JP2002511387A - Substituted semicarbazides and uses thereof - Google Patents

Abstract

  (57) [Summary] The present invention relates to substituted semicarbazides represented by formula (I) or pharmaceutically acceptable salts or prodrugs thereof, wherein R₁And R_TwoIs independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl;_Three, R_Four, R_FiveAnd R₆Is independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl, or R_ThreeAnd R_FourIs defined as above, and R _FiveAnd R₆Form together with the nitrogen atom to which they are attached, a heterocycle, including piperidine, piperazine, morpholine;₁And A_TwoIs independently aryl, heteroaryl, a saturated or partially unsaturated carbocycle or a saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is , O, S, NR₇, CH_Two, C (O), NR₇C (O), C (O) NR₇, SO, SO_TwoOr one of the covalent bonds; wherein R₇Is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n is 0, 1, 2 or 3, and m is 0, 1, 2 or 3. The present invention also provides for the treatment of neuronal injury following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions (eg, amyotrophic lateral sclerosis (ALS)), and for acute pain Or for the treatment, prevention or amelioration of both chronic pain, as an anticonvulsant, as an antidepressant, as an antimigraine, as a local anesthetic, as an antiarrhythmic, and for treating or preventing diabetic neuropathy. For the use of substituted semicarbazides.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The present invention is in the field of medical chemistry. In particular, the present invention provides novel substituted semicarbazides,
And the discovery that these compounds are anticonvulsants and act as blockers of sodium (Na ⁺ ) channels.

[0002] Several classes of therapeutically useful drugs (local anesthetics such as lidocaine and bupivacaine, propafenone and amiodarone)
), And anticonvulsants such as lamotrigine, phenytoin and carbamazepine) have been shown to share a common mechanism of action by blocking or modulating Na ⁺ channel activity (Catterall, W
. A. , Trends Pharmacol. Sci. 8: 57-65 (198
7)). Each of these agents is believed to act by interfering with the rapid influx of Na ⁺ ions.

In recent years, other Na ⁺ channel blockers (eg, BW619C89 and rifarizine) have been shown to be neuroprotective in animal models of global and focal ischemia and are currently in clinical trials (G
Raham et al. Pharmacol. Exp. Ther. 269: 854-
859 (1994); Brown et al., British J. Am. Pharmacol
. 115: 1425-1432 (1995); SCRIP 1870: 8 (19).
93); SCRIP 1773: 14 (1992)).

[0004] The neuroprotective activity of Na ⁺ channel blockers is due to its efficacy in reducing extracellular glutamate levels during ischemia, by inhibiting the release of this excitotoxic amino acid neurotransmitter. Studies have shown that, unlike glutamate receptor antagonists, Na ⁺ channel blockers prevent hypoxic injury to mammalian white matter (Stys et al., J. Neurosci. 12:
430-439 (1992)). Thus, they may provide advantages for treating certain types of seizures or neuronal trauma, where damage to the white matter tract is significant.

Another example of the clinical use of Na ⁺ channel blockers is riluzole
zole). This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Eng).
l. J. Med. 330: 585-591 (1994)) and subsequently F
Approved by the DA for treatment of ALS. In addition to the clinical uses described above, carbamazepine, lidocaine and fentoin are sometimes used to treat neuropathic pain, such as trigeminal neuralgia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trend
ds Pharmacol. Sci. 16: 309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of major depression (Denicott et al., J. Clin. Psychiatry 55: 70-
76 (1994)).

[0006] The site that specifically binds to a neurotoxin is voltage-dependent (voltage sensi).
tive) It is established that there are at least 5-6 cells on the Na ⁺ channel (Catterall, WA, Science 242: 50-61).
(1988)). Studies have further shown that therapeutic antiarrhythmias, anticonvulsants and local anesthesia, whose effects are mediated by Na ⁺ channels, increase the N 2
It has been shown to interact with the a ⁺ channel and exert its effects by allosterically inhibiting the interaction with neurotoxin receptor site 2. (Catt
erall, W.W. A. Ann. Rev .. Pharmacol. Toxicol
. 10: 15-43 (1980)).

[0007] PCT published application W096 / 40628 discloses a semicarbazone represented by the following formula:

[0008]

Embedded image Here, R _l to R ₄ are independently hydrogen, halogen, C _1-9 alkyl, C _3-9 cycloalkyl, cyano, C _1-9 alkoxy or C _6-10 aryloxy; R ₅ Is hydrogen, C _1-9 alkyl, C _3-9 cycloalkyl or C _6-10 aryl; and X
Is oxygen or sulfur. These compounds are disclosed as being useful as anticonvulsants. However, semicarbazide, which can be prepared by reduction of semicarbazone, is also not disclosed or implicated as acting as an anticonvulsant.

[0009] Dimmock et al. Med. Chem. 39: 3984-3997 (19
96) disclose (aryloxy) aryl semicarbazones, which have shown anticonvulsant activity when administered intraperitoneally to mice or orally to rats. However, it is not disclosed nor implicated that semicarbazide, which can be prepared by reduction of semicarbazone, acts as an anticonvulsant.

SUMMARY OF THE INVENTION The present invention provides a novel substituted semicarbazide represented by Formula I as an anticonvulsant
And sodium (Na⁺) Act as a channel blocker
, About an amazing discovery. The semicarbazide of formula I is the corresponding semicarbazone
Although semicarbazide and semicarbazone can be prepared by reduction,
Class of compounds. Semicarbazide is due to the presence of the basic N-1 nitrogen.
Base. Semicarbazone is not a base, but has an NH group on the N-2 nitrogen
It is crab acidic. Due to the C = N double bond of semicarbazone, this molecule is relatively
It becomes a rigid molecule. Due to the C—N single bond of semicarbazide, this molecule is relatively
The molecule is not rigid. Therefore, the semicarbazides of the present invention represented by formula I
Is an anticonvulsant, like semicarbazone, and sodium (Na ⁺ It is a surprising finding that it acts as a channel blocker. Book
The invention also provides for administering an effective amount of a compound of Formula I described herein.
This channel in mammals afflicted with sodium channel hyperactivity.
The treatment of disorders responsive to shut-down of the device.

The present invention also provides for the treatment of neuronal injury following global and focal ischemia and for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). For the treatment or prevention of diabetic neuropathy, and for the treatment of pain, including both acute and chronic pain and migraine It relates to the use of the compounds of the formula I.

A first aspect of the present invention relates to novel substituted semicarbazides of formula I.

A second aspect of the present invention relates to novel compounds of formula I as sodium channel blockers.

[0014] A third aspect of the invention is a method of treating, preventing or ameliorating neuronal loss following global and focal ischemia; treating pain, including acute and chronic pain, and neuropathic pain. A method of treating, preventing or ameliorating; a method of treating, preventing or ameliorating a neurodegenerative condition; a method of treating, preventing or ameliorating major depression; a method of treating local anesthesia, arrhythmia and convulsions, Methods are provided by administering a compound of formula I to a mammal in need of such treatment.

[0015] A fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating a disorder responsive to sodium ion channel blockade, comprising one or more pharmaceutically acceptable agents. It contains an effective amount of a compound of formula I in a mixture with a possible carrier or diluent.

A fifth aspect of the present invention relates to a method for preparing a novel compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel substituted semicarbazide of formula I which is an anticonvulsant and ⁺ It comes from the discovery that it acts as a channel blocker. Consider this discovery
In consideration, compounds of formula I impair responsiveness to sodium ion channel blockade.
Useful for treating.

Compounds useful in aspects of the invention are the novel substituted semicarbazides represented by Formula I or a pharmaceutically acceptable salt or prodrug thereof:

[0019]

Embedded image Wherein R ₁ and R ₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl,
Alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl,
R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl Or R ₃
And R ₄ are defined as above, and R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocycle (including piperidine, piperazine, morpholine)
A ₁ and A ₂ are independently aryl, heteroaryl, a saturated or partially unsaturated carbocycle or a saturated or partially unsaturated heterocycle, any of which X is O, S, NR ₇ , CH ₂ , C (O), NR ₇ C (O), C (O) NR ₇ , SO
, SO ₂ or one of the covalent bonds; wherein R ₇ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; n Is 0, 1, 2 or 3, and m is 0, 1, 2 or 3.

Preferred compounds falling within the scope of Formula I are those in which both A ₁ and A ₂ are aryl moieties, preferably both are phenyl moieties, each of which is optionally and independently , Halogen, nitro, amino, C _1-6 alkyl, C _1-6 haloalkyl,
R ₁ and R ₂ are independently substituted by 1-4 substituents independently selected from the group consisting of C _3-8 cycloalkyl, cyano, C _1-6 alkoxy or C _1-6 aryloxy; R ₃ , R ₄ , R _5, and R ₆ are independently hydrogen or C _1-6 alkyl; hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl or C _6-10 aryl; And X is O; and n and m are 0.

Also preferred compounds within Formula I are that A ₁ is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl; and
A ₂ represents pyridyl, pyrimidinyl, 1,3,5-triazinyl, furanyl, thiophenyl, naphthyl, quinolyl, 3,4-methylenedioxyphenyl, 3,4-
Compounds that are an optionally substituted heteroaryl or aryl group selected from the group consisting of ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and quinoxalinyl. It also includes biphenylmethyl and triphenylmethyl.

Further preferred compounds within formula I are also those wherein A ₁ is an optionally substituted aryl group selected from the group consisting of phenyl or naphthyl, and A ₂ is cyclopentyl, cyclohexyl , Cycloheptyl, piperidinyl,
Morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
Compounds that are optionally substituted carbocycles or heterocycles selected from the group consisting of cyclohexenyl, adamantyl, exo-norbornyl and cyclopentenyl.

Further preferred compounds within formula I include those wherein A ₁ is pyridyl, pyrimidinyl, 1
, 3,5-triazinyl, naphthyl, quinolyl, are selected from the group consisting of furanyl and thiophenyl, heteroaryl or aryl group is optionally substituted, and, A ₂ is phenyl, furanyl, thiophenyl, quinolinyl , 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and naphthyl, wherein the compound is an optionally substituted heteroaryl or aryl group. No.

In a further preferred compound within formula I, A ₁ is optionally substituted, selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl. A saturated or partially unsaturated carbocyclic or heterocyclic ring and A ₂ is phenyl, furanyl, thiophenyl, quinolinyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, Compounds that are an optionally substituted aryl or heteroaryl group selected from the group consisting of tetrahydronaphthyl or naphthyl.

Exemplary preferred compounds that can be used in the methods of the present invention include, but are not limited to: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4- 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) 1- (4- (4-trifluoromethylphenoxy) benzyl) semicarbazide; 1- (4- (4-methylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide 1- (4- (4-chloro-2-fluorophenoxy) benzyl 1- (4- (4-nitrophenoxy) benzyl) semicarbazide; 1- (4- (3-methylphenoxy) benzyl) semicarbazide; 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl) semicarbazide; 1- (4- (4-s-butylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-methylenedioxyphenoxy) benzyl) semicarbazide 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4- (5-indanyloxy) benzyl) semicarbazide; 1- (4- (6-quinolinyloxy) Benzyl) semicarbazide; 1- (4- (4-fluoro Phenoxy) -3-fluorobenzyl) semicarbazide; 1- (4- (tetrahydropyranyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl-4-methyl semicarbazide;
And 1- (4- (4-fluorophenoxy) benzyl) -2-methylsemicarbazide.

Since the compounds of formula I are blockers of sodium (Na ⁺ ) channels, a number of diseases and conditions mediated by the influx of sodium ions can be treated using these compounds. Thus, the present invention is directed to methods of treating, preventing or ameliorating stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, nerve cell damage associated with spinal cord trauma; and Alzheimer's disease, muscular atrophy Lateral sclerosis,
Methods for treating or ameliorating neurodegenerative diseases, including Parkinson's disease, and methods for treating or ameliorating anxiety, convulsions, glaucoma, migraine and muscle spasms. The compounds of formula I are also useful as anti-manic depressants, local anesthetics and anti-arrhythmic drugs; and for the treatment, prevention or amelioration of pain, including surgery, chronic and neuropathic pain. In each case, the methods of the invention require administering to an animal in need of such treatment an effective amount of a sodium channel blocker of the invention, or a pharmaceutically acceptable salt or prodrug thereof. I do.

In particular, preferred substituted semicarbazides are represented by Formulas II-VI. In particular, a preferred embodiment has the following formula II:

[0028]

Embedded image Or represented by a pharmaceutically acceptable salt or prodrug thereof, wherein: R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , X, n and m are as defined above with respect to formula I And R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are independently hydrogen, halo, haloalkyl, aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, Alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano , Acylamide, hydroxy, thio- , Acyloxy, azido, alkoxy, carboxy, carbonyl, amide or alkylthiol; or R ₉ and R ₁₀ or R ₁₁ and R _12, may form a carbocyclic or heterocyclic ring together with the carbon atoms to which they are attached I do. Examples of crosslinking R ₉ and R ₁₀ or R ₁₁ and R _{1 2,} to form together _{the, -OCH 2 O -, - OCF} 2 O -, - (C
_{H 2) 3 -, - (} CH 2) 4 -, - OCH 2 CH 2 O -, - CH 2 N (R 18) CH 2 -,
_{-CH 2 CH 2 N (R 18} ) CH 2 -, - CH 2 N (R 18) CH 2 CH 2 - and -CH
R ₁₈ is hydrogen, alkyl or cycloalkyl; R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are independently hydrogen, halo, haloalkyl,
Aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,
Heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl,
Hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamide or alkylthiol; or R ₁₃ and R ₁₄ , or One of R ₁₄ and R ₁₅ , or R ₁₅ and R ₁₆ , or R ₁₆ and R ₁₇ , together with the carbon atom to which they are attached, forms a carbocyclic or heterocyclic ring. Examples of bridge formed by R ₁₃ and R ₁₄ or R ₁₄ and R ₁₅ or R ₁₅ and R ₁₆ or R ₁₆ and R _17,,, is, -OCH ₂ O -, -
_{OCF 2 O -, - (CH} 2) 3 -, - (CH 2) 4 -, - OCH 2 CH 2 O -, - CH 2 N (R 18) CH 2 -, - CH 2 CH 2 N (R 18 _{) CH 2 -, - CH 2} N (R 18) CH 2 CH 2 - and -CH = CH-CH = CH- and; wherein, R ₁₈ is hydrogen, alkyl or cycloalkyl.

Another preferred embodiment of the present invention has the following formula III and formula IV:

[0030]

Embedded image Or a pharmaceutically acceptable salt or prodrug thereof, wherein: R ₁ -R ₆ , R ₉ -R ₁₂ , R ₁₃ -R ₁₇ , n, m, A ₁ , A ₂ and X are as defined above for formulas I and II.

Preferred compounds within the scope of formula III include those wherein A ₂ is pyridyl, pyrimidinyl,
Compounds that are optionally substituted heteroaryl or aryl groups selected from the group consisting of 1,3,5-triazinyl, naphthyl, quinolyl, furanyl and thiophenyl.

Preferred compounds within the scope of formula IV include those wherein A ₁ is pyridyl, pyrimidinyl, 1
, 3,5-triazinyl, naphthyl, quinolyl, furanyl and thiophenyl, optionally heteroaryl or aryl groups selected from the group consisting of thiophenyl.

Another preferred embodiment of the present invention is a compound of formula V and formula VI:

[0034]

Embedded image Or a pharmaceutically acceptable salt or prodrug thereof, wherein R ₁ -R ₆ , R ₉ -R ₁₂ , R ₁₃ -R ₁₇ , n, m and X are of the formula B ₁ is as defined above for I and II; and B ₁ is an optionally substituted saturated or partially unsaturated carbocycle, or an optionally substituted saturated or partially unsaturated carbocycle. And B ₂ is an optionally substituted saturated or partially unsaturated carbocycle, or an optionally substituted saturated or partially unsaturated heterocycle.

Preferred B ₁ and B ₂ independently include cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl.

In general, preferred compounds of Formulas I-VI are those in which R ₁ and R ₂ are hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, and R ₃ and R ₄ are independently hydrogen or C ₁ -C _{1. A} compound that is ₄ alkyl.

A preferred value of X in formulas I-VI is O.

Preferred values of R ₅ -R ₆ for formulas I-VI are hydrogen or C _1-4 alkyl.

For formulas II to VI, R₉~ R₁₂And R₁₃~ R₁₇Preferred values for hydrogen,
Halo, C₁~ C₆Haloalkyl, C₆~ C_TenAryl, C_Four~ C₇Cycloalkyl,
C₁~ C₆Alkyl, C_Two~ C₆Alkenyl, C_Two~ C₆Alkynyl, C₆~ C_TenAnts
(C₁~ C₆) Alkyl, C₆~ C_TenAryl (C_Two~ C₆) Alkenyl, C₆~
C_TenAryl (C_Two~ C₆) Alkynyl, C₁~ C₆Hydroxyalkyl, nitro,
Amino, ureido, cyano, C₁~ C₆Acylamide, hydroxy, thiol, C ₁ ~ C₆Acyloxy, azide, C₁~ C₆Alkoxy or carboxy
You. Alternatively, R₉And R_TenOr R₁₁And R₁₂Or two adjacent
R₁₃~ R₁₇Is -OCH_TwoO-,-(CH_Two)_Three-,-(CH_Two)_Four-, -OCH_TwoC
H_TwoO-, -CH_TwoN (R₁₈) CH_Two-, -CH_TwoCH_TwoN (R₁₈) CH_Two-, -CH _Two N (R₁₈) CH_TwoCH_Two-, And -CH = CH-CH = CH- (where R₁₈
Is hydrogen or C₁~ C₆Form a bridge selected from the group consisting of
I can do it.

[0040] With respect to novel methods of treatment of the present invention, more preferably substituted semicarbazide subset, A ₁ and A ₂ are phenyl moieties (these are each independently hydrogen, halogen, C ₁ - ₆ alkyl, C _3- R ₁ and R _{2,; 8} cycloalkyl, cyano, C ₁ - ₁₀ is substituted by 1 or 2 substituents independently selected from the group consisting of aryloxy) in Yes - ₆ alkoxy or C ₆ hydrogen, C ₁ - be ₆ alkyl or C _3-8 cycloalkyl; R ₃ and R ₄ is hydrogen or C ₁ - ₆ is alkyl; X is located at O; n and m are 0, the formula I It contains the compound of.

Useful compounds in this aspect of the invention include: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4-trifluoro) 1- (4- (4-methylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chloro- 2-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-nitro 1- (4- (3-methylphenoxy) benzyl) semicarbazide; 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl 1- (4- (4-s-butylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-methylenedioxyphenoxy) benzyl) semicarbazide; 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4- (5-Indanyloxy) benzyl) semicarbazide; 1- (4- (6-quinolinyloxy) benzyl) semicarbazide; 1- (4- (4- Fluorophenoxy) -3-fluorobenzyl) semica 1- (4- (tetrahydropyranyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) -4-methylsemicarbazide; and 1- (4- (4-fluorophenoxy) benzyl) -2-methyl semicarbazide.

[0042] Useful aryl groups, C ₆ - ₁₄ aryl, especially C ₆ -C ₁₀ aryl. Typical C ₆ - to ₁₄ aryl group, phenyl, naphthyl, phenanthryl, anthracyl (anthracyl), indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

[0043] Useful cycloalkyl groups, C ₃ - is ₈ cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and cycloheptyl.

Useful saturated or partially saturated carbocyclic groups are cycloalkyl, cycloalkenyl (eg, cyclopentenyl, cycloheptenyl and cyclooctenyl), bicycloalkyl (eg, norbornyl) as defined above, and Tetrahydronaphthyl and indanyl groups.

Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.

Useful alkyl groups include straight and branched chain C _1-10 alkyl groups, more preferably C _1-6 alkyl groups. Typical C _1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,
3-pentyl, hexyl and octyl groups. Trimethylene groups substituted at two adjacent positions on the benzene ring of the compounds of the present invention are also contemplated.

[0047] Useful alkenyl groups, C ₂ - ₆ alkenyl group, preferably a C ₂ - a ₄ alkenyl. Typical C ₂ - to ₄ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl and sec- butenyl.

[0048] Useful alkynyl groups, C ₂ - ₆ alkynyl group, preferably a C ₂ - a ₄ alkynyl. Typical C ₂ - to ₄ alkynyl groups include ethynyl, propynyl, butynyl and 2-butynyl groups.

[0049] Useful arylalkyl groups, C ₆ of any of the above - include any C _1-10 alkyl groups mentioned to be substituted by ₁₄ aryl group. Useful values include benzyl,
Phenethyl and naphthylmethyl.

[0050] Useful arylalkenyl groups, C ₆ of any of the above - include any C _2-4 alkenyl group of said substituted by ₁₄ aryl group.

[0051] Useful arylalkynyl groups, C ₆ of any of the above - include any C _2-4 alkynyl groups described above which are substituted by ₁₄ aryl group. Useful values include phenylethynyl and phenylpropynyl.

Useful cycloalkylalkyl groups include any of the above C _1-10 alkyl groups substituted by any of the above cycloalkyl groups.

Useful haloalkyl groups include C _1-10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms (eg, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 , 1-difluoroethyl and trichloromethyl groups).

Useful hydroxyalkyl groups include C _1-10 alkyl groups substituted with hydroxy, such as hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.

Useful alkoxy groups include oxygen substituted by one of the C _1-10 alkyl groups described above.

Useful alkylthio groups include sulfur, which is substituted by one of the C _1-10 alkyl groups described above.

Useful acylamino groups include any C _1-6 acyl (alkanoyl) attached to an amino nitrogen as well as aryl-substituted-C _2-6 substituted acyl groups (eg, acetamido,
Propionamide, butanoylamide, pentanoylamide, hexanoylamide).

Useful acyloxy groups include any C _1-6 acyl (alkanoyl) attached to an oxy (-O-) group (eg, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy Etc.).

Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,
Isochromanyl, chromanyl, pyrazolidinyl and pyrazolinyl groups are mentioned.

Useful heterocycloalkyl groups include any of the above-mentioned C _1-10 alkyl groups, which are substituted by any of the above-mentioned heterocyclic groups.

Useful heteroaryl groups include any one of the following: thienyl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl , Chromenil, xanthenyl, phenoxanthinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
Indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthaldinyl (
phthalzinyl), naphthyridinyl, quinozalinyl (quinozal)
inyl), cinolinyl, pteridinyl, 5aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl
1), perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido [1,2 -A] pyrimidin-4-one, 1,2-benzisoxazol-3-yl, 4-nitrobenzofurazan, benzimidazolyl, 2
-Oxyindolyl and 2-oxobenzimidazolyl. When the heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom may be in the form of an N-oxide (eg, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, etc.).

Useful heteroarylalkyl groups include any of the above-mentioned C _1-10 alkyl groups, which are substituted by any of the above-mentioned heteroaryl groups.

Useful heteroarylalkenyl groups include any of the above C _2-4 alkenyl groups substituted by any of the above heteroaryl groups.

Useful heteroarylalkynyl groups include any of the above C _2-4 alkynyl groups substituted by any of the above heteroaryl groups.

[0065] Useful amino groups, -NH _2, with -NHR ₁₄ and -NR ₁₄ R ₁₅ (wherein, R _{1 4} and R _15, C _1-10 alkyl or cycloalkyl group as defined above Is).

Useful aminocarbonyl groups are carbonyl groups substituted by —NH ₂ , —NHR ₁₄ and —NR ₁₄ R ₁₅ , wherein R ₁₄ and R ₁₅ are C _1-10 alkyl groups. is there.

For any substituents on any of the aryl, heterocyclic, heteroaryl and cycloalkyl rings in Formulas I-VI, the halo, haloalkyl, aryl, heterocyclic, cycloalkyl, heteroaryl, alkyl, alkenyl as described above , Alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, Any one of the cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, aminocarbonyl and alkylthiol groups are included. Preferred optional substituents include halo, haloalkyl, hydroxyalkyl, aminoalkyl, nitro, alkyl, alkoxy and amino.

Certain compounds of Formula I may exist as optical isomers, and the present invention relates to racemic mixtures of such optical isomers as well as individual enantiomers which can be separated according to methods well known to those skilled in the art. It contains both.

Examples of pharmaceutically acceptable addition salts include, for example, hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumaric acid Salts include inorganic and organic acid addition salts such as salts, mandelates, acetates, dichloroacetates and oxalates.

Examples of prodrugs include R such as hydroxyalkyl or aminoalkyl ₁ ~ R₆And the esters or amides of formula I having the formula
Prepared by reacting such a compound with an anhydride such as succinic anhydride
Can be done.

The present invention also relates to a method for treating such a disorder in an animal suffering from a disorder responsive to sodium channel blockade. A particularly preferred embodiment of the substituted semicarbazides used in the process according to the invention is represented by formula I as defined above.

The compounds of the present invention can be prepared using methods known to those skilled in the art, or using the novel methods of the present invention. Compounds having Formulas I-VI can be prepared from the reduction of the corresponding semicarbazone, as shown by the exemplary reaction of Scheme 1.

[0073]

Embedded image The compounds of the present invention are evaluated for sodium channel blocking activity by electrophysiological assays in dissociated hippocampal neurons. These compounds can also be assayed for binding to voltage-gated sodium channels in neurons using rat forebrain membrane and [ ³ H] BTX-B.

[0074] Sodium channels are large transmembrane proteins expressed in various tissues. These are voltage sensitive channels and are responsible for the rapid increase in Na ⁺ permeability in response to depolarization of action potentials in many excitable cells, including muscle, nerve and heart cells.

One aspect of the present invention is the discovery of the mechanism of action of the compounds described herein as specific Na ⁺ channel blockers. Based on the discovery of this mechanism,
These compounds are believed to be useful for treating or preventing neuronal loss due to localized or global ischemia, and for treating or preventing neurodegenerative disorders, including ALS, anxiety and epilepsy. They are also expected to be effective in treating, preventing or ameliorating neuropathic pain, surgical pain and chronic pain. These compounds are also expected to be useful as antiarrhythmic, anesthetic and antimanic depressants.

The present invention relates to compounds of formula I that are blockers of voltage-sensitive sodium channels. According to the present invention, those compounds having favorable sodium channel blocking properties can be used in the electrophysiological assays described herein in an amount of about 1
An IC ₅₀ of 00 μM or less is shown. Preferably, compounds of the present invention exhibit an IC ₅₀ of 10 μM or less. Most preferably, compounds of the present invention exhibit an IC _{50 of} about 1.0 μM or less. The substituted semicarbazides of the present invention can be tested for their Na ⁺ channel blocking activity by the following electrophysiological and binding assays.

Electrophysiological Assay Cell Preparation: HEK-29 Stably Showing the hSkM1 Isoform of the Na ⁺ Channel
3 cells (Dr. AL George, Vanderbilt Univers)
Entity Medical School), a standard technique as previously described (Verdoorn, TA, et al., Neuron 4: 919-9).
28 (1990)). For electrophysiology, cells were plated on 35 mm Petri dishes (pre-coated with poly-D-lysine) at a density of 1:40 on the day of reseeding from confluent medium. Cells are suitable for recording 2-3 days after plating.

Patch clamp recording of voltage sensitive Na ⁺ current: Whole cell voltage clamp recording
xopatch 200A amplifier (Axon Instruments., Fo
conventional patch clamp technology (Hamill
Et al., Pfluegers Arch. 391: 85-100 (1981)). Recordings were made within 2-3 hours after neuron dissociation. The external solution (150 mM NaCl, 5.4 mM KCl, 1.8 m
M CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES, 10 mM glucose, pH 7.4 (NaOH)) were poured at a speed of about 1 ml / min. The recording pipette was pulled from a wall-thick capillary (WPI, Sarasota, F1) and baked. Pipette 110 mM CsF, 10 mM NaCl, 5 mM M
When filled with an internal solution containing gCl ₂ , 11 mM EGTA, 10 mM HEPES and adjusted to pH 7.4 with CsOH, the resistance of this pipette was in the range of 1-3 MΩ. Osmolality, 15-20 mmol between outer and inner solution
/ Kg difference (lower intracellular). Drug and intervening washes were applied through a linear array of flow pipes (Drummond Microcaps 2-μl, 64 mm long). Compounds were dissolved in dimethylsulfoxide (DMSO) to make a 30 mM stock solution, which was then diluted into external solution to a final concentration of 0.1
１００100 μM. At the highest concentration (1%), DMSO only slightly suppressed the magnitude of the Na ⁺ current. Currents were recorded at room temperature (22-25 ° C) and activity 8
Paul Bessel Filter (Frequency Devices, Hav
erhill. MA) at 5 kHz, digitized at 10-50 μs intervals, and Pclamp6 / Clampex software (Axon In
instruments) and stored using a Digidata 1000 analog / digital interface. If necessary, the series resistance is typically about 7
Canceled to 5%. The inhibitory potency of the drug was assessed by measuring the decrease in the peak amplitude of the Na ⁺ current induced by increasing concentrations of the tested compound. The Na ⁺ current is obtained by changing the membrane potential from a holding potential in a range of −100 mV to −50 mV −
This occurred by advancing to a pulse potential of 10 mV. The duration of the test pulse was 5-10 ms and was repeated at frequencies below 1 Hz. The concentration-inhibition curve was fitted to equation 1:

[0079]

(Equation 1) Where I _control is the maximum Na ⁺ current in the absence of antagonist, [compound] is the drug concentration, and IC ₅₀ is the concentration of the compound that produces half-maximal inhibition.

Binding Assay The ability of the compounds of the invention to modulate either Na ⁺ channel site 1 or site 2 is described by Yasushi, J, Biol. Chem. 261:
6149-6152 (1986) and Creveling, Mol. Phar
macol. 23: 350-358 (1983). Rat forebrain membrane was used as a source of Na ⁺ channel protein. This binding assay was performed using [ ³ H] saxitoxin and [ ³ H] batrachotoxin as radioligands for site 1 and site 2, respectively.
Incubation was performed at 37 ° C. for 60 minutes in μM choline chloride.

The compounds of the invention can be administered in a number of antispasmodic tests in mice (audiogenic seizure models in DBA-2 mice, pentylenetetrazole-induced seizures in mice, maximal electric shock seizures) after intravenous, oral or intraperitoneal injection. Test (MES)) for in vivo antispasmodic activity.

These compounds can be tested for their neuroprotective activity following localized and global ischemia occurring in rats or gerbils according to the procedure described below: Buchan et al. (Stroke, Suppl. 148). -152 (
1993)) and Sharedown et al. (Eur. J. Pharmacol.
236: 347-353 (1993)) and Graham et al. (J. Pharm.
acol. Exp. Therap. 276: 1-4 (1996)).

These compounds can be tested for their neuroprotective activity following traumatic spinal cord injury according to the procedure described below: Wrathall et al. (Exp. Neuro
137: 119-126 (1996)) and Iwasaki et al.
J. Neuro Sci. 134: 21-25 (1995)).

Compositions within the scope of this invention include all compositions that contain an effective amount of a compound of the present invention to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each compound is within the skill of the art. Typically, a mammal (
For example, in humans), these compounds may have 0 per day, based on the weight of the mammal being treated for epilepsy, neurodegenerative disease, anesthesia, arrhythmias, manic depression and pain.
. A dose of 0025-50 mg / kg or an equivalent amount of these pharmaceutically acceptable salts may be administered orally. For intramuscular injection, this dose is generally about half of the oral dose.

In methods of treating or preventing global and focal ischemia, cerebral and spinal cord trauma, hypoxia, hypoglycemia, status epilepticus and neuronal loss in surgery, the compounds may comprise from about 0.025 to about At a dose of 10 mg / kg, it can be administered by intravenous injection.

A unit oral dose may range from about 0.01 to about 50 mg of the compound, preferably about 0.1 to about 50 mg.
It may contain about 10 mg of the compound. The unit dose can be administered as one or more tablets, one or more times daily, each containing from about 0.1 to about 10 mg, preferably about 0.25 to 50 mg of the compound or solvate thereof. Can be done.

In addition to administering the compound as a raw chemical, the compound of the invention may also be used in the preparation of pharmaceutical preparations containing suitable pharmaceutically acceptable carriers, including excipients and adjuvants. These carriers, which can be administered as part, facilitate the processing of these compounds into pharmaceutically usable preparations. Preferably, these preparations, especially those that can be administered orally and used in the preferred type of administration (eg,
Tablets, dragees and capsules), and also preparations that can be administered rectally (eg, suppositories), and solutions suitable for injection or oral administration are from about 0.01 to 99%;
Preferably, about 0.25-75% of active compound (s) will be included with the excipient.

[0088] Non-toxic pharmaceutically acceptable salts of the compounds of the invention are also included within the scope of the invention. A solution of a specific 2-aminoacetamide of the present invention and a pharmaceutically acceptable non-toxic acid (eg, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalate) Acid, dichloroacetic acid, etc.) to form acid addition salts. By mixing a solution of a specific 2-aminoacetamide of the present invention with a solution of a non-toxic pharmaceutically acceptable base (eg, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc.) A basic salt is formed.

The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. The major such animals are mammals (eg, humans), although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal mucosa. Alternatively or simultaneously, it can be administered orally.
The dosage administered will be dependent upon the age, health, and weight of the patient, type of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving or lyophilizing processes. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compounds with solid excipients, if necessary, after adding suitable auxiliaries, milling the resulting mixture,
The mixture of granules is then processed to obtain a tablet or dragee core, if desired or necessary.

Suitable excipients are, in particular, fillers, such as, for example, sugars, such as lacrose or sucrose, mannitol or sorbitol, cellulose preparations and / or
Or calcium phosphate (eg, tricalcium phosphate or calcium hydrogen phosphate) and binders (eg, corn starch, wheat starch, rice starch, starch paste using potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, carboxy) Methylcellulose sodium and / or polyvinylpyrrolidone). If desired, disintegrating agents (eg, starch, as described above, and carboxymethyl starch,
Crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof (eg, sodium alginate) may be added. All the abovementioned auxiliaries are flow regulators and lubricants, for example silica, talc, stearic acid or its salts (for example, magnesium or calcium stearate) and / or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, a concentrated saccharide solution may be used, which is optionally gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, a lacquer solution and a suitable organic solvent or mixture of solvents. obtain. To make a coating resistant to gastric juices, a solution of a suitable cellulose preparation (eg, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate) is used. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or to characterize combinations of active compound doses.

Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and glycerol or sorbitol. Softeners. Push-fit capsules can contain the active compounds in the form of granules, which include fillers (eg, lactose), binders (eg, starch) and / or lubricants (eg, talc or magnesium stearate) and It can be mixed with a stabilizer if necessary. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases are
For example, natural or synthetic triglycerides or paraffinic hydrocarbons. In addition, it is also possible to use rectal capsules of gelatin, which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salt forms, and alkaline solution forms. Additionally, suspensions of the active compounds may be administered as appropriate oily injection suspensions. Suitable lipophilic solutions or vehicles include fatty oils (e.g., sesame oil) or synthetic fatty oil esters (e.g., ethyl oleate or triglyceride or polyethylene glycol-40).
0, which is soluble in PEG-400). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. If desired, the suspension may contain stabilizers.

The following examples are illustrative, but not limiting, of the methods and compositions of the present invention. Other suitable modifications and adaptations of various conditions and parameters are usually
Encountered in clinical treatment, and these will be apparent to those of skill in the art and are within the spirit and scope of the present invention.

Example 1 (1- [4- (4-fluorophenoxy) benzyl] semicarbazide)

[0098]

Embedded image 4- (4-Fluorophenoxy) benzaldehyde semicarbazone (100 mg, 0.37 mmol) in MeOH (15 mL)
A mixture of 1) and 5% Pd / C (45 mg) was hydrogenated with 1 atm of hydrogen overnight. The catalyst was removed by filtration through celite by suction filtration and the filtrate was concentrated under reduced pressure to give the crude product, which was added a few drops of TE per 100 mL of solvent mixture.
Purification by flash chromatography using 19: 1 ethyl acetate / MeOH containing A gave the title compound as a white powder (30 mg, 38%
): ¹ H NMR (DMSO-d ₆ ) 3.74 (s, 2H), 4.97 (bs, 1)
H), 5.79 (bs, 2H), 6.91 (d, 2H), 7.00-7.04 (
m, 3H), 7.17-7.23 (m, 2H), 7.34 (d, 2H).

Example 2 (1- [4- (4-Fluorophenoxy) benzyl] -2-methylsemicarbazide)

[0100]

Embedded image 4- (4-Fluorophenoxy) benzaldehyde-2′-methylsemicarbazone (103 mg, 0.36 mmol) and 5% in MeOH (15 mL)
A mixture of Pd / C (45 mg) was hydrogenated under 1 atm of hydrogen overnight. The catalyst was removed through celite by suction filtration and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (101 mg, 97%): ¹ H NMR (
_{DMSO-d 6) 2.91 (s} , 3H), 3.79 (d, 2H), 4.50 (t
, 1H), 5.94 (bs, 2H), 6.90 (d, 2H), 6.99-7.0.
4 (m, 2H), 7.20 (t, 2H), 7.37 (d, 2H).

Using the same procedure, the following semicarbazides were prepared from the corresponding semicarbazones: 1- [4- (cycloheptyloxy) benzyl] semicarbazide; 1- [4- (cyclohexylmethoxy) benzyl] semicarbazide; 1 -[3-Fluoro-4- (4-fluorophenoxy) benzyl] semicarbazide; 1- [4- (5-Indanoxy) benzyl] semicarbazide; 1- [4- (3,4-methylenedioxyphenoxy) benzyl] semicarbazide 1- [3- (3-methylphenoxy) benzyl] semicarbazide; 1- [4- (trifluoromethyl) benzyl] -2-methylsemicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl ] -2-methylsemicarbazide; 1- [4- (5,6,7 1- [3-fluoro-4- (4-fluorophenoxy) -1-phenylethyl] semicarbazide; 1- [4- (3,4-difluorophenoxy) benzyl 1- [4- (3,5-difluorophenoxy) benzyl] semicarbazide; 1- [4- (benzyl) benzyl] semicarbazide; 1- [4- (3,4-methylenedioxyphenoxy) ) Benzyl] -2-methylsemicarbazide; 1- [4- (5,6,7,8-tetrahydro-2-naphthoxy) benzyl]-
1- [3-Fluoro-4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (exo-2-norbornoxy) benzyl] semicarbazide; 1- [4- (exo- 2-norbornoxy) benzyl] -2-methylsemicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] semicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] -2 1- [4- (phenoxy) benzyl] semicarbazide; 1- [4- (phenoxy) benzyl] -2′-methylsemicarbazide; 1- [3- [4- (2-butyl) phenoxy] benzyl] Semicarbazide.

Using the same procedure, the following semicarbazides were prepared from the corresponding semicarbazones: 1- [4- (cyclohexyloxy) benzyl] semicarbazide; 1- [3- (4-methylphenoxy) benzyl] semicarbazide; 1- [4- (3,4-difluorophenoxy) benzyl] semicarbazide; 1- [4- (2,4-difluorophenoxy) benzyl] semicarbazide; 1- [4- (2,4-difluorophenoxy) benzyl]- 2-methylsemicarbazide; 1- [4- (2-fluorobenzyloxy) benzyl] semicarbazide.

Example 3 (1- [4- (4-Fluorophenoxy) benzyl] semicarbazide as an anticonvulsant) Maximum electric shock-induced seizure of 1- [4- (4-fluorophenoxy) benzyl] semicarbazide ( The ability to inhibit MES) was measured by the following procedure.

Seizures were induced using a Ugo Basile ECT device (Model 7801) by applying current (50 mA, 60 pulses / sec, pulse width 0.8 ms, duration 1 sec, DC). The mice were restrained by grabbing the flaccid skin on their back, and saline-coated corneal electrodes were gently placed on the two corneas. Currents were applied and mice were observed for up to 30 seconds for the development of a tonic hind leg extensor response. Tension convulsions are defined as hind legs extending 90 ° or more from the body surface.

1- [4- (4-Fluorophenoxy) benzyl] semicarbazide was administered intravenously to mice 10 minutes before the test procedure. This compound showed protection against MES with an ED _{50 of} 4.2 mg / kg (50% animal protective dose). 1-
[3-fluoro-4- (4-fluorophenoxy) benzyl] semicarbazide are tested orally in mice, it was found to have an ED ₅₀ of 3.2 mg / kg.

Example 4 Nutrition of (1- [4- (4-fluorophenoxy) benzyl] semicarbazide
1- [4- (4-Fluorophenoxy) benzyl] semicarbazide is used as described above.
Tested for electrophysiological and binding assays, the potential gated sodium current
HE in which dose-dependent inhibition occurs and stably displays the hSkM1 sodium channel
K-293 cells were recorded. Na of this compound⁺The breaking effect on the current is maintained
Very sensitive to potential, 1- [4- (4-fluorophenoxy) benzyl
L] semicarbazide binds to a voltage-sensitive Na + channel in the inactive state,
And in the rest state, Na⁺Demonstrated weak effectiveness on channels
(Ragsdale et al., Mol. Pharmacol. 40: 756-765 (
1991); Kuo and Bean, Mol. Pharmacol. 46:71
6-725 (1994)). The apparent antagonist dissociation constant (K _d ) Is about 7.5 μM for the inactive sodium channel.

The present invention has now been fully described, without affecting the scope of the invention or any of its embodiments, and within a broad and equal range of conditions, formulations and other parameters. It will be appreciated by those skilled in the art that this can be implemented. All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/381 A61K 31/381 4C206 31/44 31/44 4H006 31/47 31/47 31/505 31 / 505 31/53 31/53 A61P 9/06 A61P 9/06 9/10 9/10 23/02 23/02 25/00 25/00 25/04 25/04 25/08 25/08 25/24 25 / 24 C07D 215/20 C07D 215/20 239/26 239/26 239/34 239/34 239/38 239/38 239/42 239/42 251/12 251/12 307/02 307/02 307/38 307 / 38 307/42 307/42 307/52 307/52 307/54 307/54 307/56 307/56 307/58 307/58 307/66 307/66 307/68 307/68 309/12 309/12 317 / 64 317/64 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, G , GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV , MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Hong Bae, Sue United States of America Califor Near 91765, Diamond Bar, Hawkwood Road 3241 F-term (reference) 4C022 EA02 4C031 DA04 4C037 HA04 HA15 HA26 HA30 JA01 MA02 4C062 AA22 4C086 AA01 AA02 AA03 BA03 BA07 BA13 BC28 MA01 MA04 ZA29 ZC41 4C206 AA01A02 MA03 AA03 AB21

Claims (21)

[Claims] 1. A compound having the following formula I or a pharmaceutically acceptable salt or prodrug thereof: Wherein R ₁ and R ₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl,
Alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl,
R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; Is alkyl, or
R ₃ and R ₄ are defined above, and R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; A ₁ and A ₂ is independently aryl, heteroaryl, a saturated or partially unsaturated carbocycle or a saturated or partially unsaturated heterocyclic ring, any of which is optional. X is O, S, NR ₇ , CH ₂ , C (O), NR ₇ C (O), C (O) NR ₇ , S
O, SO ₂ or one of a covalent bond; wherein R ₇ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl N is 0, 1, 2 or 3; m is 0, 1, 2 or 3; 2. The compound of claim 1, wherein A ₁ and A ₂ are phenyl optionally substituted with hydrogen, alkyl, haloalkyl or halogen; and X is O. 3. A ₁ is phenyl optionally substituted with hydrogen, alkyl, haloalkyl or halogen; and A ₂ is 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl , Indanyl or naphthyl, which are optionally substituted with hydrogen, alkyl, haloalkyl or halogen. 4. A compound according to claim 1 having the formula II:
Is a pharmaceutically acceptable salt or prodrug thereof:Where R₁, R_Two, R_Three, R_Four, R_Five, R₆, X, n and m are as defined above with respect to formula I
And R₉, R_Ten, R₁₁And R_l2Is independently hydrogen, halo, haloalkyl, ant
Aryl, cycloalkyl, saturated or partially unsaturated heterocycle, heteroaryl,
Alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,
Arylalkynyl, heteroarylalkyl, heteroarylalkenyl, f
Teloarylalkynyl, cycloalkylalkyl, heterocycloalkyl,
Droxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl
, Nitro, amino, ureido, cyano, acylamide, hydroxy, thiol,
Acyloxy, azide, alkoxy, carboxy, carbonylamide or alky!
Kirthiol; or R₉And R_TenOr R₁₁And R₁₂Together with the carbon atom to which they are attached
To form a carbocyclic or heterocyclic ring, and together R₉And R_TenOr
R₁₁And R₁₂An example of a bridge formed by is -OCH_TwoO-, -OCF_TwoO-,
− (CH_Two)_Three-,-(CH_Two)_Four-, -OCH_TwoCH_TwoO-, -CH_TwoN (R₁₈) C
H_Two-, -CH_TwoCH_TwoN (R₁₈) CH_Two-, -CH_TwoN (R₁₈) CH_TwoCH_Two-And
And -CH = CH-CH = CH-;_l8Is hydrogen, alkyl or
R is chloroalkyl;₁₃, R_l4, R_Fifteen, R₁₆And R₁₇Is independently hydrogen, halo, haloalkyl
, Aryl, cycloalkyl, saturated or partially unsaturated heterocyclic, heteroaryl
, Alkyl, alkenyl, alkynyl, arylalkyl, arylalk
Nil, arylalkynyl, heteroarylalkyl, heteroarylalkenyl
, Heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl
, Hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxya
Alkyl, nitro, amino, ureido, cyano, acylamide, hydroxy, thio
, Acyloxy, azide, alkoxy, carboxy, carbonylamide or
Is an alkyl thiol;₁₃And R₁₄Or R₁₄And R_FifteenOr R_FifteenAnd R₁₆Or
Is R₁₆And R₁₇One of which, together with the carbon atom to which they are attached,
R together forming a carbocyclic or heterocyclic ring₁₃And R₁₄Or R₁₄And
And R_FifteenOr R_FifteenAnd R₁₆Or R₁₆And R₁₇Frame formed by
An example of a bridge is -OCH_TwoO-, -OCF_TwoO-,-(CH_Two)_Three-,-(CH_Two)_Four−,
-OCH_TwoCH_TwoO-, -CH_TwoN (R₁₈) CH_Two-, -CH_TwoCH_TwoN (R₁₈) CH _Two -, -CH_TwoN (R₁₈) CH_TwoCH_Two-And -CH = CH-CH = CH-
Where R₁₈Is hydrogen, alkyl or cycloalkyl. 5. A compound according to claim 1, having the following formula III or formula IV, or a pharmaceutically acceptable salt or prodrug thereof: Wherein: R _{1 to} R ₆ , R _{9 to} R ₁₂ , R _{13 to} R ₁₇ , n, m, A ₁ , A ₂ and X are as defined above for formulas I and II. 6. A claim wherein A ₂ is an optionally substituted heteroaryl or aryl group, including pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl and thiophenyl. Item 6. The compound according to item 5, 7. The method of claim 1, wherein A ₁ is an optionally substituted heteroaryl or aryl group, including pyridyl, pyrimidinyl, 1,3,5-triazinyl, naphthyl, quinolyl, furanyl and thiophenyl. Item 6. The compound according to item 5, 8. A compound according to claim 1, having the following formula V or VI, or a pharmaceutically acceptable salt or prodrug thereof: Wherein: R ₁ -R ₆ , R ₉ -R ₁₂ , R ₁₃ -R ₁₇ , n, m and X are as defined above with respect to formulas I and II; and B ₁ is optionally B ₂ is optionally substituted a saturated or partially unsaturated carbocyclic ring, or an optionally substituted saturated or partially unsaturated heterocyclic ring; and B ₂ is optionally substituted A saturated or partially unsaturated carbocycle, or an optionally substituted, saturated or partially unsaturated heterocyclic ring. 9. The compound according to claim 8, wherein B ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl. 10. The compound according to claim 8, wherein B ₂ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl. 11. The compound according to claim 1, wherein said compound is: 1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4- (4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4 1- (4- (4-methylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide; 1- (4- (4- 1- (4- (4-nitro) chloro-2-fluorophenoxy) benzyl) semicarbazide 1- (4- (3-methylphenoxy) benzyl) semicarbazide; 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl 1- (4- (4-s-butylphenoxy) benzyl) semicarbazide; 1- (4- (3,4-methylenedioxyphenoxy) benzyl) semicarbazide; 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4-cycloheptyloxybenzyl) semicarbazide; 1- [4- (5-indanyloxy) benzyl] semicarbazide; 1- (4- (6-quinolinyloxy) benzyl) semicarbazide; 1- (4- (4-Fluorophenoxy) -3- 1- (4- (tetrahydropyranyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl-4-methylsemicarbazide; 1- (4- (4-fluorophenoxy) benzyl) 1-[(4-trifluoromethyl) benzyl] -2′-methylsemicarbazide; 1- (3- (4-methylphenoxy) benzyl) semicarbazide; 1-[(4-cyclohexylmethoxy) benzyl 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) benzyl] -2′-methylsemicarbazide; 1- [4 -(5,6,7,8-tetrahydro-2-naphthoxy) Njiru] semicarbazide; 1- [3-fluoro-4- (4-fluorophenoxy) -1-phenylethyl]
1- [4- (3,4-difluorophenoxy) benzyl] -2-methyl semicarbazide; 1- [4- (3,5-difluorophenoxy) benzyl] semicarbazide; 1- [4- (benzyl) benzyl] 1- [4- (3,4-methylenedioxyphenoxy) benzyl] -2-methyl semicarbazide; 1- [4- (5,6,7,8-tetrahydro-2-naphthoxy) benzyl] -2
-Methyl semicarbazide; 1- [3-Fluoro-4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (exo) -2-norbornoxy (norbornoxy)
1- [4- (exo-2-norbornoxy) benzyl] -2-methylsemicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] semicarbazide; 1- [3-chloro -4- (4-fluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (phenoxy) benzyl] -2-methylsemicarbazide, and 1- [3- [4- (2-butyl) phenoxy] [Benzyl] semicarbazide. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or diluent. 13. A method of treating a disease responsive to a sodium channel blockade in a mammal afflicted with the disease, comprising: administering to a mammal in need of such treatment an effective amount of the following: Administering a compound having Formula I or a pharmaceutically acceptable salt or prodrug thereof: Wherein R ₁ and R ₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl,
Alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl,
R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; Is alkyl, or
R ₃ and R ₄ are defined as above, and R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; ₁ and A ₂ are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which are optionally substituted X is O, S, NR ₇ , CH ₂ , C (O), NR ₇ C (O), C (O) NR ₇ , S
O, SO ₂ or one of a covalent bond; wherein R ₇ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl N is 0, 1, 2 or 3; m is 0, 1, 2 or 3. 14. The method of claim 13, wherein A ₁ and A ₂ are both optionally substituted aryl moieties. 15. The method of claim 13, wherein A ₁ and A ₂ are optionally hydrogen, C _1-6 alkyl, halogen, hydroxy, C _1-4 alkoxy or A phenyl moiety substituted by one or two substituents independently selected from the group consisting of trifluoromethyl; R ₁ and R ₂ are hydrogen; R ₃ and R ₄ are hydrogen or methyl R ₅ and R ₆ are independently hydrogen, C _1-6 alkyl, or C _3-7 cycloalkyl; and X is O, CH ₂ or NH. 16. The compound of claim 13, wherein said compound is selected from the group consisting of:
1- (4-phenoxybenzyl) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chlorophenoxy) benzyl) semicarbazide; 1- (4 -(4-bromophenoxy) benzyl) semicarbazide; 1- (4- (4-methoxyphenoxy) benzyl) semicarbazide; 1- (4- (4-trifluoromethylphenoxy) benzyl) semicarbazide; 1- (4- (4 1- (4- (3,4-difluorophenoxy) benzyl) semicarbazide; 1- (4- (4-chloro-2-fluorophenoxy) benzyl) semicarbazide; 1- (4- ( 4-nitrophenoxy) benzyl) semicarbazide; 1- (4- (3- 1- (4- (4-t-butylphenoxy) benzyl) semicarbazide; 1- (4- (4-propylphenoxy) benzyl) semicarbazide; 1- (4- (4-s-butyl) 1- (4- (3,4-methylenedioxyphenoxy) benzyl) semicarbazide; 1- (4-cyclohexyloxybenzyl) semicarbazide; 1- (4-cycloheptyloxybenzyl) semicarbazide; 1- 1- (4- (5-Indanyloxy) benzyl) semicarbazide; 1- (4- (6-quinolinyloxy) benzyl) semicarbazide; 1- (4- (4-fluorophenoxy) -3-fluorobenzyl) semicarbazide; 1- ( 4- (tetrahydropyranyloxy) ben L) semicarbazide; 1- (4- (4-fluorophenoxy) benzyl-4-methylsemicarbazide; 1- (4- (4-fluorophenoxy) benzyl) -2-methylsemicarbazide; 1- (3-fluoro-4- (4-fluorophenoxy) benzyl) semicarbazide; 1- (3- (4-methylphenoxy) benzyl) semicarbazide; 1- (4-trifluoromethyl) benzyl) -2′-methylsemicarbazide; 1- [3-fluoro- 4- (4-fluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (5,6,7,8-tetrahydro-2-naphthoxy) benzyl] semicarbazide; 1- [3-fluoro-4- ( 4-fluorophenoxy) -1-phenylethyl]
1- [4- (3,4-difluorophenoxy) benzyl] -2-methyl semicarbazide; 1- [4- (3,5-difluorophenoxy) benzyl] semicarbazide; 1- [4- (benzyl) benzyl] 1- [4- (3,4-methylenedioxyphenoxy) benzyl] -2-methyl semicarbazide; 1- [4- (5,6,7,8-tetrahydro-2-naphthoxy) benzyl] -2
1- [3-Fluoro-4- (5-indanoxy) benzyl] semicarbazide; 1- [4- (exo-2-norbornoxy) benzyl] semicarbazide; 1- [4- (exo-2-norbornoxy) 1- [3-chloro-4- (4-fluorophenoxy) benzyl] semicarbazide; 1- [3-chloro-4- (4-fluorophenoxy) benzyl] -2-methylsemicarbazide; 1- [4- (phenoxy) benzyl] semicarbazide; 1- [4- (phenoxy) benzyl] -2′-methylsemicarbazide, and 1- [3- [4- (2-butyl) phenoxy] benzyl] semicarbazide. 17. A method for treating, preventing or ameliorating neuronal loss following global and focal ischemia; a method for treating, preventing or ameliorating a neurodegenerative condition; a method for treating, preventing or ameliorating pain. A method of treating, preventing or ameliorating major depression; a method of providing local anesthesia; or a method of treating arrhythmia or treating convulsions, wherein the method comprises administering to a mammal in need of such treatment:
Administering an effective amount of a compound having the following Formula I or a pharmaceutically acceptable salt or prodrug thereof: Wherein: R ₁ and R ₂ are independently hydrogen, alkyl, cycloalkyl, alkenyl,
Alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl,
R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; Is alkyl, or
R ₃ and R ₄ are defined as above, and R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocycle, including piperidine, piperazine, morpholine; ₁ and A ₂ are independently aryl, heteroaryl, saturated or partially unsaturated carbocyclic or saturated or partially unsaturated heterocyclic, any of which is optionally substituted X is O, S, NR ₇ , CH ₂ , C (O), NR ₇ C (O), C (O) NR ₇ , S
O, SO ₂ or one of a covalent bond; wherein R ₇ is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl N is 0, 1, 2 or 3; m is 0, 1, 2 or 3. 18. A method of treating, preventing or ameliorating the pain, wherein the pain is one of neuropathic pain, surgical pain or chronic pain.
The method according to claim 17. 19. A ₁ and A ₂ are optionally hydrogen, C _1-6 alkyl,
A phenyl moiety substituted by one or two substituents independently selected from the group consisting of halogen, hydroxy, C _1-4 alkoxy or trifluoromethyl; R ₁ and R ₂ are hydrogen; R ₃ and R ₄ are hydrogen or methyl; R ₅ and R ₆ are independently hydrogen, C _1-6 alkyl, or C _3-7 cycloalkyl; and X is O, CH ₂ or NH The method of claim 17. 20. A ₁ is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A ₂ is pyridyl, pyrimidinyl, 1,3,5-triazinyl, Furanyl, thiophenyl, naphthyl,
An optionally substituted heteroaryl or aryl group selected from the group consisting of quinolyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, indanyl, tetrahydronaphthyl and quinoxalinyl, The method according to claim 17. 21. A ₁ is an optionally substituted aryl group selected from the group consisting of phenyl and naphthyl, and A ₂ is cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, morpholinyl, pyrrolidinyl 18. The method of claim 17, wherein the compound is an optionally substituted carbocycle or heterocycle selected from the group consisting of, tetrahydrofuranyl, tetrahydropyranyl, cyclohexenyl, adamantyl, exo-norbornyl and cyclopentenyl. .