US 2008/0306046 A1 · Pyridyl Non-Aromatic Nitrogen-Containing Heterocyclic-1-Carboxylate Derivative

Abstract

[Problem] To provide a compound usable for treatment of diseases associated with fatty acid amide hydrolase (FAAH), especially for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain. [Means for Solution] We have found that a novel pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative and its pharmaceutically acceptable salt has a potent FAAH-inhibitory activity. Further, the pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of the present invention has an excellent effect for increasing an effective bladder capacity, an excellent effect for relieving urinary frequency and an excellent anti-allodynia effect, and is therefore usable for treatment of urinary frequency and urinary incontinence, overactive bladder and/or pain.

A pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylate derivative of a general formula (I), and its pharmaceutically acceptable salt:

[the symbols in formula (I) have the following meanings:
HET1 represents a 5- to 7-membered non-aromatic nitrogen-containing hetero ring,
R1, R2 and R3 are the same or different, each representing
(1) H,
(2) OH,
(3) optionally-esterified carboxyl,
(4) cyano,
(5) lower alkyl-CO—,
(6) oxo (═O),
(7) a formula [R101—(O)m1]m2-[ALK1 optionally substituted with OH]—(O)n1-,
(m1 and n1 are the same or different, each indicating 0 or 1,
m2 is from 1 to 5,
ALK1 represents lower alkylene, lower alkenylene or lower alkynylene,
R101 represents
(i) H,
(ii) Aria optionally substituted with at least one substituent selected from the group consisting of:
(a) H2N—,
(b) halo,
(c) cyano,
(d) optionally-esterified carboxyl,
(e) a group R1011aR1012aN—CO—,
(f) HET2,
(g) Aria optionally substituted with halo, cyano, OH, lower alkyl-O— or lower alkyl,
Ar1a represents aryl,
(h) lower alkyl,
(j) OH,
(k) lower alkyl-O— optionally substituted with Ar1a or halo-Ar1a,
(l) HET2-CO— optionally substituted with halo, Aria or HETAr1a,
HET2 represents nitrogen-containing hetero ring,
HETAr1a represents nitrogen-containing heteroaryl,
(s) HET2-CONR1011a—
(t) H2NCONH—, and
(u) optionally-esterified carboxyl-ALK2a,
ALK2a represents lower alkyl or lower alkenyl,
(iii) ALK2a optionally substituted with a group R1011aR1012aN or Ar1a,
R1011a and R1012a are the same or different, each representing
(a) H,
(b) cALK,
cALK represents a cycloalkyl,
(c) ALK2a optionally substituted with halo, cALK, OH, lower alkyl-O— or Ar1a, or
(d) Ar1a—SO2— optionally substituted with halo,
(iv) HET2 optionally substituted with at least one substituent selected from the group consisting of
(a) ALK2a optionally substituted with Ar1a or halo-Ar1a,
(b) Ar1a,
(c) HETAr1a optionally substituted with lower alkyl,
(d) Ar1a—CO— or halo-Ar1a—CO—,
(v) cALK optionally substituted with ALK2a, or
(vi) optionally-esterified carboxyl,
(in this, when m2 is from 2 to 5, then [R101—(O)m1]'s may be the same or different),
(8) a group R102-ALK1—N(R103)—CO—,
(R102 represents
(i) H,
(ii) cALK,
(iii) HETAR1a, or
(iv) Ar1a optionally substituted with at least one substituent selected from the group consisting of
(a) HO,
(b) ALK2a—O—
(c) cALK-ALK1—O—,
(d) cALK—Ar1a-ALK1—O—, and
(e) Ar1a-ALK1—O—,
R103 represents
(i) H,
(ii) cALK,
(iii) ALK2a optionally substituted with at least one substituent selected from the group consisting of
(a) HET2,
(b) Ar1a, and
(c) halo-Ar1a,
(iv) HETARa, or
(v) Ar1a—[CO]m1 optionally substituted with at least one substituent selected from the group consisting of
(a) cALK,
(b) H2N,
(c) a group R1011aR1012aN—CO—, or
(d) ALK2a),
(9) a group R104aR105aN—[CO]m1-ALK1—,
(R104a and R105a are the same or different, each representing a group R103),
(10) a group R106-ALK3-L1-,
(R106 represents
(i) a group R10l—(O)m1-,
(ii) a group R104aR105aN—,
(iii) a group ALK2a—CONH—, or
(iv) a group Ar1a—CONH—,
ALK3 represents lower alkylene, lower alkenylene or cycloalkylene,
L1 represents —C(═O)— or —SO2—),
(11) ALK2a—CONH— optionally substituted with Ar1a,
(12) Ar1a substituted with halo,
(13) a group [R107—(O)m1]m2-Ar2—(O)n1-,
(Ar2 represents arylene,
R107 represents
(i) H,
(ii) halo,
(iii) ALK2a optionally substituted with at least one substituent selected from the group consisting of
(a) HO,
(b) cALK,
(c) HET2,
(d) Ar1a optionally substituted with halo, lower alkyl, lower alkyl-O—, a group R1011aR1012aN—[CO]p-, cyano or optionally-esterified carboxyl,
(e) optionally-esterified carboxyl,
(f) HET2-[CO]p- optionally substituted with a group R1011aR1012aN—[CO]p-, and
(g) a group R1011aR1012aN—[CO]p-,
p indicates 0 or 1,
(iv) a group R1011aR1012aN—[CO]p-, or
(v) a group R1011aR1012aN—[CO]p-Ar1a,
in this, when m2 is from 2 to 5, then [R107—(O)m1]'s may be the same or different, and further the group [R107—(O)m1]m2 may be methylenedioxy to form a ring),
(14) a group [R107—(O)m1]m2-Ar2—N(R103)—CO—,
(in this, when m2 is from 2 to 5, then [R107—(O)m1]'s may be the same or different),
(15) a group [R1011aR1012aN—[CO]m1]m2-Ar2—(O)m1-,
(in this, when m2 is from 2 to 5, then [R1011aR1012aN—[CO]m1]'s may be the same or different),
(16) a group [R108]m2-Ar2-L2-,
[R108 represents
(i) H,
(ii) halo,
(iii) HO,
(iv) cALK—O—,
(v) a group R109-ALK1—(O)m1-,
(R109 represents
(a) H,
(b) cALK,
(c) Ar1a optionally substituted with at least one substituent selected from the group consisting of
(1′) halo,
(2′) cyano,
(3′) NO2,
(4′) ALK2a optionally substituted with halo,
(5′) HO,
(6′) ALK2a—O— optionally substituted with halo,
(7′) optionally-esterified carboxyl, or
(8′) a group R104aR105aN—,
(d) HETAR1a, or
(e) a group R104aR105aN—[CO]m1-),
(vi) a group R1013R1014N—,
R1013 and R1014 are the same or different, each representing
(i) H,
(ii) ALK2a,
(iii) cALK-ALK1—, or
(iv) Ar1a-ALK1— optionally substituted with at least one substituent selected from the group consisting of
(1′) halo,
(2′) cyano,
(3′) ALK2a optionally substituted with halo,
(4′) ALK2a—O— optionally substituted with halo,
(vii) HET2-(O)m1- optionally substituted with lower alkyl,
L2 represents —CO— or —S(O)q—,
q indicates 0, 1 or 2,
in this, when m2 is from 2 to 5, then [R108]'s may be the same or different],
(17) a group [R101]m2-Ar2—CONH—,
(in this, when m2 is from 2 to 5, then [R101]'s may be the same or different),
(18) a group [R111]m2-HETAr2—(O)m1-,
(R111 represents
(i) H,
(ii) halo,
(iii) oxo (═O), or
(iv) a group R103a—(O)n1-,
R103a represents
(i) H,
(ii) cALK,
(iii) ALK2a optionally substituted with at least one substituent selected from the group consisting of
(a) HET2,
(b) Ar1a,
(c) cALK and
(d) halo-Ar1a,
(iv) HETAr1a, or
(v) Ar1a optionally substituted with at least one substituent selected from the group consisting of (a) cALK, (b) H2N, and (c) a group R1011aR1012aN—CO—,
HETAr2 represents nitrogen-containing heteroarylene,
in this, when m2 is from 2 to 5, then [R111]'s may be the same or different),
(19) a formula [R112]m2-HETAr2—N(R103)—CO—,
(R112 represents
(i) H,
(ii) cALK,
(iii) ALK2a, or
(iv) Ar1a optionally substituted with at least one substituent selected from the group consisting of
(a) halo,
(b) HO,
(c) ALK2a—O—, and
(d) Ar1a-ALK1—O—,
in this, when m2 is from 2 to 5, then [R112]'s may be the same or different,
(20) a formula [R108]m2-HETAr2-L2-,
(in this, when m2 is from 2 to 5, then [R108]'s may be the same or different),
provided that, when any one group of R1, R2 and R3 is a group [R111]m2-HETAr2—(O)m1- and when m1 is 0, then the remaining groups of R1, R2 and R3 are H;
R4, R5, R6 and R7 are the same or different, each representing
(1) H,
(2) halo,
(3) optionally-esterified carboxyl,
(4) HO,
(5) a group R113-ALK4—(O)m3-,
(ALK4 represents lower alkylene, lower alkenylene, or lower alkynylene,
m3 indicates 0 or 1,
R113 represents
(i) H,
(ii) HO,
(iii) lower alkyl-O— optionally substituted with optionally-esterified carboxyl,
(iv) optionally-esterified carboxyl,
(v) lower alkyl-CO—O—, or
(vi) a group R104bR105bN—[CO]m3-(R104b and R105b are the same or different, each representing a group R103),
(6) R114R115N(R114 and R115 are the same or different, each representing
(i) H, or
(ii) ALK2b optionally substituted with a group R104bR105bN,
ALK2b represents lower alkyl or lower alkenyl),
(7) a group R116-(ALK4)n2-N(R117)—CO—,
(n2 indicates 0 or 1,
R116 represents
(i) H,
(ii) HO,
(iii) lower alkyl-O—,
(iv) optionally-esterified carboxyl,
(v) a group R104bR105bN—[CO]m3-,
(vi) Ar1b optionally substituted with (a) OH or (b) ALK2b—O—,
Ar1b represents aryl,
(vii) HET3 optionally substituted with a group R104bR105bN—[CO]m3- or optionally-esterified carboxyl,
HET3 represents nitrogen-containing hetero ring,
(viii) Ar1b optionally substituted with a group R104bR105bN—[CO]m3-, or
(ix) SO3H),
R117 represents (i) H or (ii) ALK2b optionally substituted with Ar1b,
(8) Ar1b optionally substituted with at least one substituent selected from the group consisting of optionally-esterified carboxyl and a group R1011bR1012bN—[(CO)]m3-,
R1011b and R1012b are the same or different, each representing
(i) H,
(ii) cALK,
(iii) ALK2b optionally substituted with halo, cALK, OH, lower alkyl-O— or Ar1b, or
(iv) Ar1b—SO2— optionally substituted with halo,
(9) HET3 optionally substituted with optionally-esterified carboxyl,
(10) HET3-CO— optionally substituted with at least one substituent selected from the group consisting of ALK2b and a group R104bR105bN—[CO]m3-, or
(11) cyano,
provided that 4-aminopyridin-3-yl piperidine-1-carboxylate is excluded].

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Pyridyl Non-Aromatic Nitrogen-Containing Heterocyclic-1-Carboxylate Derivative

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Pyridyl Non-Aromatic Nitrogen-Containing Heterocyclic-1-Carboxylate Derivative

Life of this patent

Abstract

Claims17