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate; To yield the corresponding compound of formula (XIV).

Compounds of formula (XIV) are deprotected according to known methods to yield the corresponding compounds of formula (XV). For example, in compounds of formula (XIV) where Pg ¹ is benzyl, allyl, etc., compounds of formula (XIV) may be selected from ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl-t-butyl ether, ethanol and the like. In the same organic solvent; Deprotection by reaction with hydrogen or a hydrogen source, preferably at a pressure ranging from about 10 psi to about 15 psi, in the presence of a catalyst such as Pd / C, Pt, Pd (sulfide) / C, etc. Can be. When Pg ¹ is an SEM or silyl protecting group, the compound of formula (XIV) may be deprotected by reaction with a source of fluoride such as tetrabutylammonium fluoride or the like in an organic solvent such as THF or the like. Those skilled in the art will recognize that additional methods for removing protective groups are known in the art, as described, for example, in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Those skilled in the art will recognize that the reagent (s) selected for deprotection of the compound of formula (XIV) are selected to be substantially non-reactive with the epoxy groups on the compound of formula (XIV).

The compound of formula (XV) may be used in an organic solvent such as methanol, ethanol, THF, acetonitrile and the like, preferably methanol; Preferably at about room temperature; Preferably with an organic or inorganic base present in an amount of at least about 1 molar equivalent, more preferably in excess, such as NaOCH ₃ , Kt-butoxide, sodium carbonate, etc., preferably NaOCH ₃ ; To yield the corresponding compound of formula (V).

Those skilled in the art will recognize that when the source of epoxy-methylene is enantiomerically enriched in one of the enantiomers, upon ring opening of the epoxide, the compound of formula (V) is prepared with the corresponding enantiomerically enriched compound. For example, when enantiomerically enriched (R ) -glycidyl-m-nosylate or (R) -glycidyl tosylate is reacted with a compound of formula (XIII), The method produces the corresponding compound of formula (V) as an enantiomerically enriched (S) enantiomer at the ("*") position of the asterisk.

[Formula V]

Preferably, the method described in Scheme 1 above applies to the preparation of compounds of formula (V) in which each of R ⁵ is not nitro. Those skilled in the art will appreciate that when at least one R ⁵ group is nitro, the compound of formula (V) reacts the hydrogen (s) according to known methods, for example with a mixture of nitric acid and sulfuric acid, a mixture of nitric acid and acetic acid or potassium nitrate And by reacting with sulfuric acid to convert to the corresponding nitro group (s), it will be appreciated that one or more nitro groups can be prepared from the corresponding compound of formula (V) wherein the substituent at the required position is hydrogen.

The invention also relates to a process for the preparation of the compound of formula (V) as described in more detail in Scheme 2 below.

Scheme 2

)의 공급원, 이를 테면 글리시딜-m-노실레이트, 글리시딜-토실레이트, 에피클로로하이드린, 에피브로모하이드린 등, 바람직하게는 글리시딜-m-노실레이트 또는 글리시딜-토실레이트, 바람직하게는 에폭시-메틸렌의 거울상이성체적으로 풍부한 공급원, 더욱 바람직하게는 (R)-글리시딜-m-노실레이트 또는 (R)-글리시딜-토실레이트와 반응하여; 화학식 (XVII)의 상응하는 화합물을 생성한다.Thus, a known compound or a compound prepared by a known method, Q is -C (O) - is selected from the group consisting of (C _1-4 alkyl, where, C _{1 - 4} alkyl is preferably a primary (primary) C _{1 - 4} alkyl, more preferably -C (O) -CH ₃ or the like of the compound appropriately substituted formula (XVI) is preferably in an amount of at least about one molar equivalent, and more preferably present in an excess In the presence of an inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc., preferably K ₂ CO ₃ ; a temperature higher than about room temperature, preferably from about room temperature to about At a temperature in the range of 100 ° C., more preferably at a temperature in the range of about 40 ° C. to about 60 ° C., most preferably at about 40 ° C .; organic solvents such as DMF, THF, N-methylpyrrolidinone, and the like. Preferably in DMF; preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably from about 1 to about Epoxy-methylene (ie, present in an amount ranging from 2 molar equivalents, more preferably from about 1.1 to about 1.5 molar equivalents)

), Such as glycidyl- m -nosylate, glycidyl-tosylate, epichlorohydrin, epibromohydrin and the like, preferably glycidyl- m -nosylate or glycidyl- Reacting with an enantiomerically rich source of tosylate, preferably an epoxy-methylene, more preferably with (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate; To yield the corresponding compound of formula (XVII).

The compound of formula (XVII) may be in an organic solvent such as DCE, DCM, chloroform, acetonitrile, NMP and the like, preferably DCM; Preferably at about room temperature; Suitably selected oxidizing agents, such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate, etc., which are present in at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents, preferably m-CPBA In response; To yield the corresponding compound of formula (XVIII). When Q is -C (O)-(CH ₃ ), the compound of formula (XVII) reacts under conditions other than monomagnesium peroxyphthalate in DMF.

The compound of formula (XVIII) may be selected from organic solvents such as methanol, ethanol, THF, acetonitrile and the like, preferably methanol; Preferably at about room temperature; Preferably with an organic or inorganic base present in an amount of at least about 1 molar equivalent, more preferably in excess, such as NaOCH ₃ , Kt-butoxide, sodium carbonate, etc., preferably NaOCH ₃ ; To yield the corresponding compound of formula (V).

Those skilled in the art will recognize that when the source of epoxy-methylene is enantiomerically enriched in one of the enantiomers, upon ring opening of the epoxide, the compound of formula (V) is prepared with the corresponding enantiomerically enriched compound. For example, when enantiomerically enriched (R ) -glycidyl-m-nosylate or ( R ) -glycidyl tosylate is reacted with a compound of formula (XIII), The method produces the corresponding compound of formula (Va) as the enantiomerically enriched (S) enantiomer at the ("*") position of the asterisk.

[Formula V]

Compounds of formula (V) may be prepared by known methods (e.g., McComsey, D. et al. In US 2006/0041008 A1 published February 23, 2006; US patent published December 22, 2005). In accordance with publication US 2005/0282887 A1, as disclosed by McComsey, D. et al., To produce the corresponding compounds of formula (I).

For example, compounds of formula (I) wherein R ⁴ is hydrogen can be prepared according to the procedure outlined in Scheme 3.

Scheme 3

Thus, for example, suitably substituted compounds of formula (V), which are compounds prepared as summarized in Schemes 1 or 2 above, are activated according to known methods such that J is tosylate, Cl, Br, I, mesyl To yield the corresponding compound of formula (XIX) which is a suitable leaving group such as rate, triflate and the like.

The compound of formula (XIX) is in an organic solvent such as DMF, DMSO, acetonitrile and the like, preferably at an elevated temperature in the range of 50 ° C to about 200 ° C, more preferably from about 50 ° C to DMF, DMSO or the like At a temperature in the range of about 150 ° C. and when the organic solvent is acetonitrile or the like, at about reflux temperature, reacted with a phthalimide salt such as potassium phthalimide, sodium phthalimide and the like; To yield the corresponding compound of formula (XX).

The compound of formula (XX) is reacted with the known compound N ₂ H _{4 in an} organic solvent such as ethanol, methanol or the like, preferably at an elevated temperature in the range of about 50 ° C. to about 100 ° C., more preferably at about reflux temperature and the like. This produces the corresponding compound of formula (XXI).

The compound of formula (XXI) is preferably in an organic solvent such as THF, dioxane or the like, preferably at an elevated temperature in the range of about 50 ° C. to about 100 ° C., more preferably at about reflux temperature, preferably in the range of about 2 to about 5 equivalents. The corresponding compound of formula (Ia), which is a compound of formula (I) wherein R ¹ and R ² are each hydrogen, is reacted with a known compound, sulfamide (NH ₂ -SO ₂ -NH ₂ ), which is present in an amount Create

Alternatively, the compound of formula (XXI) is a suitable compound of formula (XXII), in the presence of a base such as TEA, DIPEA, pyridine or the like, in an organic solvent such as DMF, DMSO, or the like, or a compound prepared by a known method. Reacted with a substituted compound to yield the corresponding compound of formula (lb).

In one embodiment the present invention relates to a process for the preparation of a compound of formula (V-S) as outlined in Scheme 4 below.

Scheme 4

Thus, appropriately substituted compounds of formula (XS), which are known compounds or prepared by known methods, are preferably present in an amount of at least about 1 molar equivalent, more preferably in excess, such as organic or inorganic bases, such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , tetramethylguanidine, TEA, and the like; Preferably in the presence of K ₂ CO ₃ ; At a temperature above about room temperature, preferably at a temperature in the range of about 40 ° C. to about 100 ° C., more preferably at a temperature in the range of about 60 ° C. to about 80 ° C., most preferably at a temperature of about 60 ° C .; In an organic solvent such as DMF, THF, N-methylpyrrolidinone and the like; Benzyl bromide, allyl bromide, 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), t-butyl-diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromide (eg 4-nitro-benzyl bromide , 4-methoxybenzyl bromide and the like), 1- (C _1-4 alkoxy) methyl halide or 1- (C _1-4 alkoxy) ethyl halide (where the halide is Cl, Br or I (eg MOM-Cl, Protected by reaction with a suitable protecting agent (ie, a protecting agent that is stable under subsequent reaction conditions such as hydrolysis, oxidation); To yield the corresponding compound of formula (XI-S), wherein Pg ¹ is the corresponding alcohol protecting group. For example, when the protective agent is benzyl bromide, Pg ¹ is benzyl; When the protective agent is allyl bromide, Pg ¹ is allyl; If the protective agent is MOM-Cl, Pg ¹ is methoxy methyl ether. One skilled in the art can find additional protecting groups and methods of introducing such protecting groups in textbooks such as, for example, TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is hereby incorporated by reference in its entirety. have.

The compound of formula (XI-S) may be in an organic solvent such as DCE, DCM, chloroform, acetonitrile, NMP and the like, preferably DCM; Preferably at about room temperature; Appropriately selected oxidizing agents, such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate, etc., which are present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents, preferably m- In response to CPBA; To yield the corresponding compound of formula (XII-S).

Compounds of formula (XII-S) are in organic solvents or mixtures thereof, such as methanol, ethanol, propanol, mixtures of THF and alcohols, or in mixtures of one or more organic solvents and water, preferably in alcohols, more preferably methanol Between; Preferably at a temperature in the range from about room temperature to about reflux temperature, more preferably at about room temperature; Preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 2 to about 3 molar equivalents, such as NaOCH ₃ , Kt-butoxide, sodium carbonate , Potassium bicarbonate, and the like, preferably reacted with NaOCH ₃ ; To yield the corresponding compound of formula (XIII-S).

)의 공급원, 이를 테면 (R)-글리시딜-m-노실레이트, (R)-글리시딜-토실레이트, (R)-에피클로로하이드린, (R)-에피브로모하이드린 등, 바람직하게는 (R)-글리시딜-m-노실레이트 또는 (R)-글리시딜-토실레이트와 반응하여; 화학식 (XIV-S)의 상응하는 화합물을 생성한다.The compound of formula (XIII) is preferably an inorganic base present in an amount of at least about 1 molar equivalent, more preferably in excess, such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc. Preferably in the presence of K ₂ CO ₃ ; At a temperature above about room temperature, preferably at a temperature ranging from about room temperature to about 100 ° C., more preferably at a temperature in a range from about 40 ° C. to about 60 ° C., most preferably at a temperature of about 40 ° C .; In organic solvents such as DMF, THF, N-methylpyrrolidinone and the like, preferably in DMF; (R) — preferably present in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 1 to about 2 molar equivalents, more preferably in an amount ranging from about 1.1 to about 1.5 molar equivalents. Epoxy-methylene (ie

), Such as (R) -glycidyl-m-nosylate, (R) -glycidyl-tosylate, (R) -epichlorohydrin, (R) -epibromohydrin and the like, Preferably with (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate; To yield the corresponding compound of formula (XIV-S).

Compounds of formula (XIV-S) are deprotected according to known methods to yield the corresponding compounds of formula (XV-S). For example, in compounds of formula (XIV-S) where Pg ¹ is benzyl, allyl, etc., compounds of formula (XIV-S) are ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl-t-butyl In organic solvents such as ether, ethanol and the like; To be deprotected by reaction with hydrogen or a hydrogen source, preferably introduced at a pressure in the range of about 10 psi to about 15 psi in the presence of a catalyst such as Pd / C, Pt, Pd (sulfide) / C and the like. Can be. When Pg ¹ is an SEM or silyl protecting group, the compound of formula (XIV-S) may be deprotected by reaction with a source of fluoride such as tetrabutylammonium fluoride or the like in an organic solvent such as THF or the like. Those skilled in the art will recognize that additional methods for removing protective groups are known in the art, for example as disclosed in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Those skilled in the art will appreciate that the reagent (s) selected for deprotection of the compound of formula (XIV-S) are selected to be substantially non-reactive with the epoxy groups on the compound of formula (XIV-S).

The compound of formula (XV-S) may be used in an organic solvent such as methanol, ethanol, THF, acetonitrile and the like, preferably methanol; Preferably at about room temperature; Preferably with an organic or inorganic base present in an amount of at least about 1 molar equivalent, more preferably in excess, such as NaOCH ₃ , Kt-butoxide, sodium carbonate, etc., preferably NaOCH ₃ ; To yield the corresponding compound of formula (VS).

In another embodiment, the present invention relates to a process for the preparation of a compound of formula (V-S) summarized in Scheme 5 below.

Scheme 5

)의 공급원, 이를 테면 (R)-글리시딜-m-노실레이트, (R)-글리시딜-토실레이트, (R)-에피클로로하이드린, (R)-에피브로모하이드린 등, 바람직하게는 (R)-글리시딜-m-노실레이트 또는 (R)-글리시딜-토실레이트와 반응하여; 화학식 (XVII-S)의 상응하는 화합물을 생성한다.Thus, a known compound or a compound prepared by a known method, Q is -C (O) - is selected from the group consisting of (C _1-4 alkyl), where, C _{1 -4} alkyl is preferably 1 primary C _{1 - 4} alkyl, more preferably -C (O) -CH ₃ or the like to the general formula (XVI-S) a suitably substituted compound is preferably in an amount of at least about one molar equivalent of, and more preferably present in an excess Inorganic bases such as K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, and the like, preferably in the presence of K ₂ CO ₃ ; At a temperature above about room temperature, preferably at a temperature ranging from about room temperature to about 100 ° C., more preferably at a temperature ranging from about 40 ° C. to about 60 ° C., most preferably at a temperature of about 40 ° C .; In organic solvents such as DMF, THF, N-methylpyrrolidinone and the like, preferably in DMF; Preferably present in an amount of from about 1 to about an amount of 5 molar equivalents, more preferably about 1 to an amount of about 2 molar equivalents, more preferably in the range from about 1.1 to about 1.5 molar equivalents of (R) - Epoxy-methylene (ie

), Such as (R) -glycidyl- m -nosylate, (R) -glycidyl-tosylate, (R) -epichlorohydrin, (R) -epibromohydrin, and the like, Preferably with (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate; To yield the corresponding compound of formula (XVII-S).

Compounds of formula (XVIII-S) are in organic solvents such as DCE, DCM, chloroform, acetonitrile, NMP and the like, preferably in DCM; Preferably at about room temperature; Appropriately selected oxidizing agents, such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate, etc., which are present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents, preferably m- In response to CPBA; To yield the corresponding compound of formula (XVIII-S). When Q is -C (O)-(CH ₃ ), the compound of formula (XVII-S) reacts under conditions other than monomagnesium peroxyphthalate in DMF.

The compound of formula (XVIII-S) may be selected from organic solvents such as methanol, ethanol, THF, acetonitrile and the like, preferably methanol; Preferably at about room temperature; Preferably with an organic or inorganic base present in an amount of at least about 1 molar equivalent, more preferably in excess, such as NaOCH ₃ , Kt-butoxide, sodium carbonate, etc., preferably NaOCH ₃ ; To yield the corresponding compound of formula (VS).

Compounds of formula (VS) may be prepared by known methods (e.g., McComsey, D. et al. In US 2006/0041008 A1, published February 23, 2006; US patent published December 22, 2005. In accordance with publication US 2005/0282887 A1, as disclosed by McComsey, D. et al., To produce the corresponding compounds of formula (IS).

For example, compounds of formula (I-S) can be prepared according to the procedures outlined in Scheme 6 below.

Scheme 6

Thus, for example, suitably substituted compounds of formula (VS) which are compounds prepared as summarized in Schemes 1, 2, 4 or 5 above are activated according to known methods such that J is tosylate, Cl, Br To yield the corresponding compound of formula (XIX-S) which is a suitable leaving group such as, I, mesylate, triflate and the like.

The compound of formula (XIX-S) is in an organic solvent such as DMF, DMSO, acetonitrile and the like, preferably at an elevated temperature in the range of 50 ° C to about 200 ° C, more preferably when the organic solvent is DMF, DMSO or the like At temperatures ranging from 0 ° C. to about 150 ° C. and when the organic solvent is acetonitrile or the like, at about reflux temperature, reacted with phthalimide salts such as potassium phthalimide, sodium phthalimide and the like; To yield the corresponding compound of formula (XX-S).

The compound of formula (XX-S) is a known compound N ₂ H _{4 in} organic solvents such as ethanol, methanol and the like, preferably at elevated temperatures ranging from about 50 ° C. to about 100 ° C., more preferably at about reflux temperature and the like. And react to yield the corresponding compound of formula (XXI-S).

The compound of formula (XXI-S) is preferably in an organic solvent such as THF, dioxane or the like at elevated temperatures in the range of about 50 ° C. to about 100 ° C., more preferably at about reflux temperature, preferably in the range of about 2 to about 5 equivalents. Reaction with a known compound sulfamide (NH ₂ -SO ₂ -NH ₂ ), which is present in an amount of, yields the corresponding compound of formula (IS).

Alternatively, the compound of formula (XXI-S) is a known compound, also known as sulfamoyl chloride, in an organic solvent such as DMF, DMSO, etc., in the presence of a base such as TEA, DIPEA, pyridine, and the like (XXII-S) Reaction with a compound of yields the corresponding compound of formula (IS).

The invention also relates to the crystalline forms of the compounds of the formula (I-S), referred to below as crystalline forms (I-SA) and (I-SB). The crystalline forms of the compounds of formula (I-S) can be characterized by their corresponding powder X-ray diffraction (PXRD) spectra.

In one embodiment, the crystalline forms of the compounds of formula (I-S) can be characterized by their corresponding PXRD peaks, wherein the peaks have a relative intensity of at least about 10% relative intensity; Preferably, the peak has a relative intensity of at least about 25% relative intensity. In one embodiment, the crystalline form of the compound of formula (IS) can be characterized by its corresponding PXRD peak, wherein the peaks are their positions (° 2θ), d-spacings and relative intensities Defined by (%). In one embodiment, the crystalline form of the compound of formula (IS) can be characterized by its corresponding PXRD peak, where the peaks are defined by their position (° 2θ) and d-spacing (Å) do.

Powder XRD spectra were measured on representative samples of the crystalline form of the compound of formula (I-S) with the peaks described in Tables 2 and 3 below. PXRD spectra were scanned from 3 to 35 ° 2θ using an X-Celerator detector, with a step size of 0.0165 ° 2θ, time per step of 10.16 seconds, effective scan rate of 0.2067 ° / sec, instrument voltage of 45 kV and 40 mA Measurement was made at current setting.

Crystalline form (I-SA) can be prepared, for example, as described in Example 13 below. Melting points of crystalline form (I-SA) were measured on representative samples and showed melting point onset of 98.6 ° C and 100.8 ° C. Crystalline form (I-SA) can be characterized by its powder XRD peaks as described in Table XRD-1 below.

Crystalline form (I-SB) can be prepared, for example, by recrystallizing the compound of formula (I-S) from water according to known methods as described in Example 14 below. Melting points of crystalline form (I-SA) were measured on representative samples and indicated melting point start of 100.7 ° C and 102.8 ° C. Crystalline form (I-SB) can be characterized by its powder XRD peaks as described in Table 3 below.

1 shows representative powder X-ray diffraction patterns corresponding to the following samples: (a) the top scan corresponds to a representative sample of crystalline form (I-SB); (b) The middle and bottom scans correspond to two separately prepared samples of crystalline form (I-SA).

The present invention also includes pharmaceutical compositions containing one or more compounds prepared according to any of the methods described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more compounds of the invention disclosed herein as active ingredients can be prepared by intimate mixing of the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical combination techniques. The carrier can take a wide variety of forms depending on the route of administration desired (eg oral, parenteral). Thus, in the case of liquid oral preparations such as suspensions, elixirs and solutions, water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like are included; For solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Solid oral formulations can also be coated with a substance such as sugar or enteric coated to control the main absorption site. For parenteral administration, the carrier will usually consist of sterile water and other ingredients can be added to increase the solubility or the preservation. Injectable suspensions or solutions can also be prepared using aqueous carriers with the appropriate additives.

To prepare a pharmaceutical composition of the invention, one or more compounds of the invention as active ingredients are intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques, wherein the carrier is for example oral or parenteral. It can take a wide variety of forms depending on the form of preparation desired for oral administration, eg intramuscular administration. In preparing the compositions in oral dosage form, any common pharmaceutical medium may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like; For solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Tablets and capsules represent the most beneficial oral dosage unit forms because of their ease of administration, in which case solid pharmaceutical carriers are explicitly employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. In the parenteral case, the carrier will comprise sterile water, usually through other ingredients, which may be included for example for the purpose of helping solubility or for preservation. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical composition herein will contain the amount of active ingredient necessary to deliver the effective dose disclosed above, per dosage unit, eg, tablet, capsule, powder, injection, teaspoon amount, and the like. The pharmaceutical composition herein may contain about 1-1000 mg per unit dosage unit, eg, tablets, capsules, powders, injections, suppositories, teaspoon amounts, etc., and about 0.01-300 mg / kg / day , Or any range therein, preferably about 0.5-100 mg / kg / day, or any range therein, more preferably about 1.0-25.0 mg / kg / day, or any range therein Can be given in quantities. However, the dosage may vary depending on what the patient needs, the severity of the condition to be treated, and the compound used. The use of either daily dosing or post-periodic dosing can be used.

Preferably these compositions are tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, or metered for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or inhalation. It is present in unit dosage form such as an aerosol or liquid spray, drop, ampoule, autoinjector or suppository. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; For example, insoluble salts of the active compounds, such as decanoate salts, can be used to provide depot preparations for intramuscular injection. To prepare solid compositions such as tablets, the main active ingredient is a pharmaceutical carrier, eg, a conventional tableting ingredient, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, It is admixed with calcium diphosphate or gum and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When these preformulation compositions are homogeneous, it means that the active ingredients are uniformly dispersed throughout the composition so that the composition can be easily 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 invention. Tablets or pills of the new composition may be coated or otherwise combined to provide dosage forms that benefit from long term action. For example, a tablet or pill can include an internal dosage component and an external dosage component, the latter in the form of an envelope above the former. Both components serve to withstand disintegration in the stomach and can be separated by an enteric layer that allows internal components to pass completely into the duodenum or delay release. Various materials can be used in such enteric layers or coatings, and such materials include many polymeric acids together with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms that can be incorporated for oral or by injection administration of the novel compositions of the invention include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and edible oils and elixirs such as cottonseed oil, sesame oil, coconut oil, or peanut oil. And flavored emulsions with similar pharmaceutical vehicles. Suitable dispersing or suspending agents in aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methyl cellulose, polyvinyl-pyrrolidone or gelatin.

Methods of treating epilepsy or related disorders described herein can also be practiced using pharmaceutical compositions comprising any compound defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain about 0.1 mg to 1000 mg, preferably about 50 to 500 mg, or any range of compounds therein, and may consist of any form suitable for the mode of administration chosen. Carriers include the necessary inert pharmaceutical excipients, which include but are not limited to binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms and solutions such as pills, tablets, caplets, capsules (each including immediate release, on-time release and sustained release preparations), granules, and powders, syrups, elixirs, emulsions and Liquid forms such as suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times a day. Moreover, the compounds of the present invention may be administered in intranasal form through topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in the art. To be administered in the form of a transdermal delivery system, dose administration will of course be continuous rather than intermittent throughout the dosing regimen.

For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; Lubricants, disintegrants and colorants may also be incorporated into the mixture. Suitable binders are 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, benzoic acid Sodium, sodium acetate, sodium chloride and the like are included without limitation. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Liquid forms are suitably flavored suspending agents or dispersants, for example synthetic and natural gums such as tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are required. In general, isotonic agents containing suitable preservatives are used when intravenous administration is required.

To prepare a pharmaceutical composition of the present invention, the compound of formula (I) as active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical combination techniques, wherein the carrier is (eg, oral or parenteral). ) Can take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Society and the British Pharmacy Society.

Methods of formulating pharmaceutical compositions can be found in many literatures, 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.].

The compounds of the present invention can be administered in any of the above-described compositions and according to dosage regimens established in the art whenever the treatment of an epilepsy or related disorder is needed.

The daily dosage of the product may vary over a wide range of 0.01 to 10,000 mg per adult per day or any range therein. For oral administration, the composition is preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150 in order to adjust the dosage for the patient to be treated symptomatically. , 200, 250, 500 and 1000 milligrams of active ingredient in the form of tablets. An effective amount of drug is usually supplied at a dosage level of about 0.01 mg to about 500.0 mg or any range therein per kg of body weight per day. Preferably, the range is from about 0.5 to about 100.0 mg per kg of body weight per day or any range therein, more preferably from about 1.0 to about 50.0 mg per kg of body weight per day or any range therein. The compound may be administered in one to four regimens daily.

The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the specific compound used, the mode of administration, the strength of the formulation, the mode of administration, and the progression of the disease state. In addition, factors related to the particular patient to be treated, including patient age, weight, diet and time of administration, will require adjustment of dosage.

Those skilled in the art will recognize that the ability of test compounds to treat or prevent a given disease is predicted by both in vivo and in vitro testing using appropriate known and generally accepted cell and / or animal models.

Those skilled in the art will further demonstrate that in healthy patients and / or patients suffering from a given disease, human clinical trials, including first-in-human, dose range and efficacy studies, are completed according to methods well known in the clinical and medical arts. It will be appreciated.

The following examples are disclosed to aid the understanding of the present invention, and are not intended to limit the invention disclosed in the claims below in any way and should not be construed as limiting as described above.

In the examples that follow, some synthetic products are listed as separated as residue. Those skilled in the art will understand that the term "residue" does not limit the physical state in which the product is separated, and may include, for example, solids, oils, foams, gums, syrups, and the like.

Example 1

2-benzyloxy-5-chloro-benzaldehyde

In a 2-liter three-necked flask (equipped with a mechanical stirrer, nitrogen inlet and thermocouple) 5-chlorosalicylaldehyde (7, 23 g, 0.147 mol), benzyl bromide (25.1 g, 0.147 mol), potassium carbonate (20.3 g, 0.147 mol) and N , N -dimethylformamide (650 mL) were added. The reaction mixture was heated to 60 ° C. for 18 hours (overnight). The reaction mixture was poured into water (700 mL) and then extracted with ethyl ether (3 x 300 mL). The combined organic phases were washed with brine (2 × 200 mL), dried (MgSO ₄ ) and concentrated to afford the crude product. The crude product was dissolved in 1: 1 heptane-dichloromethane, loaded into Biotage 75S (200 g silica gel), followed by heptane (1L), 1: 9 (3L), and 3: 7 (2 L) Eluted with ethyl acetate-heptane to afford the title compound as a solid.

¹ H NMR (CDCl ₃ ) δ ppm: 10.48 (s, 1H), 7.81 (d, J = 3.1 Hz, 1H), 7.42 (m, 6H), 7.01 (d, J = 8.9 Hz, 1H), 5.19 ( s, 2H).

Example  2

Formic acid, 2-benzyloxy-5-chloro-phenyl ester

Into a 1 L one-necked flask (equipped with magnetic stirrer and nitrogen inlet) was placed 2-benzyloxy-5-chloro-benzaldehyde (8, 28.1 g, 0.114 mol) and dichloromethane (360 mL). To this solution, m-CPBA (˜75%, 31.4 g, 0.137 mol) was added. The reaction mixture was stirred at rt for 17 h (overnight) to give a white slurry. The white solid was removed by filtration, then the filtrate was washed with 10% (w / w) sodium bisulfite (200 mL) and each phase was tested with iodine starch paper to confirm that any oxidant remained. This test was negative and the organic phase was washed with sodium carbonate (2 × 150 mL), dried (MgSO ₄ ) and concentrated to afford the crude product as a solid. The crude product was used in subsequent steps without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 8.25 (s, 1H), 7.37 (m, 5H), 7.15 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H), 5.09 (s, 2H).

Example  3

2-benzyloxy-5-chloro-phenol

Crude formic acid, 2-benzyloxy-5-chloro-phenyl ester (9, 28 g, 0.107 mol), sodium methoxide (25% in methanol) in a 1-neck flask (equipped with magnetic stirrer and nitrogen inlet) w / w), 26.5 mL, 0.123 mol) and methanol (175 mL) were added. The reaction mixture was stirred for 18 hours (overnight). The reaction mixture was concentrated to a red oil and partitioned between saturated ammonium chloride (200 mL) and ethyl ether (200 mL). The aqueous phase was extracted with ethyl ether (100 mL) and the combined organic phases were washed with brine (100 mL), dried (MgSO ₄ ) and concentrated to give the title compound as an oil. The product was used for the next step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 7.41 (m, 5H), 6.95 (d, J = 1.8 Hz, 1H), 6.82 (m, 2H), 5.71 (s, 1H), 5.09 (s, 2H).

Example  4

( R ) -2- (2- Benzyloxy -5- Chloro - Phenoxymethyl ) - Oxirane

500 mL 3-necked flask (equipped with magnetic stir bar, thermocouple and nitrogen inlet) 2-benzyloxy-5-chloro-phenol (10, 11.3 g, 48.2 mmol), ( R ) -glycidyl m -nitrophenyl Sulfonate (11.3 g, 43.8 mmol) and N, N -dimethylformamide (200 mL) were added. The reaction mixture was heated to 40 ° C. for 12 h, then cooled to rt and poured into water (300 mL). The aqueous phase was extracted with ethyl ether (3 x 200 mL). The combined organic phases were washed with 1M sodium hydroxide (aq) and brine (3 x 100 mL), dried (MgSO ₄ ) and concentrated in vacuo to afford the crude product as an oil. The oil was dissolved in 1: 1 heptane-dichloromethane, loaded into an Isco cartridge (120 g silica gel) and eluted to afford the title compound as an oil.

¹ H NMR (CDCl ₃ ) δ ppm: 7.38 (m, 5H), 6.94 (d, J = 2.5 Hz, 1H), 6.85 (m, 2H), 5.11 (s, 2H), 4.28 (dd, J = 11.4 , 3.3 Hz, 1H), 4.01 (dd, J = 11.3, 5.5 Hz, 1H), 3.38 (m, 1H), 2.89 (dd, J = 5.1, 4.9 Hz, 1H), 2.77 (dd, J = 5.0, 2.6 Hz, 1H).

Example  5

( R )-4- Chloro -2- Oxiranylmethoxy -phenol

5% palladium on carbon (anhydrous, 1.0 g), ( R ) -2- (2-benzyloxy-5-chloro-phenoxymethyl) -oxirane (11, 11.7 g, 40.2 mmol) and ethyl in a Parr reaction bottle Acetate (250 mL) was added. The reaction mixture was stirred with a Parr shaker at room temperature under 5-7 psi of hydrogen gas for 2.5 hours. The catalyst was removed by filtration and ethyl acetate was removed in vacuo to yield an oil which solidified upon leaving the title compound. The product was used for the next step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 6.87 (m, 3H), 6.09 (bs, 1H), 4.25 (dd, J = 11.4, 2.6 Hz, 1H), 3.98 (dd, J = 11.3, 5.7 Hz, 1H ), 3.39 (m, 1H), 2.96 (t, J = 4.6 Hz, 1H), 2.85 (dd, J = 5.2, 2.7 Hz, 1H).

Example  6

( S )-(6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin 2-yl) -methanol

In a one-necked flask (equipped with magnetic stirring and nitrogen inlet) ( R ) -4-chloro-2-oxyranylmethoxy-phenol (12, 8.1 g, 40.4 mmol), sodium methoxide (25% in methanol (w / w), 10.5 mL, 48.4 mmol) and methanol (90 mL) were added. The reaction was stirred for 18 hours (overnight). The reaction mixture was concentrated to a red oil and partitioned between water (250 mL) and ethyl ether (200 mL). The aqueous phase is extracted with ethyl ether (2 x 100 mL) and the combined organic phases are washed with 1M aqueous sodium hydroxide (150 mL), brine (2 x 100 mL), dried (MgSO ₄ ) and concentrated to give crude product. Got. The crude product was dissolved in dichloromethane, loaded into Biotage 40M (90 g silica gel) and eluted with dichloromethane (250 mL) and 1:19 ethyl acetate-dichloromethane (1 L) to give the title compound. Obtained as a white solid (19415-132A).

Melting point: 73-75 ° C.

Beneficiation: [α] _D = -58.0 ° (c 1.99, MeOH, 23 ° C.)

¹ H NMR (CDCl ₃ ) δ ppm: 6.82 (m, 3H), 4.30 (dd, J = 11.1, 2.2 Hz, 1H), 4.24 (m, 1H), 4.10 (dd, J = 11.2, 7.4 Hz, 1H ), 3.87 (m, 2 H), 1.95 (t, J = 6.6 Hz, 1 H).

Example  7

( R ) -1- (4- Chloro -2- Oxiranylmethoxy - Phenyl ) - Ethanon

4-chloro-2-hydroxy-acetophenone (13, 687.2 g, 4.03 mol) and N, N -in a 22 L four-necked flask (equipped with a mechanical stirrer, thermocouple, Teflon stopper and argon inlet) Dimethylformamide (14.0 L) was added. To this solution was added potassium carbonate (613 g, 4.43 mol) and ( R ) -glycidyl m -nitrophenylsulfonate (1.045 kg, 4.03 mol). The reaction mixture was heated to 40 ° C. for 20 hours (overnight), then cooled to room temperature and divided into two portions. Each portion was poured into water (9 L) and extracted with methyl tert -butyl ether (3 x 2 L) and ethyl ether (2 L). The two organic phases were each washed with brine (2 × 4 L), dried (MgSO ₄ ) and concentrated in vacuo to afford the crude product which was used in the next step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 7.71 (d, J = 8.5 Hz, 1H), 7.02 (dd, J = 8.8, 1.7 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 4.39 ( dd, J = 11.0, 2.8 Hz, 1H), 3.98 (dd, J = 10.8, 6.1 Hz, 1H), 3.41 (m, 1H), 2.96 (t, J = 4.4 Hz, 1H), 2.78 (dd, J = 5.1, 2.7 Hz, 1H), 2.64 (s, 3H).

A small amount of the product prepared as described above was chromatographed (Isco silica-40 g) to give a white powder:

Melting point: 79-80 ° C.

Beneficiation: [α] _D = -19.4 ° (c 2.02, MeOH, 23 ° C.).

High resolution MS: (as C ₁₁ H ₁₂ O ₃ Cl, M ^{+ H} ): Calcd: 227.48; Found: 227.05

Example 8

( R ) -Acetic acid, 4- Chloro -2- Oxiranylmethoxy - Phenyl  ester

In a 22 L four-necked flask (equipped with a mechanical stirrer, two stoppers and a condenser with argon inlet) ( R ) -1- (4-chloro-2-oxyranylmethoxy-phenyl) -ethanone (14, 815 g, 3.60 mol) and dichloromethane (8.8 L) were added. To this solution was added m-CPBA (˜75% Lancaster, 993 g, 4.31 mol oxidant). The reaction mixture was heated at moderate reflux for 3 hours over 3 days (heat applied only with supervision). Then we added additional m-CPBA (100 g, ˜0.36 mol) and continued to reflux for 8 hours. The reaction mixture was then allowed to cool overnight to yield a white slurry upon cooling. The white solid was removed by filtration and the filtrate was divided into four portions. Each portion was washed with 10% (w / w) sodium bisulfite (1 L) and two portions were tested with iodine starch paper to confirm that any oxidant remained. This test was negative, the aqueous phase was extracted again with dichloromethane (2 x 250 mL), the combined organic phases (4 portions) were washed with saturated sodium carbonate (3 x 500 mL), dried ( MgSO ₄ ), concentrated to give the crude product which was used in the next step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 6.96 (m, 3H), 4.25 (dd, J = 10.9, 2.4 Hz, 1H), 3.94 (dd, J = 11.5, 5.6 Hz, 1H), 3.30 (m, 1H ), 2.88 (t, J = 4.8 Hz, 1H), 2.71 (dd, J = 4.8, 2.6 Hz, 1H), 2.31 (s, 3H).

A small amount of the crude product prepared as described above was chromatographed (Isco silica-12 g) to give a clear oil:

Beneficiation: [α] _D = -8.29 ° (c 2.05, MeOH, 23 ° C.)

High resolution MS: (as C ₁₁ H ₁₁ O ₃ Cl, M ⁺ ): Calcd: 242.03; Measure: 242.03

Example  9

( S )-(6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin 2-yl) -methanol

( R ) -acetic acid, 4-chloro-2-oxyranylmethoxy-phenyl ester (15, 1.019 kg impure, estimated 874 g) in a four-necked 12 L flask (equipped with mechanical stirring, two stoppers and a nitrogen inlet), 3.60 mol), sodium methoxide (25% (w / w) in methanol, 972 mL, 4.50 mol) and methanol (6.0 L) were added. The reaction mixture was stirred for 20 hours (overnight), then treated with 3M aqueous sodium hydroxide (500 mL) and stirred for an additional 6 days. The reaction mixture was concentrated to a red oil, which was diluted to a volume of 4.0 L with water. This material was divided into two portions and each aqueous phase was extracted with methyl tert -butyl ether (2 x 1.0 L) and ethyl ether (1 L). The organic phase was washed with 10% aqueous sodium bisulfite (500 mL), saturated sodium carbonate (500 mL), brine (2 x 500 mL), dried (MgSO ₄ ) and concentrated to afford crude product. The crude product was used in subsequent steps without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 6.89 (m, 1H), 6.2 (m, 2H), 4.30 (dd, J = 11.3, 2.2 Hz, 1H), 4.23 (m, 1H), 4.10 (dd, J = 10.9, 7.6 Hz, 1H), 3.91 (dd, J = 12.0, 4.2 Hz, 1H), 3.83 (dd, J = 12.1, 5.4 Hz, 1H).

A small amount of the crude product prepared as described above was chromatographed (Isco silica-12 g) to give a white solid:

Melting point: 79-81 ° C.

Beneficiation: [α] _D = -58.2 ° (c 2.05, MeOH, 23 ° C.);

Chiral HPLC: Chiralpak AS-H, hexanes / IPA (97: 3), R _t = 16.095 min,> 99% ee.

High resolution MS: (as C ₉ H ₉ O ₃ Cl, M ⁺ ): Calculated: 200.02: Found: 200.02

Example  10

( R ) -Toluene-4- Sulfonic acid , 6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2 days- methyl  ester

Into a 12 L four-necked flask (equipped with a mechanical stirrer, nitrogen inlet and two stoppers) ( S )-(6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol ( 2 , 300 g, 1.50 mol) and 4.5 L of tetrahydrofuran / dichloromethane (9: 1) were added. This solution was treated with N -methylmorpholine (362 mL, 3.29 mol), N, N -dimethylaminopyridine (36.4 g, 0.298 mol) and p -toluenesulfonyl chloride (341 g, 1.79 mol). The reaction mixture was stirred for 10 days at room temperature under nitrogen (the reaction appeared to be complete after ˜4 days). The reaction mixture was filtered to remove amine hydrochloride and split into two portions. Each portion was stirred with 20% aqueous potassium bicarbonate (3 L) for 2.5 hours. Each portion is then extracted with i -propyl acetate (2 x 1.5 L) and the organic phase is extracted with 2 M hydrochloric acid (2 x 1 L), saturated sodium carbonate (2 x 1 L), brine (500 mL) Washed with and dried (MgSO ₄ ). The resulting mixture was concentrated to give crude product. The crude product was dissolved in dichloromethane / heptane (1: 3), loaded into Biotage 150L (5 kg silica gel), heptane (8 L), 1: 9 ethyl acetate-heptane (24 L), 15: Elution with 85 ethyl acetate-heptane (48 L) and 1: 2 ethyl acetate-heptane (18 L) (30 psi) gave the title compound as an off-white solid.

¹ H NMR (DMSO-d6) α ppm: 7.79 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 2.5 Hz, 1H), 6.87 (dd , J = 8.8, 2.5 Hz, 1H), 6.8 (d, J = 8.8 Hz, 1H), 4.46 (m, 1H), 4.35 (dd, J = 11.7, 3.1 Hz, 1H), 4.29 (dd, J = 11.7, 2.5 Hz, 1H), 4.20 (dd, J = 11.3, 6.4 Hz, 1H), 3.99 (dd, J = 11.5, 6.2 Hz, 1H), 2.42 (s, 1H) Beneficiation: [α] _D = -34.73 ° (c 2.02, MeOH, 23 ° C).

Example 11

( S ) -2- (6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2- Yl methyl ) - Isoindole -1,3-dione

In a 12-L four-necked flask (equipped with a mechanical stirrer, an air condenser with a nitrogen inlet above and two stoppers), ( R ) -toluene-4-sulfonic acid, 6-chloro-2,3-dihydro-benzo [ 1,4] dioxin-2-yl-methyl ester ( 3 , 443 g, 1.25 mol), potassium phthalimide (301 g, 1.62 mol) and N , N -dimethylformamide (5 L) were added. The reaction mixture was heated to 100 ° C. for 2 hours and then cooled to room temperature for 16 hours (overnight). The reaction mixture was diluted with water (6 L) and stirred for 2.5 h. The resulting white solid was collected by vacuum filtration and dried in a vacuum oven at 55 ° C. to afford the title compound as an off white solid.

¹ H NMR (DMSO-d6) α ppm: 7.84 (m, 4H), 6.98 (d, J = 2.9 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.49 (qd, J = 6.1, 2.2, 1H), 4.36 (dd, J = 11.4, 2.7 Hz, 1H), 4.13 (dd, J = 11.9, 2.5 Hz, 1H), 3.88 (m , 2H). Melting point: 126-127 ° C.

Example  12

( S )-(6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin 2-yl) -methylamine

In a 12-L four-necked flask (equipped with a mechanical stirrer, a water condenser with a nitrogen inlet above and two stoppers), (S) -2- (6-chloro-2,3-dihydro-benzo [1,4] Dioxin-2-ylmethyl) -isoindole-1,3-dione ( 4 , 370 g, 1.12 mol), hydrazine (65.2 mL, 2.08 mol) and ethanol (4 L) were added. The reaction mixture was heated to reflux for 1.5 hours and then cooled to room temperature. The reaction mixture was acidified with 1 M hydrochloric acid (2 L) and filtered. The filtrate was concentrated to remove ethanol and then basified with 3 M sodium hydroxide (1 L) and extracted with ethyl ether (2 L, then 2 x 1 L). The combined organic phases were washed with brine (2 × 600 mL), dried (MgSO ₄ ) and concentrated to afford the title compound as a white solid, which was used in the next step without further purification.

¹ H NMR (DMSO-d6) δ ppm: 6.95 (d, J = 1.9 Hz, 1H), 6.87 (m, 2H), 4.37 (dd, J = 11.5, 2.6, 1H), 4.07 (m, 1H), 3.98 (dd, J = 10.9, 7.7 Hz, 1H), 2.83 (dd, J = 12.7, 5.4, 1H), 2.77 (dd, J = 12.7, 6.1, 1H). Melting point: 70-71 ° C.

Beneficiation: [α] _D = -81.0 ° (c 2.00, MeOH, 23 ° C.).

Example  13

( S ) - N -(6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2- Yl methyl ) - Sulfamide

In a 12-L four-necked flask (equipped with a mechanical stirrer, a water condenser with a nitrogen inlet above and two stoppers), (S)-(6-chloro-2,3-dihydro-benzo [1,4] dioxine- 2-yl) -methylamine ( 5 , 214 g, 1.07 mol), sulfamide (412 g, 4.29 mol) and iso-propyl acetate (4 L) were added. The reaction mixture was then heated to reflux for a total of 15 hours over 3 days and then cooled to room temperature. The reaction mixture was cooled in an ice bath and the residue was collected by filtration and washed with iso-propyl acetate. The filtrate was washed with 1 M hydrochloric acid (3 L), dried (MgSO ₄ ) and concentrated to afford the crude product. The whole part of the crude product was dissolved in ethyl acetate, absorbed into silica gel (600 g), loaded into the Biotage sample induction module, then heptane (2 L), 1: 9 ethyl acetate-heptane (4 L), Elution in Biotage 150M (2.5 g silica gel) with 3: 7 ethyl acetate-heptane (12 L) and 1: 1 ethyl acetate-heptane (16 L) yielded the product with the mixed fractions. The mixed fractions were heptane (1 L), 1: 9 ethyl acetate-heptane (2 L), 3: 7 ethyl acetate-heptane (6 L) and 1: 1 ethyl acetate-heptane (8 L) Re-chromatography on Biotage 75L (800 g silica) to give additional product. The two groups of products were combined to give the title compound as an off white solid.

With the title compound prepared according to the procedure as described in this example, Form (I-SA) was obtained.

¹ H NMR (DMSO-d6) δ ppm: 6.98 (d, J = 1.9 Hz, 1H), 6.89 (m, 3H), 6.67 (bs, 2H), 4.36 (dd, J = 11.7, 1.6, 1H), 4.28 (m, 1H), 4.00 (dd, J = 11.5, 6.8 Hz, 1H), 3.19 (m, 1H), 3.11 (m, 1H). Melting point: 99-100 ° C.

Beneficiation: [α] _D = -57.6 ° (c 2.14, MeOH, 23 ° C).

Chiral HPLC: Chiralpak AD-H, Hex (0.1% TEA) / IPA (80:20), R _t = 11.407 min,> 99% ee.

Elemental Analysis for C ₉ H ₁₁ ClN ₂ O ₄ S:

Calculated:% C 38.78,% H 3.98,% Cl 12.72,% N 10.05,% S 11.51.

Found:% C 38.81,% H 3.74,% Cl 12.83,% N 9.93,% S 11.53.

Example  14

( S ) - N -(6- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2- Yl methyl ) - Sulfamide  Water recrystallization

In distilled water (5 mL) test tube (S) - N - (6- chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) was added to sulfamide (0.050g), The resulting mixture was heated. The white solid was observed to dissolve in water before the water boiled. As the water cooled, the material exited as a suspension and formed white needle crystals over 2 hours. The crystals were filtered off, rinsed with water, naturally dried and collected to give crystalline form (I-SB) as defined herein.

Example 15

( R ) -Toluene-4- Sulfonic acid , (7- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2 days)- methyl  ester

AM Birch et al. (S)-(7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl) methanol prepared according to the method as disclosed in Journal of Medicinal Chemistry 1999, 42 , 3342-3355 { [α] _D = -35.6 ° (c = 1.45, EtOH), 7.12 g, 35.4 mmol} was dissolved in pyridine (50 mL) and cooled to 0 ° C. To the resulting mixture was added p-toluenesulfonyl chloride (6.68 g, 35.5 mmol) and the reaction mixture was stirred at rt for 20 h. The reaction mixture was then cooled in an ice bath and 1N HCl (750 mL) was added. The reaction mixture was extracted with diethyl ether (3x, 200 mL). The combined diethyl ether was washed with 1N HCl (2 ×, 250 mL), water, brine (2 ×), dried (MgSO ₄ ) and evaporated in vacuo to afford the title compound as a white solid.

¹ H NMR (CDCl ₃ ) δ 7.79 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.76 (m, 3H), 4.40 (m, 1H), 4.21 (m, 3H), 4.03 (dd, J = 6.2, 11.6 Hz, 1H), 2.61 (s, 3H).

Example 16

( S ) -2- (7- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2- Yl methyl ) - Isoindole -1,3-dione

( R ) -toluene-4-sulfonic acid, (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methyl ester, prepared as in Example 15 above (10.65 g) ) Is combined with potassium phthalimide (8.90 g, 48 mmol) in DMF (100 mL) and the resulting mixture is heated to reflux for 1 h, then cooled to room temperature and vigorously stirred ice water (750 mL) Poured into and stirred for 30 minutes. The resulting white solid was filtered, washed several times with water and then dried under vacuum (16 hours) to give the title compound as a powdered solid.

¹ H NMR (CDCl ₃ ) δ 7.89 (m, 2H), 7.75 (m, 2H), 6.82 (m, 3H), 4.50 (m, 1H), 4.29 (dd, J = 2.3, 11.6 Hz, 1H), 4.05 (m, 2 H), 3.89 (dd, J = 5.4, 14.2 Hz, 1 H).

Example  17

( S )-(7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine

(S) -2- (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -isoindole-1,3-dione (8.1 g, 24.6 mmol; practiced above Prepared as in Example 16), combined with hydrazine (1.57 g, 49 mmol) in EtOH (120 mL), heated to reflux for 2 hours and then cooled to room temperature. Then 1N HCl was added to the reaction mixture up to pH 2.0 and the resulting mixture was stirred for 45 minutes. The resulting white solid was filtered off, washed several times with fresh EtOH and the solid was discarded. The filtrate was evaporated in vacuo to give a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was washed once with brine, dried (Na ₂ SO ₄ ) and evaporated in vacuo to afford the title compound as a clear viscous oil.

MS 200 (MH ⁺ )

¹ H NMR (CDCl ₃ ) δ 6.90 (dd, J = 1.54, 1.1 Hz, 1H), 6.79 (m, 2H), 4.26 (dd, J = 11.2, 2.2 Hz, 1H), 4.13 (m, 1H), 3.98 (dd, J = 11.3, 7.5 Hz, 1H), 2.98 (m, 2H), 1.25 (bd s, NH ₂ )

Ore Dressing [α] _D = -54.2 ° (c = 1.55, CHCl ₃ )

Example 18

( S ) - N -(7- Chloro -2,3- Dihydro - Benzo [1,4] dioxin -2- Yl methyl ) - Sulfamide  (Compound of Formula (I-S))

(S)-(7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine (4.7 g, 23.5 mmol) and sulfamide (4.51 g, 47 mmol) were dioxane (125 mL) was refluxed for 3 h, then cooled to rt, filtered and evaporated in vacuo to give a solid. The solid (crude product) was purified by flash column chromatography (DCM: MeOH 20: 1) to give a white solid, which was recrystallized from ethyl acetate / hexanes to give the title compound as a white crystalline solid.

Melting point 118-119 ℃

MS 277 (M-1) Ore Dressing [α] _D = -40.0 ° (c = 1.20, MeOH)

¹ H NMR (DMSOd6) δ 6.97 (d, J = 2.2 Hz, 1H), 6.90 (m, 3H), 6.67 (s, 2H, NH ₂ ), 4.35 (m, 2H), 4.01 (m, 1 H) , 3.15 (m, 2H)

Chemical analysis:

Calc .: C, 38.78; H, 3.98; N, 10.05; S, 11.51

Found: C, 38.83; H, 3.88; N, 10.08; S, 11.31

Example 19

Liquid formulations

For example, compounds of formula (I-S) prepared as described above were formulated into 25 mg and 100 mg liquid formulations, respectively, with ingredients as described in Table 4, according to known methods.

Example 20-Prediction

As a specific embodiment of the oral composition, 100 mg of the compound prepared as in Example 18 was formulated using sufficiently fine lactose to provide a total amount of 580 to 590 mg to fill a hard gel capsule of size O.

Although the foregoing specification, along with the examples provided for purposes of explanation, teach the principles of the invention, the practice of the invention includes all conventional modifications, adaptations, and / or changes that fall within the scope of the following claims and their equivalents. Will be understood.

Claims (89)

Protecting a compound of formula (X); To yield the corresponding compound of formula (XI) wherein Pg ¹ is an alcohol protecting group;
The compound of formula (XI) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII);
The compound of formula (XII) in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII);
The compound of formula (XIII) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XIV);
Deprotecting the compound of formula (XIV); To yield the corresponding compound of formula (XV);
The compound of formula (XV) in an organic solvent; By reaction with an organic or inorganic base; A process for preparing a compound of formula (V), comprising producing the corresponding compound of formula (V):

Where

Is

&Lt; / RTI &gt;
Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro. Pg ¹ is benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxy The method is selected from the group consisting of ethyl. The method of claim 2, wherein Pg ¹ is selected from the group consisting of benzyl and allyl. The method of claim 1 wherein the oxidant is m-CPBA. The method of claim 1 wherein the organic or inorganic base that reacts with the compound of formula (XII) is NaOCH ₃ . The method of claim 1 wherein the source of epoxy-methylene is selected from the group consisting of glycidyl- m -nosylate and glycidyl-tosylate. The method of claim 1, wherein the epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. The method of claim 3, wherein the compound of formula (XIV) is deprotected by reaction with hydrogen or a hydrogen source. The method of claim 1 wherein the organic or inorganic base that reacts with the compound of formula (V) is NaOCH ₃ . The method of claim 1,

How to be.

end

Protecting a compound of formula (X) selected from the group consisting of: To yield the corresponding compound of formula (XI) wherein Pg ¹ is an alcohol protecting group;
The compound of formula (XI) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII);
The compound of formula (XII) in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII);
The compound of formula (XIII) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XIV);
Deprotecting the compound of formula (XIV); To yield the corresponding compound of formula (XV);
The compound of formula (XV) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (V);
By reacting a compound of formula (V); Process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising producing the corresponding compound of formula (I):

Where

silver

It is selected from the group consisting of;
Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro;
R ⁴ is selected from the group consisting of hydrogen and lower alkyl;
R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl. 12. The compound of claim 11, wherein PG ¹ is benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxy The method is selected from the group consisting of ethyl. 13. The method of claim 12, wherein Pg ¹ is selected from the group consisting of benzyl and allyl. The method of claim 11, wherein the oxidant is m-CPBA. The method of claim 11, wherein the organic or inorganic base that reacts with the compound of formula (XII) is NaOCH ₃ . The method of claim 11, wherein the source of epoxy-methylene is selected from the group consisting of glycidyl- m -nosylate and glycidyl-tosylate. 12. The method of claim 11, wherein the epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. The method of claim 13, wherein the compound of formula (XIV) is deprotected by reaction with hydrogen or a hydrogen source. The method of claim 11, wherein the organic or inorganic base that reacts with the compound of formula (V) is NaOCH ₃ . The method of claim 1,

ego; R ¹ is hydrogen, R ² is hydrogen and R ⁴ is hydrogen. Protecting a compound of formula (XS); To yield the corresponding compound of formula (XI-S) wherein Pg ¹ is an alcohol protecting group;
The compound of formula (XI-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII-S);
The compound of formula (XII-S) in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII-S);
The compound of formula (XIII-S) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XIV-S);
Deprotecting the compound of formula (XIV-S); To yield the corresponding compound of formula (XV-S);
The compound of formula (XV-S) in an organic solvent; By reaction with an organic or inorganic base; A process for preparing a compound of formula (VS), comprising producing the corresponding compound of formula (VS):

22. The compound of claim 21, wherein Pg ¹ is benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxy The method is selected from the group consisting of ethyl. The method of claim 22, wherein Pg ¹ is selected from the group consisting of benzyl and allyl. The method of claim 21, wherein the oxidant is m-CPBA. The method of claim 21, wherein the organic or inorganic base that reacts with the compound of formula (XII-S) is NaOCH ₃ . 22. The method of claim 21, (R) - epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. The method of claim 23, wherein the compound of formula (XIV-S) is deprotected by reaction of a compound of formula (XIV) with hydrogen or a hydrogen source. The method of claim 21, wherein the organic or inorganic base that reacts with the compound of formula (VS) is NaOCH ₃ . A method according to claim 21; A process for preparing a compound of formula (IS), further comprising reacting the compound of formula (VS) to produce the corresponding compound of formula (IS):

Protecting a compound of formula (XS); To yield the corresponding compound of formula (XI-S) wherein Pg ¹ is an alcohol protecting group;
The compound of formula (XI-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XII-S);
The compound of formula (XII-S) in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (XIII-S);
The compound of formula (XIII-S) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XIV-S);
Deprotecting the compound of formula (XIV-S); To yield the corresponding compound of formula (XV-S);
The compound of formula (XV-S) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (VS);
By reacting a compound of formula (VS); Process for preparing a compound of formula (IS) or a pharmaceutically acceptable salt thereof, comprising producing the corresponding compound of formula (IS):

31. The compound of claim 30, wherein Pg ¹ is benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxy The method is selected from the group consisting of ethyl. 32. The method of claim 31, wherein Pg ¹ is selected from the group consisting of benzyl and allyl. 31. The method of claim 30, wherein the oxidant is m-CPBA. The method of claim 30, wherein the organic or inorganic base that reacts with the compound of formula (XII-S) is NaOCH ₃ . 31. The method of claim 30, (R) - epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. 33. The method of claim 32, wherein the compound of formula (XIV-S) is deprotected by reaction of a compound of formula (XIV) with hydrogen or a hydrogen source. The method of claim 30, wherein the organic or inorganic base that reacts with the compound of formula (VS) is NaOCH ₃ . A product prepared according to the method of claim 11. A product made according to the method of claim 30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 39. A pharmaceutical composition prepared by mixing the product of claim 39 with a pharmaceutically acceptable carrier. A method for preparing a pharmaceutical composition comprising mixing the product of claim 39 with a pharmaceutically acceptable carrier. A method of treating epilepsy or related disorders comprising administering a therapeutically effective amount of the product of claim 39 to a subject in need thereof. The method of claim 43, wherein the disorder is epilepsy. Q is -C (O) - of a compound of formula (XVI) is selected from the group consisting of _- (C _{1 4} alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XVII);
The compound of formula (XVII) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII);
The compound of formula (XVIII) in an organic solvent; By reaction with an organic or inorganic base; A process for preparing a compound of formula (V), comprising producing the corresponding compound of formula (V):

Where

It is selected from the group consisting of;
Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro. 46. The method of claim 45, wherein Q is -C (O) -CH ₃ . 46. The method of claim 45, wherein the source of epoxy-methylene is selected from the group consisting of glycidyl- m -nosylate and glycidyl-tosylate. 48. The method of claim 47, wherein the epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. 46. The method of claim 45, wherein the oxidant is m-CPBA. 46. The method of claim 45, wherein the organic or inorganic acid that reacts with the compound of formula (XVIII) is NaOCH ₃ . The method of claim 45,

How to be.

It is selected from the group consisting of; Q is -C (O) - of a compound of formula (XVI) is selected from the group consisting of _- (C _{1 4} alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; By reaction with a source of epoxy-methylene; To yield the corresponding compound of formula (XVII);
The compound of formula (XVII) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII);
The compound of formula (XVIII) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (V);
By reacting a compound of formula (V); Process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising producing the corresponding compound of formula (I):

Where

&Lt; / RTI &gt;
Wherein b is an integer from 0 to 4; c is an integer from 0 to 2;
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro;
R ⁴ is selected from the group consisting of hydrogen and lower alkyl;
R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl. The method of claim 52, wherein Q is —C (O) —CH ₃ . The method of claim 52, wherein the source of epoxy-methylene is selected from the group consisting of glycidyl- m -nosylate and glycidyl tosylate. 55. The method of claim 54, wherein the epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. The method of claim 52, wherein the oxidant is m-CPBA. The method of claim 52, wherein the organic or inorganic acid that reacts with the compound of formula (XVIII) is NaOCH ₃ . The method of claim 52, wherein

ego; R ¹ is hydrogen, R ² is hydrogen and R ⁴ is hydrogen. Q is -C (O) - of a compound of formula (XVI-S) is selected from the group consisting of _- (C _{1 4} alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XVII-S);
The compound of formula (XVII-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII-S);
The compound of formula (XVIII-S) in an organic solvent; By reaction with an organic or inorganic base; A process for preparing a compound of formula (VS), comprising producing the corresponding compound of formula (VS):

The method of claim 15, wherein Q is —C (O) —CH ₃ . 16. The method of claim 15, (R) - epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. The method of claim 15, wherein the oxidant is m-CPBA. The method of claim 15, wherein the organic or inorganic acid reacted with the compound of formula (XVIII-S) is NaOCH ₃ . A compound of formula (XVI-S) wherein Q is selected from the group consisting of -C (O)-(C _1-4 alkyl) in the presence of an inorganic base; At a temperature above about room temperature; In an organic solvent; Reacted with a source of (R) -epoxy-methylene; To yield the corresponding compound of formula (XVII-S);
The compound of formula (XVII-S) in an organic solvent; By reaction with an oxidizing agent; To yield the corresponding compound of formula (XVIII-S);
The compound of formula (XVIII-S) in an organic solvent; By reaction with an organic or inorganic base; To yield the corresponding compound of formula (VS);
By reacting a compound of formula (VS); Process for preparing a compound of formula (IS) or a pharmaceutically acceptable salt thereof, comprising producing the corresponding compound of formula (IS):

The method of claim 64, wherein Q is —C (O) —CH ₃ . According to claim 64, (R) - epoxy-methylene is a source of (R) - glycidyl-m-nosil rate and (R) - glycidol is selected from the group consisting of glycidyl tosylate. 65. The method of claim 64, wherein the oxidant is m-CPBA. The method of claim 64, wherein the organic or inorganic acid that reacts with the compound of formula (XVIII-S) is NaOCH ₃ . A product prepared according to the method of claim 52. A product prepared according to the method of claim 64. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 70. A pharmaceutical composition prepared by mixing the product of claim 70 with a pharmaceutically acceptable carrier. A method of preparing a pharmaceutical composition comprising mixing the product of claim 70 with a pharmaceutically acceptable carrier. A method of treating epilepsy or related disorders comprising administering a therapeutically effective amount of the product of claim 70 to a subject in need thereof. 75. The method of claim 74, wherein the disorder is epilepsy. Crystalline form of the compound of formula (IS) I-SA:
[Formula IS]

Crystalline I-SA having the following powder X-ray diffraction peaks:

. Crystalline Form I-SB of a compound of Formula (IS):

. 79. The crystalline form I-SB of claim 78, wherein the crystalline form I-SA has the following powder X-ray diffraction peaks:

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 76. A pharmaceutical composition prepared by mixing the product of claim 76 with a pharmaceutically acceptable carrier. 77. A method of making a pharmaceutical composition comprising mixing the product of claim 76 with a pharmaceutically acceptable carrier. 77. A method of treating epilepsy or related disorders comprising administering a therapeutically effective amount of the product of claim 76 to a subject in need thereof. 84. The method of claim 83, wherein the disorder is epilepsy. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 78. A pharmaceutical composition prepared by mixing the product of claim 78 with a pharmaceutically acceptable carrier. 79. A method of preparing a pharmaceutical composition comprising mixing the product of claim 78 with a pharmaceutically acceptable carrier. 79. A method of treating epilepsy or related disorders comprising administering a therapeutically effective amount of the product of claim 78 to a subject in need thereof. 89. The method of claim 88, wherein the disorder is epilepsy.

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