TW200901966A - Process for the preparation of benzo-fused heteroaryl sulfamates - Google Patents

Abstract

The present invention is directed to a process for the preparation of benzo-fused heteroaryl sulfamates, useful for the treatment of epilepsy and related disorders.

Description

200901966 IX. Description of invention: Cross-referencing to the relevant slaughter application claim is claimed in 2〇〇7, 〇U u日木^Please, the interest of the case, is incorporated in its entirety as = [Technical field to which the invention belongs] The present invention is directed to a method of preparing a benzo-fused heteroarylamine sulfonate for use in the treatment of epilepsy and related diseases. 10 [Prior Art] Epilepsy is a condition used to describe an individual's slow, long-term, and repeated episodes. Because of the cause, epilepsy is classified as a clinical phenomenon rather than a single disease. With the definition of two or more unexplained episodes as epilepsy, the incidence of epilepsy is estimated to be about 0.3% to 0.5% in different populations around the world, and the prevalence of epilepsy is estimated to be in each There are 5 to 10 people among 1 person. The main steps in the assessment and management of patients with seizures determine the type of seizure that has occurred. The main characteristic of the different types of seizures is whether the seizure activity is local (equivalent to focal) or systemic local. The seizure refers to the separation activity of the seizure activity limited to the cerebral cortex. 'If the seizure is completely clear, the clinical manifestation is considered to be relatively simple and the episode is called a simple local episode (simple-partial 200901966 seizure), if the episode Insufficient consciousness, this episode is called a complex-partial seizure - important additional sub-items include those that were originally localized and re-diffused to the entire cortex, known as the part The episode evolves into a partial seizufes 5 with secondary generalization. The generalized seizures simultaneously intervene in the diffusion zone of the brain in a bilaterally symmetrical pattern. The absence of episodes (small episodes) Absence or petit Mal seizures) is characterized by sudden, short-lived loss of consciousness without loss of posture control Atypical seizures typically include a duration of more than 10 longer, less pronounced onset and interruption, and more obvious signs of motion that may include or are limited to one side; generalized stiffness Tonic-clonic or grand mal seizures are the main types of generalized seizures. They are characterized by a sudden onset of no warning. The initial stage of the attack is usually a tonic contraction of the muscles, a poor breathing, and a significantly improved sympathy. 15 sympathetic tone leads to increased heart rate, stress, and pupil size 'after 10-20 seconds' the tonic phase of epilepsy typically progresses to the clonic phase 'in tonic Muscle contraction occurs during the period of superimposed muscle relaxation, gradually progressing during relaxation until the end of the ictal phase, which usually lasts no more than 1 minute; posttic seizure (postictal 20 phase) is characterized as non-responsive (unresponsiveiiess) ), muscle flaccidity, and excessive secretion of saliva that may cause stridorous breathing and Airway obstruction; Atonic seizures are characterized by sudden loss of muscle energy in a posture, lasting 1-2 seconds, short-term unconsciousness, but usually unconscious after the episode of 200901966 (postictal confusion); muscle pumping Myoclonic seizures are characterized by a sudden and brief muscle contraction that may involve a part of the body or the entire body. (Harrison丨s Online, March 29, 2001).

McComsey, D. et al., U.S. Patent Publication No. 2006/0041008 A1, issued Feb. 23, 2006, and U.S. Patent Publication No. 2005/0282887 A1, issued toK. The use of the compounds of formula (I) and their use in the treatment of epilepsy and related diseases, McComsey, D. et al. in US Patent Publication US Patent Publication US 2006/0041008 A1 and McComsey, D. et al. A method of preparing a compound of formula (1) 'also includes reacting a suitable substituted amine with an amine acid sulphate. In the method disclosed by McComsey D. et al., the compound of the formula (1) wherein R1 and R2 are each hydrogen, and the use of the amine sulfonyl chloride (cl_s〇2_NH2) as a reagent, the reagent is not suitable for large scale In any case, there is still a need for a method for preparing a large-scale/commercial compound for preparing the compound of the formula (1). SUMMARY OF THE INVENTION The present invention is directed to a method of preparing a compound of formula (I).

(CH2)a- R4 〇 -N—S—

R1 NH where & 0) 200901966 R1 is selected from the group consisting of hydrogen and lower alkyl; R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; ©: is selected from the following Base

10 15 wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R 5 is independently selected from the group consisting of halogen, lower alkyl, and nitro

200901966 or a pharmaceutically acceptable salt thereof. The present invention is directed to a process for the preparation of a compound of formula (IA) (CH2)a-R4 〇 R1 -Ν-S-ΝΗ II , ο (ΙΑ)

Ίο is nitrogen, selected from the group consisting of hydrogen and lower alkyl; an integer from 1 to 2; selected from the group consisting of (R5)t 5 (Τ^ν^°Ν (R5)t

Η 15

200901966 where b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of _, lower alkyl and nitro

Or a pharmaceutically acceptable salt thereof; 10

A compound of the formula (X) and a compound of the formula (XI) wherein -C(0)0R is a nitrogen protecting group; in an organic or inorganic compound which does not react with a chlorine group on the compound of the formula (XI) In the presence of a base; reacting in an aprotic organic solvent to produce the corresponding compound of formula (XII);

-10-200901966 The compound of formula (XII) is subjected to a deprotection reaction to obtain a corresponding compound of formula (IA). The invention also relates to a method of preparing a compound of formula (IB)

(IB) where

10 series selected from the group consisting of lower alkyl groups; selected from the group consisting of hydrogen and lower alkyl; an integer from 1 to 2; selected from the group consisting of

15 (R5)c

And (R5)b-

-11 - 20 200901966 wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; Θ is (R5)t For when

When a is > or a pharmaceutically acceptable salt thereof; comprising /^\ /r4 (CH2)a-NH (X) Ο II Cl-S-NH II 〇-OR0 R4 (XI) (CH2 )a- (XII) >f. HN-OR0 15 a compound of formula (X) with a compound of formula (XI) wherein -CXCOOR0 is a nitrogen protecting group; an organic or inorganic base which does not react with a chloro group on a compound of formula (XI) In the presence of; reacting in an aprotic organic solvent to produce the corresponding compound of formula (XII);

-12- 200901966 A compound of the formula (XII) is reacted with a compound of the formula (XV) wherein Q is a liberating group; and the compound of the formula (XVI) is obtained by performing in an organic solvent.

The compound of the formula (XVI) is subjected to a deprotection reaction to obtain a corresponding compound of the formula (IB). In a specific embodiment, the present invention is directed to a method of preparing a compound of the formula (Ι-S)

0-S) 15 or a pharmaceutically acceptable salt thereof (also referred to as A4[(25>6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl]) Amino-sulfonamide, including

N. ^OR°

;\T -13- 20 200901966 The compound of formula (Χ-S) and the compound of formula (XI), 'where _c(〇)〇r〇 is a nitrogen protecting group' does not differ from formula (XI) The reaction of the gas on the compound in the presence of an organic or inorganic base; the reaction is carried out in an aprotic organic solvent to produce the related compound of formula (XII-S);

The compound of the formula (XII-S) is subjected to a deprotection reaction to obtain a related compound of the formula (Ι-S). The present invention is also directed to a crystal form of a compound of the formula (Ι-S), which is hereinafter referred to as a crystalline form (I-SA). The invention also targets compounds of formula (XII)

Wherein -C(〇)〇R〇 is a nitrogen protecting group and wherein

And R are each as defined, preferably, _c(〇)〇RQ is a nitrogen protecting group selected from the group consisting of Cw alkyl (preferably agricultural tri-butyl), benzoinyl, if- Methoxybenzyl and 9_ylmethyl, more preferably, _c(〇)OR0 -14- 200901966 is #三-butoxycarbonyl (ie, RG is N-butyl), formula (XII) The compound is used as an intermediate for the synthesis of the compound of formula (I). The invention is also directed to a product prepared according to the process. The description of the invention comprises a pharmaceutically acceptable carrier and a pharmaceutical composition of the product prepared according to the method of 5; the invention illustrates the preparation of the product according to the method and a pharmaceutically acceptable A pharmaceutical composition prepared by admixing a carrier; the invention illustrates a method of preparing a pharmaceutical composition comprising mixing a product prepared according to the method of the invention with a pharmaceutically acceptable carrier. An exemplary embodiment of the invention is a method of treating epilepsy or a related condition comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. DETAILED DESCRIPTION OF THE INVENTION 15 The present invention is directed to a method of preparing a compound of formula (I) R4 〇 尸1

^Rj\—{CH2)a A N-S—NH 〇(丨) 2〇 wherein R1, R4, a and each have the meaning as defined, the compound of formula (I) is used for the treatment of epilepsy (epilepsy) And related diseases. In a specific embodiment, the invention is directed to a compound of formula (IA) -15 - 200901966 method

Each is as defined above wherein R1 is hydrogen, and wherein R4, a and are meant; and pharmaceutically acceptable salts thereof. In another embodiment, the invention is directed to a method of preparing a compound of formula (IB) ίο

(IB) is wherein R1 is a group selected from the group consisting of lower alkyl groups, and wherein R4, a and 0 are each as defined; and a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to a method (Rs)b- for the synthesis of a compound of formula (IC).

(IC) 200901966 and pharmaceutically acceptable salts thereof, wherein b and R5, each as defined, preferably b is an integer from 0 to 2; more preferably, b is from 0 _ to 1 Integer, preferably, R5 is halogen, more preferably chlorine. 5 10 15 In one embodiment of the invention, R1 is selected from the group comprising hydrogen and a mercapto group; in another embodiment of the invention, R1 is hydrogen. In a specific embodiment of the invention, the -(CH2)a- is selected from the group consisting of -CH2- and -CH2-CH2-; in another embodiment of the invention, -(CH2)a- is -CH2 -. In one embodiment of the invention, R4 is selected from the group comprising hydrogen and an anthracenyl group. Preferably, R4 is hydrogen. In a specific embodiment of the invention, a is one. In a specific embodiment of the invention, b is an integer from 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 0 to 1. In another embodiment of the present invention, c is an integer from 0 to 1. In still another embodiment of the present invention, the sum of b and c is an integer from 0 to 2; preferably 0 to 1. Integer; in another embodiment of the invention, b is an integer from 0 to 2 and c is zero.

It is selected from a ring structure comprising a specific embodiment of the invention described below:

-17- 20 200901966

The system is selected to include one of the following ring structures:

, ❹ 15 In one embodiment of the invention, a ring structure comprising the following groups is selected: 2-(chromanyl), 2-(6-chloro-2,3-dihydro-benzo[1] , 4] dioxonic base), 2-(benzo[1,3]dioxanyl), 2-(5-chloro-2,3-dihydro-benzo[1,4]dioxin , 2-(7-trikily-2,3-dihydro-benzo[1,4]dioxin, and 2-(6,7-dichloro-2,3-dihydro-benzo[1] , 4] dioxonic), 2-(2,3-dihydro-naphtho[2,3-b][l,4]dioxin, and 2-(7-chloro-benzo[1] , 3] dioxin group; in another embodiment of the invention, the lanthanide is selected from a ring structure comprising the group 2-(5-chloro-2,3-dihydro-benzo[1, 4] dioxon), 2-(7-nitro-2,3-dihydro-benzo[1,4]dioxin, 2-(6,7-dichloro-2,3- Dinitro-benzo[1,4]dioxanthine base and 2-(2,3-diaza-cai[2,3-7][1,4] dioxane). In a specific embodiment of the present invention, the following selections are included: -18- 20 200901966 10

(R5)b- (R5)b-

Ni

In one embodiment of the invention, the following are selected from the group consisting of: 2-(2,3-dihydro-benzo[1,4]dioxin n well base), 2_(benzo[i,3] Di-sigma oxon 20 base), 2-(3,4-dihydro-benzo[1,4]dioxinyl), 2-(6-chloro-2,3-dihydro-benzo[1] , 4] dioxonic base), 2-(6-fluoro-2,3-dihydro-stupid [1,4] dioxane), 2-(chromanyl), 2-(5-fluoro) -2,3-dihydro-benzo[1,4]dioxin D well base), 2_(7-chloro-2,3-monohydro-stupid [1,4]dioxa 13 well base), 2_(6-chloro-benzo[1,3]dioxyl), 2-(7-nitro-2,3-dihydro-stupid [1,4]dioxin), 2-( 7-fluorenyl 2 - 3-anthracene - Benzo [1,4]-° oxa 0-base), 2-(5-chloro-2,3-dihydro-benzo-, 4]-dioxa- morphine Base, 2-(6-bromo-2,3-dihydro-benzo[1,4]dioxin), 2-(6,7-dichloro-19- 200901966

The system is selected from the group consisting of 2,3-dihydro-benzo[1,4]dioxan-1 well, 2-(8-chloro-2,3-dihydro-benzo[1,4] 2. Ester alpha well base), 2-(2,3-dihydro-naphtho[2,3-b][ 1,4]dioxanthyl) and 2-(4-methyl-benzo[ 1,3] dioxin base). In another embodiment of the present invention, the group is: 2-((benzo[I,3]dioxyl), 2-(2,3-dioxin-benzo[1,4]dioxin), 2-(6-Gas-2,3-dihydro-benzo[1,4]dioxin), 2-(7-chloro-2,3-dihydro-benzo[1,4] dioxins Tillage), 2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin, 2-(6-bromo-2,3-dihydro-benzo[1] , 4] dioxonic base) and 2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin); another embodiment of the invention

It is selected from the following bases: 2-(2,3-dihydro-benzo[1,4]dioxin), 2-(7-methyl-2,3-dihydro-benzo[1] , 4] dioxon) and 2-(6-bromo-2,3-dihydro-benzo[1,4]dioxin. In one embodiment of the invention, the R3 is selected from the group consisting of halogen, lower-grade, lower-grade alkyl substituted by a base, -0-(lower alkyl), nitro, cyano, amine , a lower alkylamino group and a di(lower alkyl)amine group; in another embodiment of the invention, the R3 is selected from the group consisting of a halogen and a nitro group; in another embodiment of the invention, the R3 system Selected from the base including chlorine and nitro. In one embodiment of the invention, R5 is selected from the group consisting of (II) halogen and lower alkyl; in another embodiment of the invention, R5 is selected from the group consisting of chlorine, fluorine, bromine and sulfhydryl groups.

In a specific embodiment of the invention, in the compound of formula (I), -20- 200901966

Is not 〇' where b is 1 and R3 is selected from the group consisting of halogen, acetyl, cyano, amine, lower alkyl, lower methoxy, and 〇(〇)〇_ (lower alkyl); In another embodiment of the invention, in the compound of formula (ι)

Wherein b is a specific implementation of the present invention, and the stereocenter system 10 15 20 of the compound of the formula (1) belongs to the S-configuration. In another embodiment of the present invention, the stereocenter of the compound of the formula (1) belongs to the R-configuration. In a particular embodiment of the invention, the compound of formula (1) is in the form of a mixture of images that are enriched in a mirror image, with an excess of (_ti〇menc ennchment, %ee) of greater than about 75%, preferably Greater than about 85%, more preferably greater than about 90%, still more preferably greater than about 95% to about 98%. In a specific embodiment, the present invention is directed to - or a plurality of representative compounds as shown in formula (1), in Table 1 below, the column means attached to the star mark The heterocyclic ring of the bond: = The symbolic symbol refers to the compound produced by the stereotype of the mixture, when labeled as "r,, or", this stereoscopic configuration is based on the image-rich starting material. . 〆 -21. 25 200901966 Table 1: Representative compounds of formula (i)

R4 〇R1 (0^(CH2)a-N-!-'2 No. 立体 Stereo (CH2)a NR4 R1 R2 1 2-(2,3-Dihydro-benzo[1,4]dioxin 4-yl) Ch2 NH HH 2 2-(benzo[1,3]dioxyl) ch2 NH HH 3 2-(3,4-dihydro-2^1-benzo[1,4]dioxyl) ch2 NH HH 4 2-(2,3-dihydro-benzo[1,4]dioxin) S ch2 NH HH 5 2-(2,3-dihydro-benzo[1,4] dioxonic R ch2 NH HH 7 2-(2,3-dihydro-benzo[1,4]dioxanyl) ch2 N(CH3) HH 8 2-(6-chloro-2,3-dihydro-benzene And [1,4] dioxonic base) S ch2 NH HH 9 2-(6-fluoro-2,3-dihydro-benzo[1,4]dioxin) S ch2 NH HH 10 2-( Chromatidine) ch2 NH HH 13 2-(5-fluoro-2,3-dihydro-benzo[1,4]dioxin) S ch2 NH HH 14 2-(7-chloro-2,3· Two rats _ benzo[1,4] dioxonic base) S ch2 NH HH -22- 200901966

15 2-(6-Chloro-benzo[1,3]dioxanyl) ch2 NH HH 16 2-(2,3-Dihydrobenzo[1,4]dioxin) ch2ch2 NH HH 18 2- (7-nitro-2,3-dihydro-benzo[1,4]dioxin) S ch2 NH HH 19 2-(7-methyl-2,3-dihydro-benzo[1, 4] Dioxin) S ch2 NH HH 20 2-(5-chloro-2,3-dihydro-benzo[1,4]dioxin) S ch2 NH HH 22 2-(8-oxime Benzyl-2,3-diindole-benzo[1,4]dioxin cultivating) S ch2 NH HH 24 2-(6-bromo-2,3-dihydro-benzo[1,4] dioxin Base) S ch2 NH HH 29 2-(6,7-dichloro-2,3-dihydro-benzo[1,4]dioxin) S ch2 NH HH 30 2-(8-chloro-2, 3-dihydro-benzo[1,4]dioxins) S ch2 NH HH 33 2-(2,3-dioxin-naphtho[2,3-b][l,4] dioxane S ch2 NH HH 35 2-(4-methyl-benzo[1,3]dioxanyl) ch2 NH HH In another embodiment of the invention, including those wherein the substituent is selected from one or more The variables defined herein (eg, a, R1, R4, '0, R5, Yi Er Xi, etc.) are independently selected from individual substituents or selected from a subset of the substituents in the complete form. By. The invention also relates to compounds of formula (XII) -23 - 200901966 R4

(XU) wherein -c(o)org is a nitrogen protecting group and wherein

a, R4 and R1 have the meanings as defined; in one embodiment, the invention is directed to a compound of formula (XII-S).

Wherein -C(O)〇R0 is a nitrogen protecting group, preferably, _c(〇)〇R0 is a nitrogen protecting group, wherein the group is selected from the group consisting of an alkoxycarbonyl group and an aryloxy group. More preferably, the RG is selected from the group consisting of cj 4 alkyl (preferably 茗=-butyl), phenyl fluorenyl, oleomethoxyphenyl, phenethyl, phenyl, More preferably, the R oxime is selected from the group consisting of Cw alkyl (preferably | tri-butyl), benzyl, dimethyl methoxy benzene 20 Further preferably, the R0 is selected from the group consisting of tris-butylbenzyl, methoxyphenylmethyl and 9-dimethyl. ^ Unless otherwise stated, "崮素" means chlorine, bromine, fluorine and moth. Unless otherwise stated, the term "烧", when used alone or as part of ',, Γ, includes the base of a straight chain and a branch, such as '炫-24- 200901966 ^ , ethyl, diyl, isopropyl, butyl, isobutylbutyl, pentyl, etc. 'Unless otherwise noted," lower dioxane; as used, means carbon bonds having one carbon atom composition. Unless otherwise indicated, 'alkoxy,' refers to an oxygen-based group of the above-mentioned linear mosquitoes, for example, methoxy, oxo-butoxy, red butoxy, Is n-hexyloxy and so on. N-propoxy,::,: ί π aryl" means an unsubstituted carbocyclic aromatic such as benzyl, etc., preferably phenyl. A is not otherwise called '" 芳 · Aryl groups (for example, benzene

= Qinji College) Replace any of the lower grade J ethyl, phenylpropyl, naphthylmethyl, etc., preferably benzyl. Here, unless otherwise indicated, the term "I, cycloalkyl" refers to a saturated ring system of any of the hexagrams or polycyclic rings, preferably a single ring 15 system' more preferably a monocyclic one. Suitable examples of the saturated ring 2 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, %hexyl, cycloheptyl, cyclooctyl, gold alkyl, and the like. The symbol here is representative of the existence of a stereoscopic center. Here, unless otherwise stated, when used, enanti〇meriCally enriched, to describe a compound having a stereogenic center, refers to a stereoscopic configuration of the compound present. Far more than its other stereo-configuration, preferably referred to as enantiomedcally enriched, the desired mirror image isomer of the compound has an enantiomeric excess of at least about 75 More preferably, at least about 85% ee, more preferably at least about ee, still more preferably from -25 to 20 200901966, at least about 95% ee, more preferably at least 98% ee, most preferably at least 99% ee ° _ Here, unless otherwise stated, the term "nitrogen protecting group" refers to any ester group which acts as a protecting group for protecting an amine, guanamine or 5-aminosulfonamide. Nitrogen, suitable examples include, but are not limited to, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and the like, for example, the nitrogen protecting group may be of the formula -C(0)0RG, wherein RG is Cw alkyl (preferably agricultural tri-butyl), phenyl fluorenyl, decyl phenyl fluorenyl, benzene Ethyl, phenyl, naphthyl, cycloalkyl, 9-fluorenylfluorenyl, and the like, and any one of the R0 groups can be further substituted for 10 generations. The abbreviations used in the specification, especially in the charts and examples As follows: BOC or Boc ~ Tertiary-butoxycarbonyl (-c(o)oc(ch3)3) DIPEA or D1EA Diisopropylethylamine DMAP 4-(N,N-didecylamino Acridine DMF N,N-dimethyldecylamine EtOAc = ethyl acetate Fmoc-9-fluorenyl methoxycarbonyl MTBE = methyl tert-butyl ether Pd/C in bar/carbon catalyst RBF round bottom Flask Rt or rt Room Temperature TEA Triethylamine-26- 200901966 ----- PTFA ___ """""One* --'''''-- Trifluoroacetic acid THF _ -- -^ ----__ Tetrahydrofuran - XRD -J — ________ ____- X-ray diffraction-----' " , --- Here, unless otherwise noted, ''epilation and related "Disease" or "_癎 and related diseases" means any 5 diseases in which a subject (preferably an adult, a child or an infant) experiences one or more seizures and/or tremors. Suitable examples include, but are not limited to, epilepsy Includes, but is not limited to, local-related epilepsy, generalized epilepsy, epilepsy with both general and localized, etc. 'because convulsions are a disease or condition (eg, associated with a brain lesion ( The onset of encephalopathy, phenylketonuria, adolescent Gaucher's disease, Lundborg's ίο type myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or cessation of drug use, alcoholism or cessation Complications of alcoholism, sleep deprivation, etc., essential tremor, restless limb syndrome, etc.; preferably, the disease is selected from epilepsy (regardless of Preferably, the disease is a primary head or a limb disorder, and the disease is epilepsy (regardless of its type, underlying cause or origin) or primary tremor. As used herein, the term "subject" is used to mean an animal, preferably a mammal, preferably a human, which is or has been the subject of treatment, care or examination. 20 The term "therapeutically effective amount" as used herein refers to the active compound or agent f, which can be cared for by a researcher, veterinarian, doctor or his clinician at 27-200901966. A tissue system, animal or human that induces a biological or W-reactant, including a symptom or disease that slows down the disease. The term 'composition,' used to cover a product It is a specific component that contains a specific amount, and any product that is produced, directly or indirectly, from a specific combination of specific components. Experts in the art will be identifiable, although not explicitly stated, the reaction steps in the patent specification and the scope of the patent application are based on known methods, under appropriate conditions (eg, temperature, pressure, appropriate use) The solvent and/or the reactants are carried out to obtain the desired product. The term "suitable conditions" means the method according to the known method 'in the appropriate conditions (for example, temperature, pressure, use of a suitable solvent and / or reactants - a reaction step to obtain the desired product. Experts in the art will also be able to recognize that, in the patent specification and the patent application, where one of the reagents or reagents is, for example, the test/valley, the specialist is detailed as a method of more than one step The individual reagents are independently selected for each reaction step and may be the same or different from each other, for example, wherein the two steps of the method detail an organic as a reagent, and the organic base selected as the first step may be selected. It is the same as or different from the organic or inorganic base in the second step. In order to provide a more concise description, some of the quantities given herein are expressed in a non-limiting manner of "about", understandable, whether or not, "to make clear instructions, each given here The quantity is based on the true given value and is also related to the approximation of the value given by the expert based on common sense, including the approximate value of the experimental and/or measurement conditions of the given value. -28 - 200901966 Unless It is also indicated that any box of non-proton solvents in the north of your family will refer to solvents that do not produce quality. Suitable examples of Bayfield include, but are not limited to, DMF, alkane, THF, benzene, and the like. Acetonitrile, pyridine, di-ethane, dioxin, MTBE, 曱 不 不 ” ” ” - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Benzene sulfonate, and the like. Not limited to Br, a, I, sulfonate, A 10 15 which can be attached to a 氮 ' ' nitrogen protecting group" - the word refers to a species, and the bean can participate in the protection of the nitrogen atom For a reaction remover, a suitable nitrogen protecting group is, for example, methyl ethyl 2 曰 ^ m phenyl di-butyl, phenyl fluorenyl, phenylethyl, chlorobenzyl methyl, 9-diyl曱基等, CH尸CH_CH2_, etc.; 酉1111 amine has the formula _C(0)-R', wherein R' is, for example, fluorenyl, phenyl, difluoroindenyl, and the like; The sulfonyl derivative is a formula of _s〇2_R, where 'R' is 'for example' phenyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethyl Full-6-yl, 2,3,6-tridecyl-4-nonyloxybenzene, and the like, other suitable nitrogen protecting groups can be found in textbooks, for example, TW Greene & PGM Wuts, PiOtective Groups In Organic Synthesis. John Wiley & Sons, 1991. When the compounds according to the invention have at least one center of the palm, they may therefore exist as enantiomers, which may re-form as non-image isomers when the compound possesses two or more pairs of palm centers. -29- 200901966 (diastereomers) 'understandable' all such isomers and mixtures thereof are covered by the scope of the invention, preferably, when the compound is present as a mirror image, The enanti〇rneric excess is present at greater than or equal to about 75%. More preferably, the mirror image is present at a mirror excess of greater than or equal to about 85%. More preferably, the mirror image is greater than or equal to the mirror excess. About 90% is present, and more preferably, the mirror image is present at a mirror excess of greater than or equal to about 95%, and more preferably, the mirror image is present at a mirrored over f of greater than or equal to about 98%, optimally' The mirror image is present in a mirror image excess of greater than or equal to about 99%, and similarly, when the compound is present in a non-mirrored material, the non-mirrored material is stored in a non-image excess (diastere 〇meric excess) of greater than or equal to about 75%. More preferably, the non-mirror object is present, if the excess is greater than or equal to about 85%, more preferably, greater than or equal to about 90% is present in the non-mirror, and more preferably, in the non-mirror excess 15 20 is present at greater than or equal to about 95%, and more preferably, greater than or equal to about 98% in a non-image excess, and most preferably greater than about 99% in a non-image excess. Furthermore, some of the crystalline forms of the compounds of the invention may exist in a one-form form and are encompassed within the scope of the invention. Furthermore, the b-di- 1 conjugates of the invention may be associated with water (ie hydrates) or The solvent forms a solvent ★ and such solvates are encompassed within the scope of the invention. The long-standing behavior is identifiable. The reaction step of the present invention can be carried out in various types of the solvent H solvent system (10). The reaction step can also be carried out in a mixture of the appropriate 1 or solvent system. When a mixture of stereoisomers 30-200901966 is produced by a method for preparing a compound according to the present invention, these isomers can be separated by conventional techniques, such as chromatography, and the compound can be prepared as an external compound. Racemic forms, or individual mirror image isomers prepared by mirror-specific synthesis or analytical methods, which compounds can be resolved, for example, by standard techniques into their component 5 mirrors, eg, An optically active acid, for example, di-Mulberry phenyl-D-tartaric acid and/or (+)-di-p-quinone-phenyl-L-tartaric acid, forms a non-mirrored counterpart by salt formation reaction, followed by Partially crystallized and regenerated into a free base; the compound can also be resolved by 10 ' or 'compounds' by forming a non-mirrored molecule or a guanamine' followed by chromatographic separation and removal of the aid to the palm It is also possible to use a HPLC column for palm separation. In any method for preparing a compound of the invention, it may be necessary and/or necessary to protect any molecularly sensitive or reactive group involved. This can be achieved by conventional methods of protecting groups, such as those Described 15 on Protective _Groups _in Organic Chemistry ed. JFW

McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M.

WutS, Organic Synthesic John Wiley &

In Sons, 1991, this protecting group can be removed at a convenient subsequent stage using methods known in the art. 〇 For medical use, the salt of the compound of the present invention is a non-toxic "pharmaceutically acceptable salt", however, other salts are also useful for the preparation of a compound according to the invention or a pharmaceutical thereof. Acceptable salts, pharmaceutically acceptable salts of the compounds include acid addition salts thereof, for example, by solution of the compound with a pharmaceutically acceptable base (preferably - 31-200901966 is formed by mixing a solution of a strong base such as NaOH, KOH, NaH, choline hydroxide, etc.. The present invention is directed to a process for preparing a compound of formula (I), formula (IA) Compounds (compounds of formula (I) wherein R1 is hydrogen) can be prepared according to the method outlined in Figure 1 which is described in more detail below. /^\ /r4 (CH2)a-NH (X)

Figure 1 15 Thus, a suitably substituted compound of formula (X) which is a compound known or obtainable by known methods, is substituted with a suitable one of formula (XI) a compound reaction wherein -c(o)orq is a suitable selected nitrogen protecting group, for example, an alkoxycarbonyl group, an aryl 2 methoxycarbonyl group, an aralkoxycarbonyl group, and the like, for example, wherein RQ Is Cw alkyl (preferably agricultural tri-butyl), phenyl fluorenyl, #-decyl phenyl fluorenyl, phenylethyl, phenyl, naphthyl, cycloalkyl, 9-fluorenyl fluorenyl, etc. And the like, and any of the Rg groups may be further substituted, a known compound or a compound prepared by a known method. 25 In the presence of an organic or inorganic base, the organic or inorganic base does not act on the chlorine group on the compound of -32-200901966. It is preferred to use an organic base, and N 糸 is tested with a tertiary amine. For example, DIPEA, TEA, pyridine, medium, porphyrin, N-methylhexahydropyridine, and the like, preferably pyridine; it is present in an amount greater than about 1 mole equivalent, more preferably present From about L1 non-quality molar molar equivalents; optimally present to be about 2.0 mole equivalents; in a good amount of organic solvent, such as DMF, THF, acetonitrile, etc., more soil: ί At about 5G. (10) A compound of the formula (XII) having a correlation between the temperature ranges. , (XII) (4) The method of knowing the compound, to obtain a compound corresponding to J ^ A), for example, a compound of the formula (XII) with an acid or a compound of the formula (ΧΠ) with hydrogen or a hydrogen source reaction, preferably, when the nitrogen protecting group (_C(0)0R.) is a BOC, the compound of the formula (XII) is de-acid (for example, 'TFA, Ηα, etc., preferably The ground is α)) when the reaction is ', [, in an organic solvent such as TJJF, ethyl acetate, etc., or the nitrogen protecting group (_c(〇)〇r.) is a benzyl group) Deprotection of the compound of =XII) is carried out in an organic solvent in the presence of a gas or a chlorine such as a hydrating agent (for example Pd/C) from about 10 psi to about 60 psi. For example, ethanol, methanol, hydrazine 20 (, crot 〇 Ucf} reacts to achieve 'or ' til protection of the phenomethyl group when the compound of formula (XII) deprotection system: by two such as a Amine test, for example, six (four), in an organic solvent (such as DMF, etc.). The basis of the formula is prepared according to the method outlined in Figure 2 below. -33- 200901966

0 (XVI)

R4 (CH2)a-·"〇OB) °^HN~R1 Figure 2 i〇 According to the chart, the appropriately substituted compound of the formula (ΧΠ) prepared in the above Table 1 is appropriately The selected compound of the formula (XV) is reacted as a pyridyl halide or an alkyl group, wherein Q is a suitable cleavage group such as 'Cl, Br, I, _〇_s〇2 -CH3 (曱 reading acid), -〇-S02-CF3 (trifluoromethane), -〇-S〇2-曱phenyl (anthracene 15), etc.; Organic or inorganic tests (eg, K2C〇3, Na2C03,

In the presence of NaOH, KOH, pyridine, DIPEA, TEA, etc.), preferably a tertiary amine base, more preferably pyridine; in an organic solvent such as THF, acetonitrile, DMF, etc.; The grounding is carried out at a temperature ranging from about ot to about 5 Torr; the relevant compound of formula (XVI) is obtained. 20 Deprotection of a compound of formula (XVI) according to a known method to produce a compound of the formula (ΙΒ), for example, reacting an eight species of formula (χνΐ) with an acid or formula (XVI) The compound is reacted with hydrogen or a hydrogen source. Fortunately, when the nitrogen protecting group (-C(O)OR0) is BOC, the deprotection of the compound of the formula (XVI) is carried out by reacting with an acid (TFA, HCl, etc., preferably 25 reaction; is carried out in an organic solvent, for example, THF, ethyl acetate, etc. -34-'200901966, or the nitrogen protecting group (-(:( 0) When 011% is a benzyl group, the deprotection of the compound of formula (XVI) is from about 10 psi to about 60 psi in the presence of a catalyst (e.g., Pd/C) with hydrogen or a source of hydrogen, such as hydrogen. Between the pressure ranges, the reaction is carried out in an organic solvent (for example, ethanol, methanol, toluene, 5 acetic acid, etc.), or the nitrogen protecting group (-C(O)OR9) is 9-» methyl group. When the compound of formula (XVI) is deprotected by an assay (eg, an amine test, eg, hexahydropurine, morphine, etc.) in an organic solvent (eg, The compound of the formula (1) is isolated according to a known method, for example, by filtration, solvent evaporation, etc., preferably, the compound of the formula (I) is known according to known methods. The method is further purified, for example, by recrystallization from a suitable solvent (for example, water, toluene, etc., preferably toluene). In a specific embodiment, the present invention is directed to a preparation formula ( The method of the compound of Ι-S) is summarized in Figure 3 below. CI—s—ΝΗ

Figure 3 -35 - 200901966 Thus, a suitably substituted compound of formula (xs), also known as C-(6-chloro-2,3-dihydro-benzo[I,4] dioxin _2_yl)-methylamine, a known compound wherein -C(O)〇R0 is a suitably selected protecting group, for example, an alkoxycarbonyl group, an aryloxycarbonyl group, an aromatic group Alkoxy 5 carbonyl, and the like, for example, wherein "Cm alkyl (preferably third butyl), benzyl, s-nonylphenyl phenyl, phenylethyl, phenyl, Naphthyl, cycloalkyl, 9-fluorenyl fluorenyl, and the like, and any of the R fluorenyl groups may be further substituted, a known compound or a compound prepared by a known method. In an organic or inorganic base In the presence of an organic or inorganic base, it does not act with a chlorine group on the compound of formula (XI), preferably an organic base, more preferably a tertiary amine, for example, DIPEA, TEA," 唆, N-methylmorpholine, N-fluorenylpyridinium pyridine, etc., preferably pyridine; wherein the base is preferably present in an amount greater than about 1 mole equivalent, more preferably present About 1]L About 3.0 mole equivalents; optimally present at about 2.0 mole equivalents; in a 15 aprotic organic solvent, such as DMF, THF, acetonitrile, etc., preferably in acetonitrile; preferably About 〇. 〇 to a temperature range of about 50 ° C; to obtain a related compound of the formula (XII-S). The compound of the formula (XII-S) is deprotected according to a known method to prepare a related formula a compound of (Ι-S), for example, a compound of the formula (XII-S) is reacted with a phthalic acid or a compound of the formula (ΧΠ-S) is reacted with hydrazine or a hydrogen source, preferably When the nitrogen protecting group (_C(0)OR〇) is B〇C, the compound of formula (xn_S) is reacted with an acid (for example, TFA, HC1, etc., preferably HCl) to deprotect; In an organic solvent, such as THF, ethyl acetate, etc., or wherein the nitrogen protecting group (-C(O)OR0) is a benzoquinone-36-200901966 base, a compound of the formula (ΧΙΙ-S) Deprotection is carried out by a reaction with rhodium or a hydrogen source such as hydrogen in the presence of a catalyst (e.g., Pd/C) at a pressure ranging from about 10 psi to about 60 psi in an organic In the presence of an agent (for example, ethanol, decyl alcohol, terpene, acetic acid, etc.), or when the nitrogen is protected (-CXCOOR% is 9-mercaptopurine, the formula (ΧΙΙ-S) Deprotection of a compound is carried out by an assay, such as an amine test, for example, hexahydropyridinium, morpholine, etc., in an organic solvent (e.g., DMF, etc.). The compound is isolated according to a known method, for example, by filtration. Preferably, the compound of the formula (Ι-S) is subjected to purification according to a known method, for example, using a recrystallization method. The crystals are reprecipitated in a suitable solvent (for example, water, toluene, etc., preferably toluene). The compound of the formula (XI) is a known compound or a compound which can be produced by a known method. For example, the compound of the formula (XI) can be produced according to the method outlined in the following Table 4. 15 〇

R〇—OH ο

Cl——S——N=C=〇

Cl—S—NH (XIII) (XIV) 〇

OR0 (XI) Figure 4 Thus, a suitably substituted compound of formula (XIII) is a known compound or a compound which can be prepared by known methods, and is suitable for a compound of formula (XIV). a selected alcohol wherein the compound of formula (XIV) is preferably present in an amount of about 1 mole equivalent; in pure form or in a non-ionic agent (for example, acetonitrile, acetic acid, benzene, etc. a diorganic; a cereal, a compound of the formula (XIII) and a compound of the formula (XIV), wherein the strip is dissolved in a solvent and does not react with a solvent; preferably, the moiety is partially C to about room temperature. The temperature range is carried out; the formula (XI), the self, and the force are obtained. The compound of the formula (XI-S), wherein R0 is the third-butyl group, is prepared in accordance with the method outlined in Table 5. ‘ can be based on Figure 0 II CI—S—N=C=0 II 0 (XIII) 乂 Η (XIV-S) 0

ο II Cl—S—NH 〇 -〇

(Xl-S) Figure 5 15 Thus, a known compound, cyanatidosulfuryl chloride, is reacted with a known compound, tert-butanol, wherein a third-butanol is present as Approximately 3 equivalents; reacted in an aprotic or in an aprotic organic solvent (eg, 'acetonitrile, ethyl acetate, toluene, etc.), provided that the compound of formula (XIII) and formula The compound of χιν) is at least partially soluble in the solvent and does not react with the solvent; preferably, it is reacted in a pure state or in acetonitrile, preferably at a temperature ranging from about to about room temperature, more preferably Joel. The underarm is carried out; the compound related to the formula (XI_s) is also referred to as [dm oxo]_amino-38- 20 200901966. A crystalline form of the compound, the powder X-ray diffraction (PXRD) spectrum of the formula G-s) is identified. ^ In a specific example, the crystal form of the compound of 4 / τ 龆 ΡΥΡΓ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 化合物 化合物 化合物 化合物About 10% of the relatively strong sound. The surname, preferably, the peak therein has a relative intensity of greater than or equal to about 25% relative intensity. 10 The crystal form of the compound of the specific formula can be confirmed by its associated PXRD peak, wherein the peak is defined by its position (.浼), ^ interval (human) and relative intensity (%); In a particular embodiment, the crystalline form of the compound of formula (I_S) can be confirmed by its associated PXRD peak, wherein the peak is defined by its position (° 2 Θ) and d-interval (human). The powder XRD spectrum of a representative sample of the crystalline form of the formula (A-S) compound OSA) is shown in Fig. 1, and the characteristic peaks are shown in Table 2 below. This PXRD spectrum uses an X-Celerator. Detector, scan from 3 to 35. 20, each step size is 0.0165. 2^, each step time is 10.16 seconds, the effective scan rate is 0.2067 < V seconds 'the instrument voltage is 45 Κ ν and the current is set to 40 mA Determined below. To a g "I-SA" type or position (°2Θ) d-space (human) relative intensity (%) 4.44 19.92 33 -39- 20 200901966 15.50 5.72 14 17.32 5.12 48 18.57 4.78 100 19.39 4.58 10 19.86 4.47 30 20.03 4.43 20 20.88 4.26 51 21.57 4.12 23 21.93 4.05 24 22.71 3.92 13 23.19 3.84 14 23.90 3.72 29 24.53 3.63 16 25.02 3.56 25 26.04 3.42 19 26.71 3.34 16 26.84 3.32 13 28.28 3.16 26 29.96 2.98 12 30.70 2.91 21 -40- 200901966 Also included is a pharmaceutically acceptable composition comprising ~10 15 a compound prepared by any of the methods described herein, and a pharmaceutically acceptable compound comprising one or more of the compounds described herein. The preparation of the pharmacy composition can be carried out according to the traditional pharmacological process of 'by close mixing of the compound or compound(s) with the genus &=, and the carrier can be visually administered to the desired path. (for example, oral, ^: Xiaohua first way) and a variety of different types can be used, so, liquid oral g agent 'like suspension, expectorant and solution, appropriate wear and additives include , glycols, oils, alcohols, flavors, preservatives, fixatives, colorants, etc.; in the case of solid oral preparations, such as powders, capsules and tablets, suitable carriers And additives include starch, sugars, release agents, granulating agents, lubricants, binders, disintegrating agents, etc., solid pharmaceutical preparations can also be coated with certain substances, such as sugars Or an enteric-coated coating to adjust the primary absorption site; for non-menstrual administration, the carrier usually contains sterile water and may be added to enhance the force: solution or preservative Other ingredients, injectable or infusible, can be formulated with an aqueous carrier and suitable additives. To prepare the pharmaceutical composition of the present invention, the conventional pharmaceutical technology is used as the active ingredient. The compound is intimately mixed with the carrier of the two, depending on the type of preparation to be administered, for example, oral, or like a parenteral manner for intramuscular injection, wherein a wide variety of forms are available, Preparation of oral dosage form Any conventional pharmaceutical medium, such as a liquid, such as a suspension, _ 丨 and _, a suitable carrier and addition of water, glycols, oils, alcohols , flavoring agents, preservatives, coloring agents, etc.; in the case of solid oral preparations, such as powders, capsules, small tablets, capsules and tablets, suitable carriers and additives include starch, sugar, Diluents, granulating agents, lubricants, binders, disintegrating agents, etc., due to the convenience of administration, tablets and capsules represent the most favorable oral dosage form, of which solids are obviously used. Pharmaceutical carriers, if necessary, tablets can be coated with sugar or enteric film by standard techniques; for parenteral administration, the carrier usually contains sterile water, but other additives may be added. Ingredients, for example, to help dissolve or to be added for preservation; it is also possible to prepare an injectable suspension, in which appropriate liquid carriers, suspending agents, and the like can be used; Each dosage unit, for example, a tablet, Capsules, powders, injections, teaspoons, and the like, will contain an appropriate amount of active ingredient for the delivery of an effective amount as described above, the pharmaceutical composition herein, in each dosage unit, for example, tablets, capsules Agents, powders, injections, suppositories, teaspoons, and the like, will contain from about 1 to about 1000 mg and can be administered at a dose of from about 0.01 to 300 mg/kg/day, or any range therebetween, preferably from A dose of about 0.5-100 mg/kg/day, or any range therebetween, more preferably from about 1.0-25.0 mg/kg/day, or any range of doses thereof, however, this dose may be based on the needs of the patient, The severity of the condition being treated and the compound used may be varied and may be administered daily or post-cycle. Preferably, these compositions are in unit dosage form, for example, tablets, pellets, capsules, powders, granules, sterile parenteral solutions or suspensions, metered gas solutions or liquid sprays, drops Agent, ampoule, automatic-42-200901966 injection design or suppository; for parenteral, intranasal, sublingual or rectal administration of the mouth' or for inhalation or insufflation; or The composition may be in a form suitable for administration once a week or once a month, for example, an insoluble salt of the active compound, such as a citrate, may be placed in a storage formulation (dep〇) For the preparation of solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, traditional tablet ingredients, for example, corn starch, lactose, sucrose , sorbitol, talc, stearic acid, stearyl magnesium, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, water' to form a compound containing the invention or a pharmaceutical thereof Can be forked a solid pre-formulated composition of a homogeneous mixture of salts; the so-called pre-formulated composition is a homogeneous 'system, wherein the active ingredient is laid down from the ground

Liao a low-reverse release, enteric film or coating, alcoholic and cellulose acetate polymerized acid anti-disintegration in the stomach and allow the inner layer to enter the twelve fingers f various materials can be used as such The steroidal materials include many having the appearance of a face, recording can be added for oral or oral administration or (4) shooting with the hair _ novel composition -43-200901966 liquid type including aqueous solutions, properly seasoning Thick slurry, aqueous or oily suspension, and emulsions flavored with edible oils (eg, cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as tinctures and similar pharmaceutical media, for aqueous suspensions Suitable dispersing or suspending agents include synthetic and natural gums, for example, tragacanth, acacia, alginate, dextran, carboxy Sodium methylcellulose, decyl cellulose, polyethylene pyrrolidone or gelatin. 10 15 20 The method for treating epilepsy and related diseases according to the present invention may also be carried out using a pharmaceutically acceptable composition comprising any one of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may be: a compound having a W between about 0.1 mg and 1 mg, preferably between about 5 pg and 500 g, or any amount in between, and may be The structure is a form suitable for any selected mode of administration; the carrier comprises an essential and inert pharmaceutical excipient, including, but not limited to, a binder, a buoyant, a slip agent, a flavor Agents, sweeteners, preservatives, colorants, and coatings; those suitable for oral administration include solid type, such as Shikou 'Le Pill, Rotary, Small Medicine, Capsule (each containing immediately Release, timing release = holding = release of the formulation), granules, and powders, as well as liquid type, non (four) liquid, concentrated liquid, granules, emulsion, and suspension, are used for non-chemical treatment Types include domain solutions, emulsions, and floats. In the ground, the compound of the present invention may be administered once or twice the dose of the bismuth, or the compound of the invention may be used as the skill; the expert's office ^ 44-200901966 by the nose The dosage form for internal administration, which is applied by topical application using a suitable intranasal vehicle or patch, is preferably administered in a continuous, relatively intermittent manner. For example, in the form of oral administration of a rotary tablet or capsule, the active drug έ and eight can be combined to provide a π-servable, non-toxic pharmaceutically acceptable inert carrier, for example, ethanol, glycerin, water. And, in addition, if necessary, it is necessary to add to the mixture, suitable (four) agents, lubricants, disintegration and coloring agents, suitable binders include, without limitation, starch, animal glue, natural sugars, for example Glucose or beta • lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, Sodium benzoate, sodium acetate, sodium chloride, and the like; disintegrators include, without limitation, starch, sulfhydryl cellulose, amaranth, bentonite, xanthangum, and the like. a liquid-sorrowing form of a suitable suspending or dispersing agent, for example, synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose, etc.; In the case of non-digestive tract administration, it is necessary to use sterile suspensions and solutions; when intravenous administration is necessary, isotonic preparations containing appropriate preservatives are usually employed. In order to prepare the pharmaceutical composition of the present invention, the compound of the formula (1) as an active ingredient is first intimately mixed with a pharmaceutically acceptable carrier according to a conventional pharmaceutical compounding technique, wherein the carrier is administered (for example, orally). Or a non-gastrointestinal form of the formulation may be selected in a variety of forms, suitable pharmaceutically acceptable carriers are well known in the art, some of which are -45-200901966, a commercially acceptable carrier The description can be found from: The Handbook of Pharmaceutical Excipients, a method for formulating a pharmaceutical composition by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. It is described in numerous publications such as: Pharmaceutical Dosage Forms: Tablets. Second Edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited by Avis et Al ; and Pharmaceutical Dosage Forms: Disperse Systems. Volumes 1- 2, edited by

Lieberman et al ; published by Marcel Dekker, Inc. When it is desired to treat epilepsy or a related condition, the compounds of the present invention can be administered in any of the foregoing compositions and in dosage regimens established in accordance with the present teachings. 15 The dose per sputum of the product may vary from 〇1 to 10,000 mg/adult/per 曰, or a wide range of any range therebetween, and when administered orally, the composition preferably contains 0.01, 〇 .5, οι, 〇5, ίο, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 mg of the active ingredient tablet form provides symptomatic adjustment of the dose of the patient being treated 2 〇 an effective amount of the drug is conventionally used from about 〇〇1 〇 〇 mg of the green body, or an amount in the range of -, preferably 4 (four) from ^:; to about 100.03⁄4 g / public body weight / day Or, in any range therebetween, more preferably from about 1.0 to about 50.0 gram per gram of body weight per day, or any amount in between, the compound can be divided into 一天4 times a day. -46 - 200901966, the optimum dosage can be easily changed by the expert in the art to apply the special compound, the mode of administration, the residual strength, and the progress of the condition. Seeing the special treatment: depending on the factors 'including the patient's age, weight, diet and time spent' will lead to the need to adjust the dose. / The expert in this skill understands that using appropriate, known, and sly

The rain and I in the test of the cell and/or animal model carried out by the test I can predict the ability of the test compound to treat or prevent a disease. Experts in the art also understand that human clinical trials, including the third human body, dose range and efficacy tests, in healthy patients and/or those suffering from the alleged disease, may be based on clinical and medical skills. The known method is completed. The following examples are intended to aid in the understanding of the invention, and are not intended to be, and should not be construed as limiting the scope of the invention. In the examples that follow, some of the synthesized products are indicated as being separated into a residue, as understood by those skilled in the art, the residue "" is not limited to the physical state of the product being separated from the list' May include, for example, a solid, an oily substance, a foam, a gum, a thick slurry, and the like. [Embodiment] ΜΛ 甲苯 甲苯 · 4 4 ι ι ι ι 4 6 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009

In a 5 liter three-neck-round bottom bottle with a reflux condenser, an air vent, an overhead stirrer, a heating mantle and a temperature control unit, 6-chloro-2,3-two is placed. Hydrogen-benzo[1,4]dioxin-2-yl)-nonanol (176 g, 877 mmol) tetraoxo π π nan (2 liters), 4_(n,N-didecylamine Base) 0 to α, j) MAP (25 g, 204.6 mmol) and 曱 曱 sulfonyl chloride (200.70 g, 1 〇 5 mol)' then warm the reaction mixture to 40 C ' Add another portion of DMAP (5 g) and potential-nonylbenzenesulfonyl chloride (10 g, 52.45 mmol), and let the reaction continue overnight. [After the reaction is consumed, add water (500 mL) to stop the reaction. The mixture was extracted with MTBE (1.2 liters), washed with water (300 liters, 2 liters), then with EtOAc (400 liters, 1 liters) and with additional water (1 liters). The title compound was obtained as a viscous oil. The title compound was obtained as a viscous oil.

200901966 In a three-necked-round flask with nitrogen vent, magnetic stir bar, heating mantle and a temperature control unit, 6-chloro-2,3-dihydro-benzo[1,4] ° ° -2- 2-yl methyl ester 4- benzene sulfonate (300 g; 845.5 mmol), N, N-dimethylformamide (330 〇 ml) and potassium phthalamide (2〇3 59g, L10 mole) 'The obtained slurry was heated to 10 ° C and stirred at this temperature for 2 hours' and then the reaction mixture was cooled to room temperature on an ice bath, stirring Pour into the stirred ice/water mixture (1 liter) and give a white solid upon stirring. After 2 hours at room temperature, the precipitate was filtered and dried to give the title compound as a white solid. Example 3

In a four-necked-round flask with a nitrogen vent, reflux condenser, overhead stirrer, heating mantle and temperature control unit, (8)_2' ((6-chloro-2,3-) Dihydrobenzo[b][1,4]dioxin-2-yl)hydrazino)isoindoline-1,3-dione (242 g, 733.9 mmol), ethanol (2.6 L) and associated Amine (48 g '50 mol), the mixture was heated to reflux. After 7 h, the reaction mixture was cooled to room temperature, then HCl (2N) was added until acid; and the solid was filtered off. Then add MTBE (1 liter) and sodium bismuth oxide (3N, 200 liters) and stir the mixture, separate the organic layer, wash with water, 49·200901966 (200 ml), and then pass brine (200 ml) Washing, drying the organic layer (NajCXO, filtration and concentration to give the title compound. Example 4 iV-ff(2S)-6-氲-2·3-dione-1,4 benzene technology 啰〇 well _2 _ some 1 methyl dimethyl dimethyl sulfhydryl)

Add (8) _(6_Chloro-2 3 dihydro-benzo [ in a 3 liter - RBF with a nitrogen vent, magnetic stir bar, addition funnel, internal thermometer and cooling bath) 1,4] bis-oxo- 0-yl)-decylamine (135 g, 676.2 mmol), acetonitrile (1000 ml), 4-(Ν, Ν-dimethylamino) η than bite , DMAP (2.07 g 15 16.9 mmol) and pyridine (82 ml, 80.24 g), the mixture was cooled to 〇 ° C and added to EtOAc (50 mL) -Boc (168 g, 779 mmol). The mixture was then warmed to room temperature and then heated to 45 ° C (5 hr), then 1 HCI1 was added until acidity was taken to terminate the reaction. After extracting the mixture into 20 layers, 3N NaOH (300 ml) was added to the organic layer, and the aqueous layer was cooled on ice bath, then water (20 ml) and 2N HCl. The title compound was obtained as a pale yellow solid. -50- 200901966 Example 5 Dihydro-1·4-ceadiobicin-2-one-1 methyl-- sure diamine

15 20 A 2-liter 3-neck round bottom flask with a 250 ml addition funnel, nitrogen vent, overhead stirrer, heating mantle and temperature control unit, with (S)-third butyl hydrazine- ((6-Gas-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)aminosulfonylcarbazate (256 g; 540.6 mmol) Ear), ethyl acetate (409 ml), then add concentrated hydrochloric acid (177.54 ml, 2.16 mol), stir the mixture to 5 ° C, after 1 hour, cool to room temperature, then add NaOH (2N, 220 liters) neutralized, the product was extracted with ethyl acetate (2 χ 200 liters). The organic layer was washed with brine (1 mL) and dried, filtered and concentrated to yield viscous oils. (1 gram of crude product). The oily substance was placed in hot (99-10 (rc) water (95 ml), and the resulting solution was filtered to remove insoluble oil and other impurities, and the resulting mixture was recooled to 25. (: U (4) @体, dried, the title compound was obtained as a white solid. IQJ·::·:^Methylamino-based helium •51· 200901966

For a 100 ml three neck-RBF with a nitrogen outlet, a funnel, a temperature sensor and a 5 ice bath, fill in (70.76 ml, 811.47 mmol) and acetonitrile (50 ml). After cooling to 0 ° C, a third-butanol solution (60.15 g, 77.08 ml, 811.47 mmol) dissolved in acetonitrile (50 ml) was added via an addition funnel and slowly added to allow the internal temperature to be maintained. Below 10 ° C, after the addition, the reaction should be complete, and the mixture should be concentrated to obtain a white amorphous solid, which is mixed into heptane, collected by filtration, and then washed with heptane. The title compound was obtained. Example 7 Recrystallization of 7V-[[(2*S>6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-sulfonamide diamine in toluene

Dissolve /^-[[(❼❼-石-氯-2,3-二风-1,4-benzophenanthroline-2-yl]] sulfhydryldiamine (0.5g) in After the hot benzene (5 ml) was filtered, the title compound was obtained as crystals, which was purified by filtration to remove the insoluble material. -52-200901966 Melting point: 98 ° C. Example 8 Liquid formulation According to a known method, for example, the compound of the formula (Ι-S) prepared in Example 7 above was formulated to be 25 mg each. And 1 mg of the liquid formulation, the composition of which is shown in Table 3 below. Table 3: Liquid formulation component role 25 mg / ml suspension 1 〇〇 mg / ml suspension type (Ι -S) compound active agent 25 mg 1 mg of hypromellose (also known as HPMC or hydroxypropyl methylcellulose) Suspending agent 5 mg 5 mg pure water solvent __——' Supplement to 1 ml--------- Supplement to 1 ml-----Prophetic example as a clear specific embodiment of oral composition '100 mg of the compound of the formula (--s) prepared according to Example 7 was prepared with fully subdivided lactose to a total of 590 gram, filled to the hard capsule of the nickname J. The foregoing description of the present invention has been described in the specification of the present invention. It is also to be understood that the present invention is intended to cover all of the embodiments of the present invention. Variation _, modification and λ or modification. [Simplified Schematic] Figure 1 illustrates a representative XRD spectrum of the crystalline form of the compound of formula (Ι-S).

Claims (1)

200901966 X. Patent application scope: 1. A method for preparing a compound of formula (IA) 5 (IA) wherein R1 is hydrogen; ίο R4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; -55- 200901966 where b is an integer from 0 to 4; and wherein δ is an integer from 0 to 2; 'each R5 is independently selected from the group consisting of halogens, lower alkyl groups, and Or a pharmaceutically acceptable salt thereof; 10 A compound of the formula (X) and a compound of the formula (XI), wherein -C(0)0RQ is a nitrogen protecting group; in an organic or inorganic compound which does not react with a chlorine group on the compound of the formula (XI) In the presence of a base; reacting in an aprotic organic solvent to produce a related compound of formula (XII); R4 Ο I II (CH2)a-N-S-NH2 (ΙΑ) 0 -56- 20 200901966 The compound of the formula (XII) is subjected to a deprotection reaction to obtain a compound of the formula (IA). 2. According to the method of claim 1 of the patent application, wherein a is 1; R4 is hydrogen and 0 is 2-(6-chloro-2,3-dihydro-benzo[1,4]dioxin p well base). 3. According to the method of claim 1, wherein the organic or inorganic base is a tertiary amine base selected from the group consisting of DIPEA, TEA, pyridoxine, N-methylmorphine and N-mercaptohexahydro 11 than the test. 4. According to the method of patent application No. 1, the organic or inorganic test system bites. 5. The method of claim 3, wherein the tertiary amine is present in an amount ranging from about 1.1 to about 3.0 mole equivalents. 6. The process according to claim 5, wherein the tertiary amine base is present in an amount of about 2.0 mole equivalents. 7. According to the method of claim 1, wherein the aprotic organic solvent is selected from solvents including DMF, THF and acetonitrile. δ· According to the method of claim 7, wherein the aprotic organic solvent is acetonitrile. 9. The method according to claim 1, wherein the _c(〇)〇Ro is selected from the group consisting of a Ci_4 alkoxy group, an aryloxy group and an aryloxyalkyl group. 1〇.=According to the method of the ninth paragraph of the patent application scope, _C(0)〇R〇 is selected from the group consisting of lower alkyl, phenylhydrazine, labor-methoxyphenyl fluorenyl and 9-dimethyl The basis. u. According to the method of claim 1, wherein -C(O)〇R0 is -57-200901966 -c(o)〇-third-butyl. 12. The method of claim 2, wherein the compound of formula (XJI) is deprotected by reacting a compound of formula (ΧΠ) with an acid. 0 5 13 • according to the method of claim 12 Wherein the compound 14 of the formula (XII) is deprotected by reacting a compound of the formula (XII) with hydrochloric acid. Method for preparing a compound of formula (IB) 10 R4 Ο r Λ I ιι / \^)~(CH2)a-N-S-NH ~ 0 (IB) wherein R1 R4 a It is selected from the group consisting of lower alkyl; selected from the group consisting of hydrogen and lower alkyl; an integer from 1 to 2; selected from the group 20 (R5), rv- 〇 -58- 200901966 Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; 10 15 each R5 is independently selected from the group consisting of halogen, lower alkyl, and schlossyl; Or a pharmaceutically acceptable salt thereof; R4 (CH2)a - NH (XI) -59- (X) 20 200901966 5 a compound of formula (X) with a compound of formula (XI) wherein -(:(0)01^ is a nitrogen protecting group; in a compound which does not form a compound of formula (XI) The reaction of the above-mentioned chloro group in the presence of an organic or inorganic base; the reaction is carried out in an aprotic organic solvent to obtain a related compound of the formula (XII); The compound of the formula (XII) is reacted with a compound of the formula (XV) wherein Q is a cleavage group; and the compound of the formula (XVI) is obtained in an organic solvent. The compound of the formula (XVI) is subjected to a deprotection reaction to obtain a related compound of the formula (IB). 15. The method according to claim 14, wherein the organic or inorganic base is a tertiary amine base selected from the group consisting of DIPEA, TEA, pyridin, N-mercaptoline and N-mercaptohexahydro ° than the bite and the like. 16. According to the method of claim 15 of the scope of the patent application, in which the organic or inorganic -60-200901966 system is determined. 17. The method of claim 14, wherein the tertiary amine base is present in an amount ranging from about 1.1 to about 3.0 mole equivalents. 18. The method of claim 17, wherein the tertiary amine base is present in an amount of about 2.0 mole equivalents. 19. The method of claim 14, wherein the aprotic organic solvent is selected from the group consisting of solvents such as DMF, THF, and acetonitrile. 20. The method according to claim 19, wherein the aprotic organic solvent is acetonitrile. Ίο 21. The method of claim 14, wherein -C(0)0RG is selected from the group consisting of a CU4 alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkoxycarbonyl group. 22. The method according to claim 21, wherein -C(0)0R° is selected from the group consisting of a lower alkyl group, a benzyl group, a s-methoxyphenyl fluorenyl group and a 9- 15 fluorenylmethyl group. . 23. The method according to claim 14, wherein -C(0)0RG is -c(o)o-third-butyl. 24. The method of claim 14, wherein the Q series is selected from the group consisting of Cb Br, I, -0-S02-CH3, -0-S02-CF3, and -0-S02-曱20 phenyl. 25. The method of claim 14, wherein the compound of formula (XII) is deprotected by reacting a compound of formula (ΧΠ) with an acid. 26. The method according to claim 25, wherein the compound of formula (XII) is deprotected by reacting a compound of formula (XII) with hydrochloric acid. 27. A method for preparing a compound of the formula (Ι-S) — (i-s) or a pharmaceutically acceptable salt thereof; A compound of the formula (Χ-S) and a compound of the formula (XI) wherein -C(0)0R° is a nitrogen protecting group; in a chlorine group which does not form a compound of formula (XI) In the presence of a reaction organic or inorganic base; reacting in an aprotic organic solvent to produce a related compound of formula (XII-S); The compound of the formula (XII-S) is subjected to a deprotection reaction to obtain a related compound of the formula (Ι-S). • 62- 200901966 28. According to the method of claim 27, the organic or inorganic test is a test of a tertiary amine selected from the group consisting of DIPEA, TEA, π-pyridine, hydrazine-hydrazinomorpholine and hydrazine- a base such as mercapto hexahydropyridine. 29. According to the method of claim 27, wherein the organic or inorganic test system 10 is determined by σ. 30. The method of claim 28, wherein the tertiary amine base is present in an amount ranging from about 1.1 to about 3.0 mole equivalents. 31. The method of claim 30, wherein the tertiary amine base is present in an amount of about 2.0 mole equivalents. 10 15 32. The method according to claim 27, wherein the aprotic organic solvent is selected from the group consisting of solvents such as DMF, THF and acetonitrile. 33. The method of claim 32, wherein the aprotic organic solvent is acetonitrile. 34. According to the method of claim 27, wherein -0(0)01^ is selected from the group consisting of (^_4 alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl). The method of item 34, wherein -C(0)0RG is selected from the group consisting of a lower alkyl group, a benzoinyl group, a fluorenyl phenyl fluorenyl group, and a 9-fluorenylmethyl group. The method of item 27, wherein -C(0)0R° is -c(o)o-third-butyl. 37. The method according to claim 27, wherein the compound of formula (XII-S) is Deprotection by reacting a compound of formula (XII-S) with an acid. -63- 20 200901966 According to the method of claim 37, wherein the compound of formula (xn_s) is by formula (XII- The compound of S) is deprotected by reaction with hydrochloric acid. 39. The method of claim 27, wherein the compound of formula (I_S) is further recrystallized. 40. According to the method of claim 39, The compound of the formula (js) is recrystallized in a solvent selected from water and toluene. 41. A compound of the formula (XII) Wherein -C(0)0R° is a nitrogen protecting group; R is selected from the group consisting of hydrogen and lower alkyl; Selected from the group consisting of hydrogen and lower alkyl; an integer from 1 to 2; selected from the following 200901966 and C is a total of 0 to 2 15 Each R5 is independently selected from the group of a nitro group; provided that it includes a _ element, a lower alkyl group, and (R5)b-f- 〇 〇 Or 20, then a is 1. According to the compound of claim 41, wherein a is 1; hydrogen is hydrogen and the base is 2-(6-gas-2,3-dihydro-benzo[ι,4]dioxinu well according to the patent application A compound according to the item 41, wherein _c(〇)〇R0 is selected from the group consisting of an alkoxycarbonyl group, an aryloxycarbonyl group and an aralkoxy-65-43 200901966 carbonyl group. A compound of the formula wherein -C(0)0Rg is selected from the group consisting of a lower alkyl group, a benzoinyl group, a potential-methoxybenzyl group, and a 9-fluorenylfluorenyl group. 45. According to the scope of claim 41 a compound wherein -C(0)0R° is -C(0)0-tri-butyl. 46. The method of formula 39, wherein the compound of formula (Ι-S) is self-benzene Recrystallization. 47. - Compound of formula (XII-S)〇Η VN, /OR〇 r\ T (XII-S) wherein -C(0)0R° is a nitrogen protecting group. Is a compound according to claim 47, wherein -C(0)0Rg is selected from the group consisting of a Cm alkoxycarbonyl group, an aryloxycarbonyl group and an aralkoxy group. 49. A compound according to claim 47, wherein -C(0)ORg is selected from the group consisting of lower alkyl, benzoinyl, decyloxyphenyl and 209-fluorenyl fluorenyl. 50. A compound according to claim 47, wherein -C(0)0R° is -C(0)0-tert-butyl. 51. A product prepared according to the method of claim 1 of the scope of the patent application. 52. A product prepared according to the method of claim 27 of the patent application. -66 - 200901966 53. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a product according to item 52 of the patent application. 54. A pharmaceutical composition prepared by mixing a product according to item 52 of the patent application with a pharmaceutically acceptable carrier. 5 55. A method for making a pharmaceutical composition comprising mixing a product according to item 52 of the patent application with a pharmaceutically acceptable carrier. 56. A method for treating epilepsy or a related condition comprising administering to a subject in need thereof a therapeutically effective amount of a product according to the scope of the patent application. 57. According to the method of claim 56, the disease is epilepsy. 58. The crystalline form of the compound of the formula (Ι-S) (I-SA) \/NH2 hN, o (丨-s): ο 59. According to the crystalline form (I-SA) of claim 58 of the patent application, wherein the knot 2 crystal form (I-SA) has the following powder X-ray The diffraction peak, its position and d-space are: position (°2Θ) d-space (person) 4.44 19.92 -67- 200901966 15.50 5.72 17.32 5.12 18.57 4.78 19.39 4.58 19.86 4.47 20.03 4.43 20.88 4.26 21.57 4.12 21.93 4.05 22.71 3.92 23.19 3.84 23.90 3.72 24.53 3.63 25.02 3.56 26.04 3.42 26.71 3.34 26.84 3.32 28.28 3.16 29.96 2.98 30.70 2.91