Compositions useful as inhibitors of voltage-gated sodium channels

• US 20060025415A1
• Filed: 02/17/2005
• Published: 02/02/2006
• Est. Priority Date: 08/08/2003
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Termin, Andreas P., Martinborough, Esther, Zimmerman, Nicole, Gonzalez, Jesus E. III
• Granted Patent: US 7,615,563 B2
• Time in Patent Office: Days
• US Class Current: 514/235.500
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: C04B 35/632 Organic additives
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 311/51 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 209/80 [b, c]- or [b, d]-condensed
• CPC Class Codes: C07D 209/92 Naphthostyrils
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 231/42 Benzene-sulfonamido pyrazoles
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 237/22 Nitrogen and oxygen atoms
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/52 Two oxygen atoms
• CPC Class Codes: C07D 239/545 with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/69 Benzenesulfonamido-pyrimidines
• CPC Class Codes: C07D 241/22 Benzenesulfonamido pyrazines
• CPC Class Codes: C07D 261/16 : Benzene-sulfonamido isoxazoles
• CPC Class Codes: C07D 263/50 : Benzene-sulfonamido oxazoles
• CPC Class Codes: C07D 277/52 : to sulfur atoms, e.g. sulfonamides
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 285/125 : with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 285/135 : Nitrogen atoms
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

1. A compound of formula I-A:

2. The compound according to claim 1, wherein, Z is selected from:

11. The compound according to claim 1, wherein R⁶ is hydrogen.

13. The compound according to claim 1, wherein X² is selected from —

CH₂—

, —

CH₂—

CH₂—

, —

(CH₂)₃—

, —

C(Me)₂—

, —

CH(Me)—

, —

C(Me)═

CH—

, —

CH═

CH—

, —

CH(Ph)—

, —

CH₂—

CH(Me)—

, —

CH(Et)—

, —

CH(i-Pr)—

, or cyclopropylene.

14. The compound according to claim 1, wherein p is 1 and X₁ is O.

16. The compound according to claim 1, wherein T naphthyl, tetralin, or decalin, optionally substituted with up to 3 substituents independently selected from halo, cyano, trifluoromethyl, OH, C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, NHC(O)C_1-4 alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, or C(O)C_1-4 alkyl.

17. The compound according to claim 16, wherein T is optionally substituted napthyl.

18. The compound according to claim 1, wherein T is selected from:

21. The compound according to claim 1, p is 0.

24. The compound according to claim 1, having formula:

46. The compound according to claim 1, 25 or 44, wherein Z in claim 1, Z^N in claim 25 and Z^M in claim 44 are independently selected from:

59. The compound according to claim 44, wherein T^M is The compound according to claim 1, wherein T^M is phenyl or naphthyl, optionally substituted with up to 3 substituents independently selected from halo, cyano, trifluoromethyl, OH, C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, NHC(O)C_1-4 alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, or C(O)C_1-4 alkyl.

76. A pharmaceutical composition comprising a compound according to any one of claims 1, 25, or 44, and a pharmaceutically acceptable adjuvant or carrier.

109. The method according to claims 108, wherein said compound is selected from any one of claims 1, 25, or 44.

117. The compound according to claim 1, 25, or 44 selected from FIG. 1.

3-10. -10. (canceled)

12. (canceled)

15. (canceled)

19-20. -20. (canceled)

22-23. -23. (canceled)

25. A compound having formula III:

26. The compound according to claim 25, wherein Z^N is selected from:

35. The compound according to claim 25, wherein each R^N is hydrogen.

37. The compound according to claim 25, wherein X₂ is selected from —

CH₂—

, —

CH₂—

CH₂—

, —

(CH₂)₃—

, —

CH(Me)—

, —

C(Me)═

CH—

, —

CH═

CH—

, —

CH(Ph)—

, —

CH₂—

CH(Me)—

, —

CH(Et)-, —

CH(i-Pr)—

, or cyclopropylene.

38. The compound according to claim 37, wherein X₂ is selected from —

CH₂—

, —

CH(Me)—

, —

C(Me)₂—

, —

CH₂—

CH₂—

, or —

(CH₂)₃—

.

39. The compound according to claim 38, wherein X₂ is —

CH₂—

.

40. The compound according to claim 25, wherein T^N is an optionally substituted 5-6 membered monocyclic ring.

41. The compound according to claim 40, wherein T^N is selected from 1-pyrrolyl, 2,3-dihydro-1H-pyrrol-1-yl, 1-pyrazolyl, 1-imidazolyl, 1-pyrrolidinyl, 1,2,3,4-tetrahydropyrid-1-yl, 1,2,3,6-tetrahydropyrid-1-yl, 1-zpiperidinyl, 1-piperazinyl, 1-morpholinyl, 1-azepinyl, or 1-azepanyl, wherein said ring is optionally substituted with up to 3 substituents.

42. The compound according to claim 41, wherein T^N is fused to a phenyl ring, wherein said phenyl ring is optionally substituted with up to three substituents.

43. The compound according to claim 41 or 42, wherein said substituents are independently selected from halo, cyano, trifluoromethyl, OH, C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, trifluoromethoxy, C(O)NH₂, NH₂, NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, NHC(O)C_1-4 alkyl, or C(O)C_1-4 alkyl.

27-34. -34. (canceled)

36. (canceled)

44. A compound having formula IV:

45. The compound according to claim 44, wherein Z^M is selected from:

54. The compound according to claim 44, wherein each R^N is hydrogen.

56. The compound according to claim 44, wherein Z^M is an optionally substituted 5-6 membered monocyclic ring.

57. The compound according to claim 44, wherein X₁ is NH.

58. The compound according to claim 44, wherein X₁ is O.

60. The compound according to claim 44, wherein T^M is selected from:

61. The compound according to claim 44, wherein T is selected from:

47-53. -53. (canceled)

55. (canceled)

62-75. -75. (canceled)

77. A method of inhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in:

(a) a patient;

or

(b) a biological sample;

which method comprising administering to said patient, or contacting said biological sample with a compound of formula I;

T-L₁-A-L₂-Z 

 

(I);

or a pharmaceutically acceptable derivative thereof;

wherein;

L₁ is —

(X₁)_p—

(X₂)_q—

R_y—

;

wherein;

X₁ is O, S, or NR_x

p is 0 or 1;

q is 0 or 1;

R_x is H or R²;

X₂ is R²;

R_y is —

C(O)—

NR²—

;

or

L₂ and Ry are independently selected from OC(O), C(O)O, S(O), SO₂, N(R⁵)SO₂, N(R⁶)SO₂, SO₂N(R⁵), SO₂N(R⁶), C(O)N(R⁵), C(O)N(R⁶), NR⁵C(O), NR⁶C(O), C(NOR⁵)R⁶, C(NOR⁵)R⁶, C(NOR⁶)R⁵, C(NOR⁶)R⁶, N(R⁵), N(R⁶), NR⁵C(O)O, NR⁶C(O)O, OC(O)NR⁵, OC(O)NR⁶, NR⁵C(O)N(R⁵), NR⁵C(O)N(R⁶), NR⁶C(O)N(R⁵), NR⁶C(O)N(R⁶), NR⁵SO₂N(R⁵), NR⁵SO₂N(R⁶), NR⁶SO₂N(R⁵), NR⁶SO₂N(R⁶), N(OR⁵), or N(OR⁶);

Z is hydrogen, cycloaliphatic, heterocyclic, aryl, or heteroaryl ring;

T is aliphatic, cycloaliphatic, aryl, heteroaryl, or heterocyclic ring;

A is aryl or heteroaryl ring;

wherein each of T, A, and Z is optionally substituted with up to 4 suitable substituents independently selected from R¹, R², R³, R⁴, or R⁵;

R¹ is oxo, ═

NN(R⁶)₂, ═

NN(R⁷)₂, ═

NN(R⁶R⁷), R⁶ or (CH₂)_n—

Y;

n is 0, 1 or 2;

Y is halo, CN, NO₂, CF₃, OCF₃, OH, SR⁶, S(O)R⁶, SO₂R⁶, NH₂, NHR⁶, N(R⁶)₂, NR⁶R⁸, COOH, COOR⁶ or OR⁶;

or

two R¹ on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;

R² is aliphatic, wherein each R² is optionally substituted with up to 2 substituents independently selected from R¹, R⁴, or R⁵;

R³ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R¹, R², R⁴ or R⁵;

R⁴ is OR⁵, OR⁶, OC(O)R⁶, OC(O)R⁵, OC(O)OR⁶, OC(O)OR⁵, OC(O)N(R⁶)₂, OC(O)N(R⁵)₂, OC(O)N(R⁶R⁵), OP(O)(OR⁶)₂, OP(O)(OR⁵)₂, OP(O)(OR⁶)(OR⁵), SR⁶, SR⁵, S(O)R⁶, S(O)R⁵, SO₂R⁶, SO₂R⁵, SO₂N(R⁶)₂, SO₂N(R⁵)₂, SO₂NR⁵R⁶, SO₃R⁶, SO₃R⁵, C(O)R⁵, C(O)OR⁵, C(O)R⁶, C(O)OR⁶, C(O)N(R⁶)₂, C(O)N(R⁵)₂, C(O)N(R⁵R⁶), C(O)N(OR⁶)R⁶, C(O)N(OR⁵)R⁶, C(O)N(OR⁶)R⁵, C(O)N(OR⁵)R⁵, C(NOR⁶)R⁶, C(NOR⁶)R⁵, C(NOR⁵)R⁶, C(NOR⁵)R⁵, N(R⁶)₂, N(R⁵)₂, N(R⁵R⁶), NR⁵C(O)R⁵, NR⁶C(O)R⁶, NR⁶C(O)R⁵, NR⁶C(O)OR⁶, NR⁵C(O)OR⁶, NR⁶C(O)OR⁵, NR⁵C(O)OR⁵, NR⁶C(O)N(R⁶)₂, NR⁶C(O)NR⁵R⁶, NR⁶C(O)N(R⁵)₂, NR⁵C(O)N(R⁶)₂, NR⁵C(O)NR⁵R⁶, NR⁵C(O)N(R⁵)₂, NR⁶SO₂R⁶, NR⁶SO₂R⁵, NR⁵SO₂R⁵, NR⁶SO₂N(R⁶)₂, NR⁶SO₂NR⁵R⁶, NR⁶SO₂N(R⁵)₂, NR⁵SO₂NR⁵R⁶, NR⁵SO₂N(R⁵)₂, N(OR⁶)R⁶, N(OR⁶)R⁵, N(OR⁵)R⁵, N(OR⁵)R⁶, P(O)(OR⁶)N(R⁶)₂, P(O)(OR⁶)N(R⁵R⁶), P(O)(OR⁶)N(R⁵)₂, P(O)(OR⁵)N(R⁵R⁶), P(O)(OR⁵)N(R⁶)₂, P(O)(OR⁵)N(R⁵)₂, P(O)(OR⁶)₂, P(O)(OR⁵)₂, or P(O)(OR⁶) (OR⁵);

R⁵ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring is optionally substituted with up to 3 R¹ substituents;

R⁶ is H or aliphatic, wherein R⁶ is optionally substituted with a R⁷ substituent;

R⁷ is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring and each R⁷ is optionally substituted with up to 2 substituents independently chosen from H, aliphatic, or (CH₂)_n-Z′

;

Z′

is selected from halo, CN, NO₂, C(halo)₃, CH(halo)₂, CH₂(halo), —

OC(halo)₃, —

OCH(halo)₂, —

OCH₂(halo), OH, S-aliphatic, S(O)-aliphatic, SO₂-aliphatic, NH₂, NH-aliphatic, N(aliphatic)₂, N(aliphatic)R⁸, COOH, C(O)O(-aliphatic), or O-aliphatic; and

R⁸ is an amino protecting group.

81. The method according to claim 77, wherein X₁ is NR_x;

and R_x is H.

83. The method according to claim 77, wherein X₂ is a straight or branched (C1-C6)alkyl optionally substituted with up to two substituents independently selected from R₁ and R₅.

84. The method according to, claim 77 wherein R_y is H or straight or branched (C1-C6)alkyl or (C2-C6)alkenyl or alkynyl, optionally substituted with up to two substituents independently selected from R₁ and R₅.

86. The method according to claim 77, wherein Z is phenyl or napthyl.

88. The method according to claim 77, wherein Z is selected from thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, or pyrrolyl.

90. The method according to claim 77, wherein A is phenyl or naphthyl.

92. The method according to claim 77, wherein A is pyridyl, pyrazyl, triazinyl, furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazole, isothiazole, oxadiazole, imidazolyl, triazolyl, thiadiazolyl, or pyrimidinyl.

94. The method according to claim 77, wherein A is quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolizinyl, indolyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazine, quinazolinyl, quinaoxalinyl, naphthylirinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, anthracenyl, fluorenyl, dibenzofuranyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl.

97. The method according to claim 77, wherein T is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or adamantyl.

99. The method according to claim 98claim 77, wherein T is phenyl, napthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furanyl, benzofuranyl, oxazolyl, quinolinyl phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridiyl, furanyl, benzofuranyl, oxazolyl, quinolinyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolinyl, cinnolinyl phthalazinyl, quinazolinyl, quinoxalinyl, napthyridinyl, pteridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxainyl, or carbazolyl.

100. The method according to claim 77, wherein T is a heterocyclic ring.

101. The method according to claim 100, wherein T is tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, dioxoianyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperazinyl, or trithianyl.

102. The method according to claim 77, wherein R¹ is oxo.

103. The method according to claim 77, wherein R¹ is R⁶ or (CH₂)_n—

Y.

104. The method according to claim 103, wherein R¹ is (CH₂)_n—

Y, wherein n is 0.

105. The method according to claim 77, wherein R² is a straight or branched (C1-C6) alkyl or (C2-C6)alkenyl or alkynyl, optionally substituted with up to two R¹ substitutions.

106. The method according to claim 77, wherein:

Z is thiazol-2-yl;

A is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl;

L₁ is —

(X₁)_p—

(X₂)_q—

R_y—

;

wherein;

X₁ is O, S, or NR_x

p is 0 or 1;

q is 0 or 1;

R_x is H or R²;

X₂ is R²;

R_y is —

C(O)—

NR²—

; and

L₂ is SO₂N(R⁵) or SO₂N(R⁶).

107. The method according to claim 77, wherein said compound has formula I-A, formula IIA-i, formula IIB-i, formula IIC-i, formula IID-i, formula III, formula IV, or formula V.

78-80. -80. (canceled)

82. (canceled)

85. (canceled)

87. (canceled)

89. (canceled)

91. (canceled)

93. (canceled)

95-96. -96. (canceled)

98. (canceled)

108. A method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epileptic conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, stroke, bipolar disorders, or cancer pain, comprising the step of administering to said patient an effective amount of a compound according of formula I.

110. The method according to claim 108, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels.

111. The method according to claim 108, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated calcium channels.

112. The method according to claim 111, wherein the disease, condition, or disorder is acute, chronic, neuropathic, inflammatory pain, or inflammatory breakthrough pain.

113. The method according to claim 108, wherein the disease, condition, or disorder is radicular pain, sciatica, back pain, head pain, neck pain, or neuropathies.

114. The method according to claim 108, wherein the disease, condition, or disorder is severe or intractable pain, acute pain, post-surgical pain, back pain, or cancer pain.

115. The method according to claim 77 or 108, wherein said compound is selected from FIG. 1.

116. (canceled)