AMINES CYCLIQUES MODULANT L'ACTIVITE DES RECEPTEURS DE CHIMIOKINES

CYCLIC AMINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

Abrégé français

La présente invention se rapporte à des amines cycliques représentées par la formule (I), dans laquelle R?1¿, R?2¿, R?3¿, m et n sont définis dans le descriptif de l'invention. Ces amines s'avèrent utiles en tant que modulateurs de l'activité des récepteurs de chimiokines, et notamment des récepteurs CCR-1, CCR-2, CCR2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3 et/ou CXCR-4.

Abrégé anglais

The present invention is directed to cyclic amines of formula (I), (wherein
R1, R2, R3, m and n are defined herein) which are useful as modulators of
chemokine receptor activity. In particular, these compounds are useful as
modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-
4, CCR-5, CXCR-3, and/or CXCR-4.

Revendications

WHAT IS CLAIMED IS:
1. A compound of the formula:
<IMG>
wherein:
wherein:
R1 is selected from a group consisting of:
C3, C4, C5, C6, C7, or C8 linear or branched alkyl, which is
unsubstituted or mono, di or tri-substituted, where the
substituents are independently selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') phenyl,
(2') hydroxy,
(3') C1-3alkyl,
(4') cyano,
(5') halogen, and
(6') trifluoromethyl,
(e) C1-6 alkyl, unsubstituted or substituted with hydroxy,
(f) -NR6CO-R7, wherein R6 is hydrogen or C1-3 alkyl,
unsubstituted or substituted with C5-8 cycloalkyl, and
R7 is C1-6 alkyl, benzyl or phenyl which is
unsubsituted or substituted with halo, CF3, C1-3alkyl,
or C1-3alkoxy,
(g) -COR6,
(h) -OR6,
(i) -NR6S(O)j-R7, where j is 1 or 2,
(j) -NR6S(O)j-heteroaryl, wherein heteroaryl is selected
from the group consisting of:
-182-

(1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
(7') isooxazolyl,
(8') isothiazolyl,
(9') oxadiazolyl,
(10') oxazolyl,
(11') pyrazinyl,
(12') pyrazolyl,
(13') pyridyl,
(14') pyrimidyl,
(15') pyrrolyl,
(16') quinolyl,
(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl is unsubstituted or mono di or
tri- substituted, where the substituents are independently
selected from:
(a') phenyl,
(b') hydroxy,
(c') oxo,
(d') cyano,
(e') halogen, and
(f') trifluoromethyl;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
-183-

(4) -O-C1-6 alkyl,
(5) phenyl,
(6) -N(CH3)-CO-N(H)(CH3),
(7) -N(H)-CO-O-CH3, and
(8) -CO-CH3;
R3 is selected from the group consisting of:
(1) Ar,
(2) -(C1-6 alkyl)-Ar,
(3) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar, and
(4) -N(R4)-CO-O-(C1-6 alkyl)-Ar, wherein R4 is selected from
hydrogen, C1-10 linear or branched alkyl, and C0-6 alkyl
substituted with C3-8 cycloalkyl,
(5) -N(R4)-CO-O-R7;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyrazinyl,
(3) pyrazolyl,
(4) pyridyl,
(5) pyrimidyl, and
(6) thienyl,
wherein the Ar is unsubstituted or mono or di-substituted,
and the substituents are independently selected from:
(a) C1-3 alkyl, unsubstituted or substituted with
(1') oxo,
(2') hydroxy,
(3') -OR7,
(4') phenyl, and
(5') trifluoromethyl,
(b) halogen,
(c) -OC1-6 alkyl,
(d) trifluoromethyl,
(e) -NO2,
-184-

(f) CONR6-(C1-2 alkyl),
(g) CO2H,
(h) CO2-(C1-2 alkyl),
(i) CH2NR6-(C1-2 alkyl),
(j) CH2NH-C(O)-C1-3alkyl,
(k) CH2NH-C(O)NH2,
(l) CH2NH-C(O)NHC1-3alkyl,
(m) CH2NH-C(O)N-diC1-3 alkyl),
(n) CH2NH-S(O)j-C1-3alkyl,
(o) CH2-heteroaryl, with the heteroaryl is selected from
the group consisting of:
(1') imidazolyl,
(2') oxazolyl,
(3') pyridyl,
(4') tetrazolyl,
(5') triazolyl,
and the heteroaryl is unsubstituted, mono, di or
tri-substituted, where the substituents selected from:
(a') hydrogen,
(b') C1-6 alkyl, branched or unbranched,
unsubstituted or mono or di-substituted,
the substituents being selected from
hydrogen and hydroxy;
and pharmaceutically acceptable salts thereof.
2. The compound of Claim 1 wherein:
R1 bears at least one substituent which is selected from:
(a) -NR6CO-R7, wherein R6 is C1-3 alkyl, unsubstituted
or substituted with cyclohexyl, and R7 is C1-6 alkyl,
benzyl or phenyl which is unsubsituted or substituted
with halo, CF3, C1-3alkyl, or C1-3alkoxy, and
(b) -NR6S(O)j-R7, where j is 1 or 2.
3. The compound of Claim 1 wherein:
-185-

R1 bears at least one substituent which is:
-NR6S(O)j-R7, wherein R6 is C1-3 alkyl, unsubstituted or
substituted with cyclohexyl, and R7 is C1-6 alkyl,
benzyl or phenyl which is unsubsituted or substituted
with halo, CF3, C1-3alkyl, or C1-3alkoxy, and where j
is 1 or 2.
4. The compound of Claim 1 wherein:
R1 is selected from the group consisting of:
C4, C5, or C6 linear alkyl, which is substituted, where the
substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') hydroxy,
(2') methyl or ethyl,
(3') Cl or F, and
(4') trifluoromethyl,
(c) C1-6 alkyl, unsubstituted or substituted with hydroxy,
(d) -NR6CO-R7, wherein R6 is methyl, unsubstituted or
substituted with cyclohexyl, and R7 is phenyl which
is unsubstituted or substituted with Cl, F, CF3,
C1-3alkyl or C1-3alkoxy, and
(e) -NR6S(O)j-R7, where j is 1 or 2.
5. The compound of Claim 1 wherein:
R1 is C4 linear alkyl, which is substituted, where the substituents are
independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') hydroxy,
(2') methyl or ethyl,
(3') Cl or F, and
-186-

(4') trifluoromethyl,
(c) C1-6 alkyl, unsubstituted or substituted with hydroxy,
and
(d) -NR6S(O)j-R7, where R6 is methyl, unsubstituted or
substituted with cyclohexyl, and R7 is phenyl which
is unsubstituted or substituted with Cl, F, CF3,
C1-3alkyl or C1-3alkoxy, and j is 1 or 2.
6. The compound of Claim 1 wherein:
R1 is selected from the group consisting of
<IMG>
7. The compound of Claim 1 wherein:
R1 is selected from the group consisting of
<IMG>
-187-

<IMG>
8. The compound of Claim 1 wherein:
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy, and
{3) phenyl.
9. The compound of Claim 1 wherein:
R2 is hydrogen.
10. The compound of Claim 1 wherein:
R3 is selected from:
(1) Ar,
(2) -N(R4)-CO-O-(C1-6 alkyl)-Ar, wherein R4 is selected from
hydrogen, C1-10 linear or branched alkyl, and C0-6 alkyl
substituted with C3-8 cycloalkyl.
11. The compound of Claim 1 wherein:
R3 is -N(R4)-CO-O-(C1-6 alkyl)-Ar, wherein R4 is selected from
hydrogen, C1-10 linear or branched alkyl, and C0-6 alkyl substituted
with C3-8 cycloalkyl.
12. The compound of Claim 1 wherein:
R3 is selected from:
(1) phenyl, and
(2) -N(R4)-CO-O-(C1-6 alkyl)-phenyl, wherein R4 is selected
from hydrogen, C1-10 linear or branched alkyl, and C0-6
alkyl substituted with C3-8 cycloalkyl.
-188-

13. The compound of Claim 1 wherein:
R3 is:
-N(R4)-CO-O-(CH2)-phenyl, wherein R4 is selected from hydrogen,
C1-6 linear or branched alkyl, and CH2 substituted with
C3-8 cycloalkyl.
14. The compound of Claim 1 wherein:
R3 is:
-N(R4)-CO-O-(CH2)-phenyl, wherein R4 is selected from hydrogen
and C1-6 alkyl.
15. A compound which is selected from the group
consisting of:
<IMG>
-189-

<IMG>
-190-

<IMG>
-191-

<IMG>
-192-

<IMG>
-193-

<IMG>
-194-

<IMG>
-195-

<IMG>
-196-

<IMG>
-197-

<IMG>
-198-

<IMG>
-199-

<IMG>
-200-

<IMG>
-201-

<IMG>
-202-

<IMG>
-203-

<IMG>
-204-

<IMG>
-205-

<IMG>
-206-

<IMG>
-207-

<IMG>
-208-

<IMG>
-209-

<IMG>
-210-

<IMG>
-211-

<IMG>
-212-

<IMG>
-213-

<IMG>
-214-

<IMG>
-215-

<IMG>
-216-

<IMG>
-217-

<IMG>
-218-

<IMG>
-219-

<IMG>
-220-

<IMG>
-221-

<IMG>
-222-

<IMG>
-223-

<IMG>
-224-

<IMG>
- 225 -

<IMG>
-226-

<IMG>
-227-

<IMG>
-228-

<IMG>
-229-

<IMG>
-230-

<IMG>
-231-

<IMG>
-232-

<IMG>
-233-

<IMG>
-234-

<IMG>
-235-

<IMG>
-236-

<IMG>
-237-

<IMG>
-238-

<IMG>
-239-

<IMG>
-240-

<IMG>
-241-

<IMG>
-242-

<IMG>
-243-

<IMG>
-244-

<IMG>
-245-

<IMG>
-246-

<IMG>
-247-

<IMG>
-248-

<IMG>

<IMG>
- 250 -

<IMG>
-251-

<IMG>
- 252 -

<IMG>
- 253 -

<IMG>
-254-

<IMG>
-255-

<IMG>
-256-

<IMG>
-257-

<IMG>
and pharmaceutically acceptable salts thereof.
-258-

16. A compound which is selected from the group
consisting of:
(R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-methylbenzene-
sulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzylpiperidin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide;
(R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonyl-4-phenylpiperidin-1-
yl)but-1-yl)-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-aminocarbonyl-4-phenylpiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-hydroxymethyl-4-phenylpiperidin-1-yl )but-1-yl)-
N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(piperidin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide;
(R,S)-N-[2-Phenyl-4-(4-pentylaminocarbonylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-(2-Phenyl-4-(4-isopropylaminocarbonylpiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methylaminocarbonylmethylene-4-phenyl-
piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methylaminocarbonyl(methylamino)methylene-4-
phenylpiperidin-1-yl)but-1-yl)-N-methylbenzenesulfonamide;
-259-

(R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminomethylene-4-
phenylpiperidin-1-yl)but-1-yl)-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methylaminocarbonylaminomethylene-4-
phenylpiperidin-1-yl)but-1-yl)-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-(2-methyl)phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-morpholinocarbonylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(2-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(2-Thienyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Thienyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Thienyl)-4-(4-benzylpiperidin-1-yl)but-1-yl]-N-methyl-
benzenesulfonamide;
(R,S)-N-[2-Cyclohexyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methyl-
benzenesulfonamide;
(R,S)-N-[2-(3,5-Dichlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-methyl-
benzenesulfonamide;
-260-

(R,S)-N-[2-(3-Ethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methyl-
benzenesulfonamide;
(R,S)-N-[2-(3-Carboethoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-(2-(3-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3,4-Difluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Biphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Pyridyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(Naphthalen-2-yl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(4-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(2-Pyridyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Fluoro-4-methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-(3,4-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide;
-261-

(R,S)-N-[2-(3,5-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide;
(R,S)-N-[2-(4-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-(3-Trifluoromethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-(3-Methyl-4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[4-(4-Benzylpiperidin-1-yl)-2-(3-chlorophenyl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[4-(4-(3-Phenylprop-1-yl)piperidin-1-yl)-2-(3-chlorophenyl)but-
1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-t-butylpiperidin-2-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-(cis-octahydro-2H-benzimidazol-2-on-1-
yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-(1,2,3,4-tetrahydro-2H-quinazolin-2-on-1-
yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(3-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-hydroxy-4-phenylpiperidin-1-yl)but-1-yl]-
-262-

N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-(2,3-dihydro-2H-benzimidazol-2-on-1-
yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-[4,4-diphenylpiperidin-1-yl]-butyl}-N-
methylbenzenesulfonamide;
(S)-N-[4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-2-(3-chlorophenyl)-
but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[4-(4-Acetyl-4-phenylpiperidin-1-yl)-2-(3-chlorophenyl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[4-[4-(4-Chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl]-2-
(3-chlorophenyl)but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-methoxycarbonylphenyl)piperidin-1-yl]-
but-1-yl)-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-[4-hydroxy-4-(3-trifluoromethyl)phenyl-piper-
idin-1-yl]-but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-
yl]but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piper-
idin-1-yl]but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-oxo-3H-benzo[d][1,4]oxazin-1-yl)piper-
idin-1-yl]but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[4-(4-Benzoylpiperidin-1-yl)-2-(3-chlorophenyl)but-1-yl]-N-
methylbenzenesulfonamide;
-263-

(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-methoxy)phenylpiperidin-1-yl]but-1-
yl)-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl)-4-(4-piperidin-1-ylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[2-(3,4-Methylenedioxyphenyl)-4-(4-phenylpiperidin-i-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(4-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(S)-N-[2-(3,4-Dichlorophenyl)-4-(4-phenylpiperidin-1-yl)-but-1-yl]-N-
ethylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methylphenyl-
acetamide;
(R,S)-N-[2-Phenyl-4-[4-acetyl(ethylamino)piperidin-1-yl]but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-[4-(oxazolidin-2-on-3-yl)piperidin-1-yl]but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(ethylamino)piperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonylaminopiperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(prop-1-ylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminopiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide;
-264-

(R,S)-N-[2-Phenyl-4-(4-aminocarbonylaminopiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-aminopiperidin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide;
(R,S)-N-[2-Phenyl-4-(4-acetylaminopiperidin-1-yl)but-1-yl]-N-
methyibenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-isopropylcarbonylaminopiperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methylsulfonylaminopiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-isopropylcarbonyl(ethylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methylsulfonyl{ethylamino)piperidin-1-yl)but-
1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-t-butoxycarbonylaminopiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(methylamino)piperidin-1-yl)but-
1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-{pyrrolidin-2-on-1-yl)piperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclobutylmethylamino)-
piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
-265-

(R,S)-N-[2-Phenyl-4-(4-ethoxycarbonyl(ethylamino)piperidin-1-yl)but-1-
yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-isobutyloxycarbonyl(ethylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-piperidin-2-on-1-ylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(benzylamino)piperidin-1-yl)but-
1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(prop-1-ylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(but-1-ylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclohexylmethylamino)-piper-
idin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclopropylmethylamino)-piper-
idin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(pent-1-ylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(methylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(ethylamino)piperidin-1-yl)but-
1-yl]-N-rnethylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(but-1-ylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
-266-

(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(pent-1-ylamino)piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(cyclobutylmethylamino)-piper-
idin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(cyclohexylmethylamino)-piper-
idin-1-yl)but-1-yl]-N-methylbenzenesulfonamide;
(S)-N-[2-(3-Chlorophenyl-4-(4-benzyloxycarbonyl(ethylamino)-piperidin-1-
yl)but-1-yl]-N-methylbenzenesulfonamide;
(R,S)-N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide;
(R,S)-N-Methyl-N-[2-methyl-2-phenyl-4-(4-phenylpiperidin-1-yl)but-1-
yl]benzenesulfonamide;
(R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-methyl-2-
phenylbut-1-yl]-N-methylbenzenesulfonamide; and
(R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-ethyl-2-
phenylbut-1-yl]-N-methylbenzenesulfonamide;
and pharmaceutically acceptable salts thereof.
17. A pharmaceutical composition which comprises an
inert carrier and a compound of Claim 1.
-267-

18. A method for the modulation of chemokine receptor
activity in a mammal comprising the administration of an effective
amount of a compound of formula I:
<IMG>
wherein:
R1 is selected from a group consisting of:
linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl,
wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono,
di, tri or tetra substituted, where the substituents are
independently selected from:
(a) hydroxy,
(b) oxo,
(c) cyano,
(d) halogen which is selected from F, Cl, Br, and I,
(e) trifluoromethyl,
(f) phenyl
(g) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') phenyl,
(2') hydroxy,
(3') C1-3alkyl,
(4') cyano,
(5') halogen,
(6') trifluoromethyl,
(7') -NR6COR7,
(8') -NR6CO2R7,
(9') -NR6CONHR7,
(10') -NR6S(O)jR7, wherein j is 1 or 2,
(11') -CONR6R7,
-268-

(12') -CORE,
(13') -CO2R6,
(14') -OR6,
(15') -S(O)k R6, wherein k is 0, 1 or 2,
(h) C1-6 alkyl, unsubstituted or substituted with hydroxy,
(i) -NR6R7,
(j) -NR6COR7,
(k) -NR6CO2R7,
(l) -NR6CONHR7,
(m) -NR6S(O)j-R7,
(n) -CONR6R7,
(o) -COR6,
(p) -CO2R6,
(q) -OCOR6,
(r) -CN,
(s) -OR6,
(t) -S(O)k R6,
(u) -NR6CO-heteroaryl,
(v) -NR6S(O)j-heteroaryl, and
(w) heteroaryl, wherein heteroaryl is selected from the
group consisting of:
(1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
(7') isooxazolyl,
(8') isothiazolyl,
(9') oxadiazolyl,
(10') oxazolyl,
(11') pyrazinyl,
(12') pyrazolyl,
(13') pyridyl,
-269-

(14') pyrimidyl,
(15') pyrrolyl,
(16') quinolyl,
(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl is unsubstituted or mono di or
tri-substituted, where the substituents are independently
selected from:
(a") phenyl,
(b") hydroxy,
(c") oxo,
(d") cyano,
(e") halogen, and
(f') trifluoromethyl;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) substituted C1-6 alkyl, where the substituents are
independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) halogen,
(e) trifluoromethyl,
(f) -N(R4)(R5), wherein R4 and R5 are independently
selected from hydrogen, C1-10 linear or branched
alkyl, and C0-6 alkyl substituted with C3-8 cycloalkyl,
(g) -N(R4)-CO-O-(R5), and
(h) -N(R4')-CO-N(R4)(R5), wherein R4' is selected from
the definitions of R4,
(5) -O-C1-6 alkyl, and
-270-

(6) phenyl;
R3 is selected from the group consisting of:
(1) Ar,
(2) -N(R4)-CO-O-(C1-6 alkyl)-Ar,
(3) -N(R4)-CO-O-R7,
(4) -(C1-6 alkyl)-Ar,
(5) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar, and
(6) -(C1-6 alkyl)-O-(C1-6 alkyl)-Ar;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) naphthyl,
(5) furyl,
(6) pyrryl,
(7) thienyl,
(8) isothiazolyl,
(9) imidazolyl,
(10) benzimidazolyl,
(11) tetrazolyl,
(12) pyrazinyl,
(13) quinolyl,
(14) isoquinolyl,
(15) benzofuryl,
(16) isobenzofuryl,
(17) benzothienyl,
(18) pyrazolyl,
(19) indolyl,
(20) isoindolyl,
(21) purinyl,
(22) isoxazolyl,
(23) thiazolyl,
(24) oxazolyl,
(25) triazinyl, and
(26) benzthiazolyl,
-271-

(27) benzoxazolyl,
(28) imidazopyrazinyl,
(29) triazolopyrazinyl,
(30) naphthyridinyl,
(31) furopyridinyl,
(32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof,
(33) pyridazinyl,
(34) quinazolinyl,
(35) pteridinyl,
(36} triazolopyrimidyl,
(37) triazolopyrazinyl,
(38) thiapurinyl,
(39) oxapurinyl, and
(40) deazapurinyl,
wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted,
where the substituents are independently selected from:
(a) C1-3 alkyl, unsubstituted or substituted with a
substituent selected from:
(1') oxo,
(2') hydroxy,
(3') -OR7,
(4') phenyl,
(5') trifluoromethyl, and
(6') phenyl or mono, di or tri-substituted phenyl,
where the substituents are independently
selected from: hydroxy, cyano, halogen, and
trifluoromethyl,
(b) halogen,
(c) -OC1-6 alkyl,
(d) trifluoromethyl,
(e) hydroxy,
(f) -NO2,
(g) -(CH2)p S(O)k-(C1-6 alkyl), wherein p is 0, 1 or 2,
(h) -(CH2)p S(O)j-NH2,
(i) -(CH2)p S(O)j-NH(C1-6 alkyl),
-272-

(j) -(CH2)p S(O)j-NHR6,
(k) -(CH2)p S(O)j-NR6-(C1-6 alkyl),
(1) -(CH2)p CONH2,
(m) -(CH2)p CONH-(C1-6 alkyl),
(n) -(CH2)p CONHR6,
(o) -(CH2)p CONR6R7,
(p) -(CH2)p CO2H,
(q) -(CH2)p CO2-(C1-6 alkyl),
(r) -(CH2)p NR6R7,
(s) -(CH2)p NH-C(O)-C1-6alkyl,
(t) -(CH2)p NH-C(O)-NH2,
(u) -(CH2)p NH-C(O)-NHC1-6alkyl,
(v) -(CH2)p NH-C(O)-N(C1-6 alkyl)2,
(w) -(CH2)p NH-S(O)k-C1-6alkyl,
(x) -(CH2)p N(C1-3alkyl)-C(O)-N(diC1-6 alkyl),
(y) -(CH2)p-heteroaryl, -C(O)-heteroaryl or
-(CH2)p-O-heteroaryl , wherein the heteroaryl is
selected from the group consisting of:
(1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
(7') isooxazolyl,
(8') isothiazolyl,
(9') oxadiazolyl,
(10') oxazolyl,
(11') pyrazinyl,
(12') pyrazolyl,
(13') pyridyl or oxopyridyl,
(14') pyrimidyl,
(15') pyrrolyl,
(16') quinolyl,
-273-

(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl group of items (1') to (21') is
unsubstituted, or mono, di or tri-substituted, where
the substituents are selected from:
(a') hydrogen,
(b') C1-6 alkyl, branched or unbranched,
unsubstituted or mono or di-substituted,
where the substituents are selected from:
hydrogen and hydroxy,
(c') hydroxy,
(d') oxo,
(e') -OR6,
(f) halogen,
(g') trifluoromethyl,
(h') nitro,
(i') cyano,
(j') -NHR6,
(k') -NR6R7,
(l') -NHCOR6,
(m') -NR6COR7,
(n') -NHCO2R8,
(o') -NR6CO2R7,
(p') -NHS(O)j R6,
(q') -NR6(O)j R7,
(r') -CONR6R7,
(s') -COR6,
(t') -CO2R6, and
(u') -S(O)j R6;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
-274-

(3) substituted C1-6 alkyl, where the substituents are
independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
{d) cyano,
(e) halogen,
(f) trifluoromethyl, and
(g) C5-8 cycloalkyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents
are independently selected from:
(a) hydroxy,
(b) C1-3alkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
R7 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl or C5-8 cycloalkyl,
(3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the
substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the
substituent is independently selected from:
(1') hydroxy,
(2') C1-3alkyl,
(3') cyano,
(4') halogen,
(5') trifluoromethyl, and
(6') C1-3alkyloxy,
(b) hydroxy,
(c) oxo,
(d) cyano,
-275-

(e) halogen, and
(f) trifluoromethyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents
are independently selected from:
(a) hydroxy,
(b) C1-3alkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
or R6 and R7 may be joined together to form a 5-, 6-, or
7-membered monocyclic saturated ring containing 1 or 2
heteroatoms independently selected from nitrogen, oxygen,
and sulfur, and in which the ring is unsubstituted or mono
or di-substituted, the substituents independently selected
from:
(1) hydroxy,
(2) oxo,
(3) cyano,
(4) halogen,
(5) trifluoromethyl,
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2,
and pharmaceutically acceptable salts thereof.
19. A method for the modulation of chemokine receptor
activity in a mammal comprising the administration of an effective
amount of the compound of Claim 1.
20. A method for preventing infection by HIV, treating
infection by HIV, delaying of the onset of AIDS, or treating AIDS
comprising the administration to a patient of an effective amount of the
compound of Claim 1.
-276-

Description

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
TITLE OF THE INVENTION
CYCLIC AMINE MODULATORS OF CHEMOKINE RECEPTOR
ACTIVITY
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines that are released by
a wide variety of cells to attract macrophages, T cells, eosinophils,
basophils and neutrophils to sites of inflammation (reviewed in Schall,
C 'ne, 3 165-183 (1991) and Murphy, Rev. Immun., I2, 593-633 (1994)).
There are two classes of chemokines, C-X-C (a) and C-C ([3), depending
on whether the first two cysteines are separated by a single amino acid
(C-X-C) or are adjacent (C-C). The a-chemokines, such as interleukin-8
(IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth
stimulatory activity protein (MGSA) are chemotactic primarily for
neutrophils, whereas (3-chemokines, such as RANTES, MIP-la, MIP-1(3
monocyte chemotactic protein-I (MCP-1), MCP-2, MCP-3 and eotaxin
are chemotactic for macrophages, T-cells, eosinophils and basophils
(Deng, et al., Nature, ~, 661-666 (1996)).
The chemokines bind specific cell-surface receptors
belonging to the family of G-protein-coupled seven-transmembrane-
domain proteins (reviewed in Horuk, Trends Pharm Sci , 15,159-165
(1994)) which are termed "chemokine receptors." On binding their
cognate ligands, chemokine receptors transduce an intracellular signal
though the associated trimeric G protein, resulting in a rapid increase
in intracellular calcium concentration. There are at least seven human
chemokine receptors that bind or respond to (3-chemokines with the
following characteristic pattern: CCR-1 (or "CKR-1" or "CC-CKR-1")
[MIP-la, MIP-1(3, MCP-3, RANTES] (Ben-Barruch, et al., . i 1.
em., 270, 22123-22128 (1995); Beote, et al, Cell, ~, 415-425 (1993)); CCR-
2A and CCR-2B (or "CKR-2A"/"CKR-2A" or "CC-CKR-2A"/"CC-CKR-
2A") [MCP-1, MCP-3, MCP-4]; CCR-3 (or "CKR-3" or "CC-CKR-3")
[eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem., ~0,
16491-16494 (1995); CCR-4 (or "CKR-4" or "CC-CKR-4") [MIP-la,
RA1VTES, MCP-1) (Power, et al., J. Biol. Chem., 2~( ,19495-19500 (1995));
CCR-5 (or "CKR-5" or "CC-CKR-5") [MIP-1a, R,ANTES, MIP-1(3]
-1-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
(Sanson, et al., $iochemistry, ,~, 3362-3367 (1996)); and the Duffy blood-
group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 2~6 ,
7835-7838 (1994)). The (3-chemokines include eotaxin, MIP ("macrophage
inflammatory protein"), MCP ("monocyte chemoattractant protein") and
RANTES ("regulation-upon-activation, normal T expressed and
secreted").
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A,
CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated
as being important mediators of inflammatory and immunoregulatory
disorders and diseases, including asthma and allergic diseases, as well
as autoimmune pathologies such as rheumatoid arthritis and
atherosclerosis. Accordingly, agents which modulate chemokine
receptors would be useful in such disorders and diseases.
A retrovirus designated human immunodeficiency virus
(HIV-1) is the etiological agent of the complex disease that includes
progressive destruction of the immune system (acquired immune
deficiency syndrome; AIDS) and degeneration of the central and
peripheral nervous system. This virus was previously known as LAV,
HTLV-III, or ARV.
Certain compounds have been demonstrated to inhibit the
replication of HIV, including soluble CD4 protein and synthetic
derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate,
the dyes Direct Yellow 50, Evans Biue, and certain azo dyes (U.S. Patent
No. 5,468,469). Some of these antiviral agents have been shown to act by
blocking the binding of gp120, the coat protein of HIV, to its target, the
CD4 gyycoprotein of the cell.
Entry of HIV-1 into a target cell requires cell-surface CD4
and additional host cell cofactors. Fusin has been identified as a cofactor
required for infection with virus adapted for growth in transformed T-
cells, however, fusin does not promote entry of macrophagetropic
viruses which are believed to be the key pathogenic strains of HIV in
vivo. It has recently been recognized that for efficient entry into target
cells, human immunodeficiency viruses require the chemokine
receptors CCR-5 and CXCR-4, as well as the primary receptor CD4
(Levy, N. ~',~ngl. J. Med., ,5(20), 1528-1530 (Nov. 14 1996). The principal
-2-

CA 02296314 2000-O1-13
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cofactor for entry mediated by the envelope glycoproteins of primary
macrophage-trophic strains of HIV-1 is CCRS, a receptor for the (3-
chemokines RANTES, MIP-1a and MIP-1(3 (Deng, et al., Na_t~re, ~,
661-666 (1996)). HIV attaches to the CD4 molecule on cells through a
region of its envelope protein, gp120. It is believed that the CD-4 binding
site on the gp120 of HIV interacts with the CD4 molecule on the cell
surface, and undergoes conformational changes which allow it to bind to
another cell-surface receptor, such as CCR5 and/or CXCR-4. This
brings the viral envelope closer to the cell surface and allows interaction
between gp41 on the viral envelope and a fusion domain on the cell
surface, fusion with the cell membrane, and entry of the viral core into
the cell. It has been shown that (3-chemokine ligands prevent HIV-1
from fusing with the cell (Dragic, et al., N a e, ~$1, 667-673 (1996)). It
has further been demonstrated that a complex of gp120 and soluble CD4
interacts specifically with CCR-5 and inhibits the binding of the natural
CCR-5 ligands MIP-1a and MIP-1(i (Wu, et al., re, X4,179-183
(1996); Trkola, et al., re, x,184-187 (1996)).
Humans who are homozygous for mutant CCR-5 receptors
which do not serve as co-receptors for HIV-1 in vitro apper to be
unusually resistant to HIV-1 infection and are not
immunocompromised by the presence of this genetic variant (tee,
3~, 722-725 (1996)). Absence of CCR-5 appears to confer protection from
HIV-1 infection (Nature, 3~2, 668-669 (1996)). Other chemokine receptors
may be used by some strains of HTV-1 or may be favored by non-sexual
routes of transmission. Although most HIV-1 isolates studied to date
utilize CCR-5 or fusin, some can use both as well as the related CCR-2B
and CCR-3 as co-receptors (Nature Medicine, 2_(11),1240-1243 (1996)).
Nevertheless, drugs targeting chemokine receptors may not be unduly
compromised by the genetic diversity of HIV-1 (Zhang, et al., Nature,
,'~, 768 (1996)). Accordingly, an agent which could block chemokine
receptors in humans who possess normal chemokine receptors should
prevent infection in healthy individuals and slow or halt viral
progression in infected patients. By focusing on the host's cellular
immune response to HIV infection, better therapies towards all subtypes
of HIV may be provided. These results indicate that inhibition of
-3-

CA 02296314 2000-O1-13
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chemokine receptors presents a viable method for the prevention or
treatment of infection by HIV and the prevention or treatment of AIDS.
The peptides eotaxin, RANTES, MIP-1a, MIP-1~3, MCP-1,
and MCP-3 are known to bind to chemokine receptors. As noted above,
the inhibitors of HIV-1 replication present in supernatants of CD8+ T
cells have been characterized as the ~-chemokines RANTES, MIP-la
and MIP-1(3. PCT Patent Publication WO 97/10211 and EPO Patent
Publication EP 0,673,928 disclose certain piperidines as tachykinin
antagonists.
SUMMARY OF THE INVENTION
The present invention is directed to compounds which are
modulators of chemokine receptor activity and are useful in the
prevention or treatment of certain inflammatory and immunoregulatory
disorders and diseases, including asthma and allergic diseases, as well
as autoimmune pathologies such as rheumatoid arthritis and
atherosclerosis. The invention is also directed to pharmaceutical
compositions comprising these compounds and the use of these
compounds and compositions in the prevention or treatment of such
diseases in which chemokine receptors are involved.
The present invention is further concerned with compounds
which inhibit the entry of human immunodeficiency virus (HIV) into
target cells and are of value in the prevention of infection by HIV, the
treatment of infection by HIV and the prevention and/or treatment of the
resulting acquired immune deficiency syndrome (AIDS). The present
invention also relates to pharmaceutical compositions containing the
compounds and to a method of use of the present compounds and other
agents for the prevention and treatment of AIDS and viral infection by
HIV.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of
formula I:
-4-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
R2 ~ m
N - R1
R3 ~~ n
I
wherein:
R1 is selected from a group consisting of:
linear or branched C1_g alkyl, linear or branched C2_g alkenyl,
wherein the C1_g alkyl or C2_g alkenyl is optionally mono,
di, tri or tetra substituted, where the substituents are
independently selected from:
(a) hydroxy,
(b) oxo,
(c) cyano,
(d) halogen which is selected from F, Cl, Br, and I,
(e) trifluoromethyl,
(f) phenyl
(g) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') phenyl,
(2') hydroxy,
(3') C1_3alkyl,
(4') cyano,
(5') halogen,
(6') trifluoromethyl,
(7') -NR6COR7
,
(8') -NRSC02R7,
(9') -NR6CONHR7
,
{10') -NR6S(O)jR7, wherein j
is 1 or 2,
(11') -CONR6R7
,
(12') -CORE
,
(13') -C02R6,
(14') -ORS
,
_5_

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
(15') -S(O)kRS~ wherein k is 0, 1 or 2~
(h) C1_g alkyl, unsubstituted or substituted
with hydroxy,
(i) -NR6R7
,
(j) -NRSCOR7
,
(k) -NR6C02R7,
(1) -NR6CONHR7
,
(m) -NRSS(O)j-R7,
(n) -CONRSR7,
(o) -CORE
,
(p) -C02R6
,
(q) -OCORS,
(r) -CN,
(s) -OR6,
(t) _S(O)kRS,
(u) -NR6C0-heteroaryl,
(v) -NRSS(O)j-heteroaryl, and
(w) heteroaryl, wherein heteroaryl is selected
from the
group consisting of:
(1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
(7') isooxazolyl,
($') isothiazolyl,
(9') oxadiazolyl,
(10') oxazolyl,
(11') pyrazinyl,
(12') pyrazolyl,
(13') pyridyl,
(14') pyrimidyl,
(15') pyrrolyl,
(16') quinolyl,
-6-

CA 02296314 2000-O1-13
WO 99/04794 PCT/LTS9$/14990
(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl is unsubstituted or mono
di or tri-
substituted, where the substituents are independently
selected from:
{a") phenyl,
(b") hydroxy,
( c") oxo,
(d") cyano,
(e") halogen, and
(f') trifluoromethyl;
R2 is selec ted from the group consisting of
(1) hydrogen,
(2) hydroxy,
{3) C1_g alkyl,
(4) substituted C1-g alkyl, where the substituents
are
independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) halogen,
(e) trifluoromethyl,
(f) -N(R4)(R5), wherein R4 and R5 are independently
selected from hydrogen, C 1-10 linear or branched
alkyl, and CO_6 alkyl substituted with Cg-g cycloalkyl,
(g) -N(R4)-CO-O-(R5), and
(h) -N(R4~)-CO-N(R4)(R5), wherein R4~ is selected
from
the definitions of R4
,
(5) -O-C 1_g alkyl, and
(6} phenyl;
-7-
*rB

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
R3 is selected from the group consisting of
(1) Ar,
(2) -N(R4)-CO-O-(C1-g alkyl)-Ar,
(3) -N(R4)-CO-O-R7
,
(4) -(C1-g alkyl)-Ar,
(5) -{C1-g alkyl)-O-(C1_g alkyl)-Ar,
and
(6) -(C1_g alkyl)-O-(C1_g alkyl)-Ar;
Ar is selected from the group consisting of
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) naphthyl,
(5) furyl,
(6) pyrryl,
(?) thienyl,
{8) isothiazolyl,
(9) imidazolyl,
(10) benzimidazolyl,
(11) tetrazolyl,
(12) pyrazinyl,
(13) quinolyl,
{14) isoquinolyl,
(15) benzofuryl,
(16) isobenzofuryl,
(17) benzothienyl,
(18) pyrazolyl,
(19) indolyl,
(20) isoindolyl,
(21) purinyl,
(22) isoxazolyl,
(23) thiazolyl,
(24) oxazolyl,
(25) triazinyl, and
_g_

CA 02296314 2000-O1-13
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(26) benzthiazolyl,
(27) benzoxazolyl,
(28) imidazopyrazinyl,
(29) triazolopyrazinyl,
(30) naphthyridinyl,
(31} furopyridinyl,
(32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide
thereof,
(33) pyridazinyl,
(34) quinazolinyl,
(35) pteridinyl,
(36) triazolopyrimidyl,
(37) triazolopyrazinyl,
(38) thiapurinyl,
(39) oxapurinyl, and
(40) deazapurinyl,
wherein items (1) to (40) are unsubstituted or mono or
Ar di-substituted
,
where the
substituents
are independently
selected
from:
{a) C1-3 alkyl, unsubstituted or substituted
with a
substituent selected from:
(1') oxo,
( 2' ) hydroxy,
(3') -OR7
,
(4') phenyl,
(5') trifluoromethyl, and
(6') phenyl or mono, di or tri-substituted phenyl,
where the substituents are independently
selected from: hydroxy, cyano, halogen, and
trifluoromethyl,
(b) halogen,
30 (c) -OC1_g alkyl,
(d) trifluoromethyl,
(e) hydroxy,
(~ -N02,
(g} -(CH2)pS(O)k-(C1-g alkyl), wherein p is 0,
1 or 2,
35 (h) -(CH2)pS(O)j-NH2,
-g_

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
(i) -(CH2)pS(O)j-NH(C1-g alkyl),
G) -(CH2)pS(O)j-NHR6,
(k) -(CH2)pS(O)j-NR6-(C1-g alkyl),
(1) -(CH2)pCONH2,
(m) -(CH2)pCONH-(C1-6 alkyl),
(n) -(CH2)pCONHR6,
(o) -(CH2)pCONRSR7,
(p) -(CH2)pC02H,
(q) -(CH2)pC02-(C1-g alkyl),
(r) -(CH2)pNR6R7,
(s) -(CH2)pNH-C(O)-C1_galkyl,
(t) -(CH2)pNH-C(O)-NH2,
(u) -(CH2)pNH-C(O)-NHC1_galkyl,
(v) -(CH2)pNH-C(O)-N(C1-6 alkyl)2,
1~ (w) -(CH2)pNH-S(O)k-C1_6alkyl,
(x) -(CH2)pN(C1_3alkyl)-C(O)-N(diCl-g alkyl),
(y) -(CH2)p-heteroaryl, -C(O)-heteroaryl
or
-(CH2)p-O-heteroaryl , wherein the
heteroaryl is
selected from the group consisting
of
24 (1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
(7') isooxazolyl,
(8') isothiazolyl,
(9') oxadiazolyl,
(10') oxazolyl,
30 (11') pyrazinyl,
(12') pyrazolyl,
(13') pyridyl or oxopyridyl,
(14') pyrimidyl,
(15') pyrrolyl,
-10-

CA 02296314 2000-O1-13
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(16') quinolyl,
(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl group of items (1') to (21')
is
unsubstituted, or mono, di or tri-substituted, where
the substituents are selected from:
(a') hydrogen,
(b') C1_g alkyl, branched or unbranched
,
unsubstituted or mono or di-substituted
,
where the substituents are selected from:
hydrogen and hydroxy,
( c' ) hydroxy,
(d') oxo,
( e' ) -OR6
,
(f ) halogen,
(g') trifluoromethyl,
(h') nitro,
{i') cyano,
(j'> -NHRs,
(k') -NR6R7
,
(1') -NHCOR6,
m' ) -NR6COR7
,
(n') -NHC02R6
,
-~6C02R7
>
(P') -NHS(O)jR6,
(q') -NR6S(O)jR7,
30 (r') -CONR6R7
,
(s') -CORE
,
(t') -C02R6, and
(u') -S(O)jR6;
35 R6 is selected from the group consisting of:
-11-

CA 02296314 2000-O1-13
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(1) hydrogen,
(2) C1_s alkyl,
(3) substituted C1_g alkyl, where the substituents
are
independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) cyano,
(e) halogen,
(f) trifluoromethyl, and
(g) C5_g cycloalkyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the
substituents
are independently selected from:
(a) hydroxy,
(b) C1_galkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
R7 is selected from the group consisting of:
(1) hydrogen,
(2) C1_g alkyl or C5_g cycloalkyl,
(3) substituted C1_g alkyl or C5_g cycloalkyl, where the
substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the
substituent is independently selected from:
( 1') hydroxy,
(2') C1_3alkyl,
(3') cyano,
(4') halogen,
(5') trifluoromethyl, and
(6') C1_galkyloxy,
(b) hydroxy,
-12-

CA 02296314 2000-O1-13
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(c) oxo,
(d) cyano,
(e) halogen, and
trifluoromethyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents
are independently selected from:
(a) hydroxy,
(b) C1_galkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
or R6 and R7 may be joined together to form a 5-, 6-, or 7-
membered monocyclic saturated ring containing 1 or 2
heteroatoms independently selected from nitrogen, oxygen,
and sulfur, and in which the ring is unsubstituted or mono
or di-substituted, the substituents independently selected
from:
(1) hydroxy,
(2) oxo,
(3) cyano,
(4) halogen,
(5) trifluoromethyl,
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2,
and pharmaceutically acceptable salts thereof.
Preferred compounds of the present invention include those
of formula Ia:
~m
N - R1
~~ n
-13-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
Ia
wherein:
R1 is selected
from a group
consisting of
C3~ C4~ C5, C6, C7~ or Cg linear or branched alkyl,
which is
unsubstituted
or mono, di
or tri-substituted,
where the
substituents
are independently
selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where
the
substituents are independently selected
from:
(1') phenyl,
( 2' ) hydroxy,
(3') C1_3alkyl,
(4') cyano,
(5') halogen, and
(6') trifluoromethyl,
(e) C 1_g alkyl, unsubstituted or substituted
with hydroxy,
(f) -NR6C0-R7, wherein R6 is hydrogen or C1_g
alkyl
,
unsubstituted or substituted with C5_g
cycloalkyl, and
R7 is C1_g alkyl, benzyl or phenyl which
is
unsubsituted or substituted with halo,
CFg, C1_galkyl,
or C1_galkoxy,
(g) -CORE
,
(h) -OR6
(i) -NR6S(O)j-R7, where j is 1 or 2,
(j ) -NR6S{O)j-heteroaryl, wherein heteroaryl
is selected
from the group consisting of
(1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
35 (?') isooxazolyl,
-14-

CA 02296314 2000-O1-13
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(8') isothiazolyl,
(9') oxadiazolyl,
(10') oxazolyl,
(11') pyrazinyl,
(12') pyrazoiyl,
(13') pyridyl,
(14') pyrimidyl,
(15') pyrrolyl,
(16') quinolyl,
(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl
is unsubstituted or
mono di or tri-
substituted, where the substituents are independently
selected from:
(a') phenyl,
(b') hydroxy,
( c' ) oxo,
(d') cyano,
(e') halogen, and
(f ) trifluoromethyl;
R2 is selected from the group consisting of:
( 1) hydrogen,
(2) hydroxy,
(3) C 1_6 alkyl,
(4) -O-C 1-s alkyl,
(5) phenyl,
(6) -N(CH3)-CO-N(H)(CH3),
(?) -N(H)-CO-O-CH3, and
(8) -CO-CH3;
R3 is selected from the group consisting of
-15-

CA 02296314 2000-O1-13
WO 99104794 PCTIUS98/14990
(1) Ar,
(2) -(C1_6 alkyl)-Ar,
(3) -(C1_6 alkyl)-O-(C1_6 alkyl)-Ar, and
(4) -N(R4)-CO-O-(C1_6 alkyl) Ar, wherein R4 is selected
from
hydrogen, C1_10 linear or branched alkyl, and
CO_g alkyl
substituted with C3_g cycloalkyl,
(5) -N(R4)-CO-O-R7;
Ar is
selected
from
the group
consisting
o
(1) phenyl,
(2) pyrazinyl,
(3) pyrazolyl,
(4) pyridyl,
(5) pyrimidyl, and
(6) thienyl,
wherein the Ar is unsubstituted or mono or di-substituted
,
and the aubstituents are independently selected
from:
(a) C1-3 alkyl, unsubstituted or substituted
with
(1') oxo,
(2') hydroxy,
(3') -OR7,
(4') phenyl, and
(5') trifluoromethyl,
(b) halogen,
(c) -OC1_6 alkyl,
(d) trifluoromethyl,
(e) -N02,
(f) CONR6-(C1-2 alkyl),
(g) C02H,
(h) C02-(C1-2 alkyl),
(i) CH2NR6-(C1-2 alkyl),
(j ) CH2NH-C(O)-C 1_3alkyl,
(k) CH2NH-C(O)NH2,
(1) CH2NH-C(O)NHC1_3alkyl,
(m) CH2NH-C(O)N-diCl-3 alkyl),
-16-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
(n) CH2NH-S(O)j-C1_3alkyi,
(o) CH2-heteroaryl, with the heteroaryl is selected from
the group consisting of
(1') imidazolyl,
(2') oxazoiyl,
(3') pyridyl,
(4') tetrazolyl,
( 5' ) triazolyl,
and the heteroaryl is unsubstituted, mono, di or tri-
substituted, where the substituents selected from:
(a') hydrogen,
(b') C1_g alkyl, branched or unbranched,
unsubstituted or mono or di-substituted,
the substituents being selected from
hydrogen and hydroxy;
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2, with the proviso that the sum of
m+nis2;
and pharmaceutically acceptable salts thereof.
More preferred compounds of the present invention include
those of formula Ib:
R2
N - R'
R3
Ib
wherein:
R1, R2 and R3 are as defined herein;
and pharmaceutically acceptable salts thereof.
In the present invention it is preferred that
-1?-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
R1 is selected
from the group
consisting
of
C3~ C4~ C5 , C6, C7~ or Cg linear or branched alkyl,
which is
unsubstituted
or mono, di
or tri-substituted,
where the
substituents
are independently
selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where
the
substituents are independently selected
from:
(1') phenyl,
(2') hydroxy,
(3') C1_galkyl,
(4') cyano,
(5') halogen, and
(6') trifluoromethyl,
(e) C1_g alkyl, unsubstituted or substituted
with hydroxy,
(f) -NR6C0-R7, wherein R6 is hydrogen or C 1-3
alkyl
,
unsubstituted or substituted with C5_g cycloalkyl,
and
R7 is C1_g alkyl, benzyl or phenyl which
is
unsubsituted or substituted with halo, CF3,
C1_galkyl,
or C 1_galkoxy,
(g) -CORE,
(h) -OR6
,
(i) -NR6S(O)j-R7, where j is 1 or 2,
(j) -NR6S(O)j-heteroaryl, wherein heteroaryl
is selected
from the group consisting of
(1') benzimidazolyl,
(2') benzofuranyl,
(3') benzoxazolyl,
(4') furanyl,
(5') imidazolyl,
(6') indolyl,
(7') isooxazolyl,
(8') isothiazoiyl,
-18-

CA 02296314 2000-O1-13
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(9') oxadiazolyl,
(10') oxazolyl,
(11') pyrazinyl,
(12') pyrazolyl,
(13') pyridyl,
(14') pyrimidyl,
(15') pyrrolyl,
(16') quinolyl,
(17') tetrazolyl,
(18') thiadiazolyl,
(19') thiazolyl,
(20') thienyl, and
(21') triazolyl,
wherein the heteroaryl
is unsubstituted or
mono di or tri-
substituted, where the substituents are independently
selected from:
(a') phenyl,
(b') hydroxy,
( c' ) oxo,
(d') cyano,
(e') halogen, and
(f ) trifluoromethyl.
In the present invention it is preferred that if R3 is Ar, m is
1, n is 1, and R1 is C5 alkyl which bears a group selected from: -NR6R7,
-NR6COR7, -NR6C02R7, or -NR6CONHR7, then R1 does not bear a
substituent which is 2,3-dichlorophenyl.
In the present invention it is preferred that
Rl bears at least one substituent which is selected from:
(a) -NR6C0-R7, wherein R6 is C1_3 alkyl, unsubstituted
or substituted with cyclohexyl, and R7 is C1_g alkyl,
benzyl or phenyl which is unsubsituted or substituted
with halo, CF3, C1_3alkyl, or C1_3alkoxy, and
(b) -NR6S(O)j-R7, where j is 1 or 2.
-19-

CA 02296314 2000-O1-13
WO 99/04794 PCT/LTS98/14990
In the present invention it is more preferred that
R1 is selected from the group consisting of
C4~ C5~ C6~ C7 or Cg linear or branched alkyl, which is mono, di-
or tri-substituted, where the substituents are independently
selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') hydroxy,
(2') methyl or ethyl,
(3') Cl or F, and
(4') trifluoromethyl,
(e) C1_g alkyl, unsubstituted or substituted with hydroxy,
(f7 -NR6C0-R'~, wherein R6 is C1_3 alkyl, unsubstituted
or substituted with cyclohexyl, and R7 is C1_6 alkyl,
benzyl or phenyl which is unsubsituted or substituted
with halo, CF3, C1_galkyl, or C1_galkoxy,
(g) -NR6S(O)j-R7, where j is 1 or 2.
In the present invention it is still more preferred that
R1 is selected from the group consisting of:
C4, C5, or Cg linear alkyl, which is substituted, where the
substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') hydroxy,
(2') methyl or ethyl,
(3') Cl or F, and
(4') trifluoromethyl,
(c) C1_g alkyl, unsubstituted or substituted with hydroxy,
-20-

CA 02296314 2000-O1-13
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{d) -NR6C0-R7, wherein Rs is methyl, unsubstituted or
substituted with cyclohexyl, and R7 is phenyl which
is unsubstituted or substituted with Cl, F, CFg, C1_
galkyl or C1_galkoxy, and
(e) -NR6S(O)j-R7, where j is 1 or 2.
In the present invention it is still more preferred that
R1 is C4 linear alkyl, which is substituted, where the substituents are
independently selected from:
(a) phenyl,
{b) mono, di or tri-substituted phenyl, where the
substituents are independently selected from:
(1') hydroxy,
(2') methyl or ethyl,
(3') Cl or F, and
(4') trifluoromethyl,
(c) C1_g alkyl, unsubstituted or substituted with hydroxy,
and
(d) -NRSS(O)j-R7, where R6 is methyl, unsubstituted or
substituted with cyclohexyl, and R7 is phenyl which
is unsubstituted or substituted with Cl, F, CF3, C1_
3alkyl or C1_galkoxy, and j is 1 or 2.
In the present invention it is even more preferred that
R1 is:
N, S02-B
I
Rs
R12
Rio
R11
wherein:
B is selected from the group consisting of:
(a) phenyl, and
-21-

CA 02296314 2000-O1-13
WO 99/04794 PCTNS98/14990
(b) di or tri-substituted phenyl, wherein the substituents on
phenyl are independently selected from: chloro, methyl,
phenyl, C1_~alkoxy, and CF3;
R6 is C1_g alkyl, unsubstituted or substituted with cyclohexyl;
R10 is selected from the group consisting of
(1) hydrogen, and
(2) C 1_g alkyl, unsubstituted or substituted with hydroxy;
R11 and R12 are independently selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) methyl or ethyl,
(4) Cl or F, and
(5) trifluoromethyl.
In the present invention it is highly preferred that
R1 is selected from the group consisting of:
N, sot \ /
CH3
CH3 CH20H
N~S02 \ / N~S02 \ /
t i
CH3 / I CH3
and
In the present invention it is most preferred that
R1 is selected from the group consisting of:
-22-

CA 02296314 2000-O1-13
WO 99/04794 PCTNS98/14990
CH3 CH3
N~S02 ~ ~ N~S02
t t
CH3 / I CH3
CH20H CH20H
N, S02 ~ ~ N~ S02
t t
CH3 / CH3
\
and
In the present invention it is preferred that
R2 is selected from the group consisting of
(1) hydrogen,
(2) hydroxy,
(3) C1_g alkyl,
(4) -O-C1_g alkyl,
(5) phenyl,
(6) -N(CH3)-CO-N(H)(CH3),
(7) -N(H)-CO-O-CH3, and
(8) -CO-CH3.
In the present invention it is more preferred that
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy, and
(3) phenyl.
In the present invention it is most preferred that
R2 is hydrogen.
In the present invention it is preferred that
R3 is selected from the group consisting of
-23-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
(1) Ar,
(2) -(C1_g alkyl)-Ar,
(3) -(C1_g alkyl)-O-(C1_g alkyl)-Ar, and
(4) -N(R4)-CO-O-(C1_g alkyl)-Ar, wherein R4 is selected
from
hydrogen, C 1-10 linear or branched alkyl, and
C0_g alkyl
substituted with Cg_g cycloalkyl,
(5) -N(R4)-CO-O-R7.
In the present invention it is more preferred
that
R3 is selected from the group consisting of:
(1) Ar,
(2) -(C1_g alkyl)-Ar,
(3) -N(R4)-CO-O-(C1_6 alkyl)-Ar, wherein R4 is selected
from
hydrogen, C1_10 linear or branched alkyl, and
C0_6 alkyl
substituted with Cg_g cycloalkyl, and
(4) -N(R4)-CO-O-R7.
In the present invention it is preferred that
Ar is selected
from the
group
consisting
of:
(1) phenyl,
(2) pyrazinyl,
(3) pyrazolyl,
(4) pyridyl,
(5) pyrimidyl, and
(6) thienyl,
wherein the Ar is unsubstituted or mono or di-substituted
,
and substituents are independently selected
from:
(a) C1-3 alkyl, unsubstituted or substituted
with
(1') oxo,
(2') hydroxy,
-OR7~
(4') phenyl, and
(5') trifluoromethyl,
(b) CONR6-(C1-2 alkyl),
(c) C02H,
-24-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
(d) C02-(C1-2 alkyl),
(e) CH2NR6-(C1-2 alkyl),
(f) CH2NH-C(O)-C1_galkyl,
(h) CH2NH-C(O)NH2,
(i) CH2NH-C(O)NHC1_3alkyl,
(j) CH2NH-C(O)N-diC1-3 alkyl),
(k) CH2NH-S(O)j-C1_3alkyl,
(1) CH2-heteroaryl, with the heteroaryl is
selected from
the group consisting of
(1') imidazolyl,
(2') oxazolyl,
(3') pyridyl,
(4') tetrazolyl,
(5') triazolyl,
and the heteroaryl is unsubstituted, mono,
di or tri-
substituted, where the substituents selected
from:
(a') hydrogen,
(b') C1_6 alkyl, branched or unbranched
,
unsubstituted or mono or di-substituted
,
the substituents being selected from
hydrogen and hydroxy.
In the present invention it is more preferred that
Ar is selected from:
phenyl, mono substituted phenyl or di-substituted phenyl,
wherein the substituents are selected from the group consisting
of
(a) C1-3 alkyl, unsubstituted or substituted with
(1') oxo,
(2') hydroxy, or
(3') -OR6, wherein RO is hydrogen or C1_g alkyl,
(b) -CH2NR6-(C1-2 alkyl),
(c) -CH2NH-C(O)-C1_galkyl,
(d) -CH2NH-C(O)NH2,
-25-

CA 02296314 2000-O1-13
WO 99!04794 PCT/US98/14990
(i) -CH2NH-C(O)NHC1_3alkyl,
()) -CH2NH-C(O)N-diCl-3 alkyl),
(k) -CH2NH-S(O)j-C1_3aikyl,
(1) -CH2-heteroaryl, where heteroaryl is selected from the
group consisting of
(1') imidazolyl,
(2') oxazolyl,
(3') pyridyl,
{4') tetrazolyl,
(5') triazolyl,
and where heteroaryl is unsubstituted, mono, di or tri
substituted, where the substituents are independently
selected from:
( a' ) hydrogen,
(b') Cl_6 alkyl, branched or unbranched,
unsubstituted or mono or disubstituted, where
the substituents are selected from: hydrogen
and hydroxy.
In the present invention it is more preferred that
R3 is selected from:
(1) phenyl, and
(2) -N(R4)-CO-O-(C1_g alkyl)-phenyl, wherein R4 is selected
from hydrogen, C1_10 linear or branched alkyl, and Cp_6
alkyl substituted with C3_g cycloalkyl.
In the present invention it is even more preferred that
R3 is:
-N(R4)-CO-O-(CH2)-phenyl, wherein R4 is selected from hydrogen,
C1_g linear or branched alkyl, and CH2 substituted with
C3_g cycloalkyl.
In the present invention it is still more preferred that
R3 is:
-26-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98114990
-N(R4)-CO-O-(CH2)-phenyl, wherein R4 is selected from hydrogen
and C1_g alkyl.
In the present invention it is most preferred that
R3 is:
-N(CH2CHg)-CO-O-(CH2)-phenyl.
In the present invention it is preferred that
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2, with the proviso that the sum of
m + n is 2.
In the present invention it is more preferred that
m is 1, and n is 1.
As appreciated by those of skill in the art, halo as used
herein are intended to include chloro, fluoro, bromo and iodo. Similarly,
C1_g, as in C1_salkyl is defined to identify the group as having 1, 2, 3, 4,
5,
or 6 carbons, such that C1_galkyl specifically includes methyl, ethyl,
propyl, butyl, pentyl, hexyl, and cyclohexyl.
Exemplifying the invention is the use of the compounds
disclosed in the Examples and herein.
-27-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
Preferred compounds of the present invention include the
compounds of the formula:
Ra N N, S02 I \
I /
/ Me
Rb
wherein:
Ra Rb
hydrogen
chloro
O'I hydrogen
O~N~'
O~I chloro
\ O~N~'
hydrogen
chloro
\ O~~ hydrogen
\ O~~ chioro
and pharmaceutically acceptable salts thereof.
-28-

CA 02296314 2000-O1-13
WO 99/04794 PCTlUS98/14990
Specific compounds within the present invention include a
compound which selected from the group consisting of:
\
I O~ \
N N,S,O
i
j Me
CI
\ O, \
N N, S
O
Me
CI
\
I O, \
N N, S~.
i O
Me
O
O
-29-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N~ n ~ ~:S. \
~O
i
Me
O
O-J
\ /
I O, \
N N,S,O
i
j Me
F
I O, \
~N . N,S..
i O
j Me
Cl
\ /
I O~ \
N N, SAO
i
/ Me
CI \ CI
-30-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N. ,O
OI' O'S
~O~ N ( /
H
I
I
O N N~S ~
O'
~N~ N I /
I H
I~
I
O N N~S O
II '~
O I
~N~N
H H
O ,S O
II '~
H2N~N I /
H
I
N N
O
-31-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
~I
\
I O, \
~N
N ~S~O
Me
\I
CH2CH3
N ~O
N ~I
I O,
N N. SAO
Me
\ I
CI
H
N\/O
N ~I
I ~ ~ o,, \
N-S~.
i O
Me
\I
CI
I
\ ~I
I O, \
N N.S~O
i
Me
\ I
C02Et
-32-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
1
I ~ ~ / I
N N.S
\
O
/I
I O~ \
I ~ N N,s,o
/ = Me
I
CI
OH /
o,; w I
N.S,O
i
Me
~i
CI
I
N\S,O
'~
I - /
-33-
*rB

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N~ ,O
OS \
\
CI /
N~S O
\ O
/
N~ ,O
OS \
-34-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N~S O
I
I
N~S ,O
H2N O, \
/
I \
N~ ,~
OS \
N
H v /
/I
-35-

w~,~,~",
CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/I
o,, \
N N,S.O
j CH2CH3
-CI
CI
\
I
N~S O
HO O~ \
/
/
I
O N~S O
O ~~ \
-36-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N~ ,O
N. ,O
H N~S,O
N O, \
/
O
N~ ,O
O
-37-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N OS O
~N' \
Me
CF3
\
I O, \
N N~S,O
i
Me
F
\
I O, \
N N,S.O
i
Me
OCH3
H N~ ,,O
,N ~ S \
-38-

CA 02296314 2000-O1-13
WO 99/04794 PCTIUS98/14990
N~S O
~N O O', \
/
H /
f
N \
I
\ O
/
N \
I
O
-39-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
OII N, ,O
OS \
N~N
H ~
/
\
I
N, ,,O
w US \
O N
O
\ CI
to
N N S
O
\ a
-40-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I
N-S
O
/
I
N, ,O
OS \
N N ~ /
H H /
~S O
,N~ \
\ Me I /
/
Me
F
-41-
/ \

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
OH
CI
I O
N-S
O
N
OS O
\ v ~ N. ~ \
Me /
N O
., ~~ ~,O
,S \
Me /
\ /
I O~ \
N~S~.
O
Me
F
- 42 -

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
J
/
N~ 00
I/
I /
S
,o
os~ w
/
i
N N, S.O
O
1
/
N. ,O
I~ I/
-43-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N'S,O
'~
O
_ /
\
I O, \
N N,S.O
i
Me
CH3
'i
I o, \
N N, S.O
i
Me
' '
I O, \
N fV~S,O
Me
I I
N
_44_

CA 02296314 2000-O1-13
WO 99/04794 PCTlUS98/14990
Ov i0
N~S ~ \
Me /
\
I O, \
~~S~O
i
Ae
/
N~ ,O
N 'S \
\ O,
-45-
*rB

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O
HN
N I
N O,S
N~ ~O
i
j Me
~I
CI
O,
,S
N
O
j Me
~I
CI
I O,
N N, S',
i O
Me
I
CH3
~I
I O,
N N~S~O
N Me
I
-46-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I ~, \
IV N~S,O
i
Me
~F
CH3
O\ \
N I ~ \O
CI
\ ~ OH
1 0,
N~S,O
j Me
CI
-47-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/ IO
\
I O~ \
N, S,O
Me
CI
F3
CI
OH /
O.
N~S,O
Me
CI
/
I O, \
N~S~O
i
Me
CH3
CH3
-48-

CA 02296314 2000-O1-13
WO 99!04794 PCT/US98/14990
\
I O, \
N,S,O
i
/ Me
H3C \ CH3
OCH3
O, ~\
N, SAO
i
Me
\
CI
CF3
OH /
O, \
N. S,O
i
j Me
CI
-49-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
F
\ I off
1 0,, \ t
N
N~S~O
I
N N~S O
'~ \
\ ° I ~
I _
i
N. ,,O
N %S \
~N O.
O
o~ ,o
s~~
0
-50-
Me
CI

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O O
N /I
I \ ~ O~ \
N N,S,O
i
Me
\ I
CI
0~0
N / I
O, \
N~S~O
j Me
CI
I~
O
~ ~~N N. ~/
S
o i
0
~(
o,, \
/ N~~N,S~.
i O
Me
\I
CI

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
OCH3
O,
N N, S,O
i
j Me
CI
f O
~N
N ~S~O
/ Me
C02H
I
O N N\S,O
0
o~
I~
I
O N N,~,O
o, y
O N /
J
-52-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N~ .O
N ~j S \
H2N I
I
N\S O
'~ \
~N O
H
N\ .O
O ~S \
~. N ~ /
H
\
I
O N N,S O
O~ \
N
H
-53-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I\
I
w ~~ N N ~S O \
~S~ N O
o I/
I \
I
O N N~S O
~N o, I \
/
I\
/
O N N,S O
O, ( \
_N /
J
I
N\S O
'~ \
O I
O
-54-

CA 02296314 2000-O1-13
WO 99/04794 PCTlUS98/14990
I~
O N N~ S O
o, I
O H /
I
i
O N N'S~O
~ O
wO~N ( /
i
O N N~S O
O
~O~N ( /
/ I
/I
I O,
N N,S~O
/ Me
~I
OCH3
-55-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
i /
N I
I O, \
N
N ~ S~O
Me
\I
CI
( \
O
N N / I
I\
H /
~N
.N / I
O Me. N. S \
02
I\
I
N N'SO
O~ I
/
/
-56-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
OH
O, \
~S
N N, ~.
O
Me
CI
F /
\~
I O, \
N~~N~S,O
Me
CI
O N N, S,O
O~ \
I
O N N,S O
O~ \
~O~N
-57-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I
O N N'S~~
O
/~O~N
I
O N N'g~~
O
O~N
~O
O ~N O S
N I/
I
O N N'S~O
O
~O~N ( /
-58-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
\
I
O N N~S O
I~ \
wO~N
\
I
O N N,S O
'I O,
~O~N
I
O N N~S ~
II O
~O~N
i
-59-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I
O N N,S O
O
wO~N ( /
i
O N N'S'O
~ O°
~ O"N I
O N,S,O
O
~O~N I /
-60-

CA 02296314 2000-O1-13
WO 99/04794 PCT1US98/14990
N~ N
~N /
O, \ I
N N,S..
i O
Me
\ I
CI
CI \
I /
I
O N N, S O
O~ \
\ O~N I /
I/ J
I\
/
I
O N N~S O
O~ \
\ O~N I /
I /
-61-
N
~ S02Ph

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I\
O N N~S O
~ O~ \
\ O" N
I /
O N\S O
O~ \
\ O~N I /
I /
I
O N\S,O
II '~ \
\ O~ O I
I/
-62-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I \
O N N~S O
O~ \
\ O~N I /
I/
I\
N. ,O
,N 'O S \
I \ O N I /
\
I
N N. S02
~N
o2s
-63-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/I4990
/I
I ' ~' 1 p, \
/ N N~S~,
O
Me
\I
CI
CFA
/I
O~ \
N, SAO
Me
CI
/ I '~ N o,S \ I
\ O~N~~
I
/ \
I ~ N ~~S,
\ O~N~~,~ i ~O
IOI
\i

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O N N N ' S.~ \
'~~ I O
O
/
O N N O'So \
O
O
N O.S \
O~N'~~ N, ..
O
O
/ I N O, S
\ O~N~~~ N' ~O
/
-65-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I / ~O O, \ I
N N~S,O
j Me
CI
o
O N N..S~
O
I \
Ph~O N /
J
0
o . s,
~ 0
I\
Ph~O~N /
J
N N~N
.N I /
O, \ (
I N N~S~O
Me
\I
CI
-66-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N' N
\ N~IV~ /
~ / O~ \ ~
N N~S,O
j Me
CI
OH /
I O, \
N N~S,,
O
j Me
\)
CI
OH /
/ O,S \
N, ,O
j Me
CI
OCH3 /
o,, \
/ ~N N~S,,
O
j Me
CI
_g7_

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
' N N _ S02
'N /
02S
I
N N_ SOZ
'N /
02S
N N _ S02
~N /
02S
CI
-68-

CA 02296314 2000-O1-13
WO 99!04794 PCT/US98/14990
/ ~ N O, S
\ O~N~~~ N ~O
COI
\ l
/ )
O N N N~~S
O
O
/l
o. \
~O~N N N,S~O
IO /
\ l
/l
O N O~~S'' \
O
O / l
-69-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/
O O /
N O,S \
N'~~ N, ,O
/
O~O /
N O,S \
N'~~ N, ,O
O\/O /
O,
N N N~S,O\
-70-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/
O O /
o, \ I
N N N~S,O
/ )
/
O~O
O, \
N N N~S~~O
/I
~ \
/I
O\' O
/I
'N~ N N .S,, \
O
/I
-?1-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US9$/14990
O O /
N O,S \
N'~~ N, .O
I /
O\/O
N ~~S \
N'~~ N, ,O
I
I
I /
O\/O
N O,S , \
N '.~~ I , , O
-72-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
N. ,O
~S \
I \ O N I /
O N~S,O
O, \
\ O~N I /
I/ J
I\
/
O N N~S O
O~, \
\ O~N I /
I /
I \
O
O w N S,.
O, \
\ O~N
I/
-73-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/I4990
I\
o N O~ I \
\ /
O~N
I/ J
I\
/
O
O N O S~ \
\ O' _N I /
I/
I\
O
O N O S~~ \
\ O~N I /
I/
I \
' O
O N o S~ \
\ O~N I /
I /
-74-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
I\
O
O N O S~~ \
\ O~N ( /
I/ J
I\
O
,
N ~ S~ \
\ o N I /
I/ J
I\
/
O
O N ,S
I' O
\ O~N I /
I/ J
I\
/
O
O N p S~ \
\ O~N
I/
-75-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O
\ p"
I /
I\
O N ,S ~
O~ \
\ OJ~N i /
I/ J
I ~ N p,S \ I
\ O~N~~~ i' ~O
o /I
I
/ I ~ N O S. \
\ O~N~,e~ N .O
O /
\ I
-76-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/
\
O N NHS,,
I ~ O
O
o, \
O N~~~N N~S~O
O
/
\
O N~V~ N N~S~~O
O
/ O \ ~
\ I O N~~~N N~S~O
O
-77-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US9$/14990
/ p,
\ ~ O N~~~N N.S,O
O
\
O, \
N'V~ N ~S~ O
O
O, \
i0 N'~~N N.S,O
O
/
N O~ \
i 0 11 N'~~ NHS, O
O
-78-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O O
O, \
N'~~N N.S,O
\
\
O O
N p,S \ I
N '~~ N. ,,
O
~I
O O ~ I
O, \
N'~~N N.S,O
~I
_79_

CA 02296314 2000-O1-13
WO 99/04794 PCT/US9$/14990
/
0 0 /
\
N'~~N N.S,O
/
O~O
O, \
N'~~N N.S,O
\
/
O~O
N O,S \
N'~~ N. ,O
-80-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O O
N O,S
N~.G i N. , o
0 0
o,
N~.~~N N.S,O
I
I~
I
O N _ N. S O
Phi O~ H3C O
J
I~
O
o N"~,- N~ ..
C ,,S w
Ph O N O I ,
J

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O O
O, \
N ~,e~N N . So0
O O
N O,S \ L
N'.e~ N~ ~O
O~O
O, \
N'~~ N N~SoO
-82-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
O O
N O,S \
N '~~ N. .O
/
/
O, \
N'~~~ N N~S~ O
F3C /
/ O,
\ I O N~~~N N~S'O\
O
Ph Me
N
N ~ S02Ph
Et ~ N OH
PhCH20 ~ O
-83-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/ p \
\ ( O N~~~N N~S O
CF3 O /
CF3 /
/ o
\ I O N~~~N N~S~O
O / I
\
/ O \ ~
\ I O N ~~~N N~ S~ O
O /
/ o \~
\ I O N.~~~N N ~ S~ O
O /
-84-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/ ~ ' \.
O N~V~ N N'S~ O
O
\ / I N o,s \ I
/ \ O~N~~~ i' ~O
O / I
\
N O, S \ I
/ O~N'~~ i ~ ~O
\I o /
\ I
\
/
Me / I
N N ~S
02
Et ~N OH
\ O - '' O
I /
-85-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
Me
i
S \
Et ~ N \ OH 02
\ O- ' O
/
/ \
N o
\ O~N~~~ i ' ~O
IO'
N O,S
\ O~N~~~ i' ~O
_ O
\
O,
O N ~~~N N' S~O
O /
-86-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
o, \ I
O N~~~ N N~S~ O
I \ " 1~ I
/ o /I
/
/ \
I N o,s
\ O~N~~~ i ~ ~O
O / I
/ I
O, \
'\~O~N',e~N N~S,~O
I
O / I
o, \ I
O N~V~ N N~S~ O
I
O
_87_

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
Ph
N
O 'N \ S02Ph
Ph~O_ _N
Me
Ph
N
N \ S02Ph
Et ~ N OMe
PhCH20- ' O
N
O~N'~e~ ~ , ~O
/ o /)
I
O N N~S02Ph
O
Ph~O~N /~
O
J
Ph Me
N
' N \ SOzPh
Et ~ OMe
N
PhCH20 ~ O
_88_
*rB

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
Me
N
N ~ S02Ph
Et ~N NHMe
PhCH20 ~ O
/ O
O N~~~N N~S~O
O
CI
/ O
O N~~~ N N~S~ o
O
CI
O N N~S02Ph
C F3
Ph~O N
J
-89-

CA 02296314 2000-O1-13
WO 99/04794 PCT/IJS98/14990
/ O \ I
,.
\ I O N~~~N N~S O
I
O
S
/ o \ I
,
\ I O N~~~N N~S O
I
O
S
Ph Me
N
' N \ S02Ph
OH
N
PhCH20 ~ O
N o, S \ I
o ~ N \~~ i N. ,,
o
o ~I
/I

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
o, \ ~
O N~~~N N'S~O
O /
/
N O,,S \
O~N~~~ N. ,,
o
o i
\I
/I
\
o~'o~
/I
o,, \
O N~~~N - N~S~O
I
O
\ CI
/
O~O~
-91-

CA 02296314 2000-O1-13
WO 99/04794 PCT/US98/14990
/
\
O N~~~N N~S O
O
S
O~O~
/
O,, \
O N~J~N _ N~S~O
O
/I
OOH
/
O,, \
O~N'~~N _ N.S O
O /
CI
O OH
-92-

CA 02296314 2000-O1-13
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0
O N~~~N N~S~O\
O
S
/
O'~O H
/
O,, \
0 N~~~N N~S O
O
/
O'~NH2
/
O, \
O N~~~N ~S~O
O
\ CI
/.
O'~ NH2
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WO 99/04794 PCTlUS98/14990
/
\
O N~~~N N'S~O
O
S
/
O NH2
/)
N ~~S \
O Ny~ ~ ~O
O /
/
O \
O
O, \
O N~V~ N N'S~O
O /
\ CI
/
O \
O
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CA 02296314 2000-O1-13
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O N N O' S~~ \
l~ O
o ' \>
s
/I
,o \
0
/I
o, \
O N ~~~N N' S~ O
O /
HO
O
O~,
O N~~~N - N~S~O\
O /
\ CI
/
HO \
O
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CA 02296314 2000-O1-13
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'\
O N~~N N~S O
O
S
HO
O
O,
O N~V~ N N~S~O
O /
H2N \
O
O, \
O N~V~N N~S~O
O /
\ CI
H2N
O
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CA 02296314 2000-O1-13
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O N~V~ N N~S~O
O
S
H2N
O
N O~~S \
O~ N ',e~ i ~ ~ O
O
c/
N \
O
/
O, \
O N~V~N N~S~O
O /
\ CI
CN \
O
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CA 02296314 2000-O1-13
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O N~,~~N N'S~O
O /
S
CN
O
Ph Me
N
' N w S02Ph
CN
~ N
PhCH20 ~ O
"~ N' S
,N
v
N ~ / OH ~ S
N~~ -N
N
Ph
N
~ S 02Ph
OH
and pharmaceutically acceptable salts thereof.
The subject compounds are useful in a method of
modulating chemokine receptor activity in a patient in need of such
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CA 02296314 2000-O1-13
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modulation comprising the administration of an effective amount of the
compound.
The present invention is directed to the use of the foregoing
spiro-substituted azacycles as modulators of chemokine receptor activity.
In particular, these compounds are useful as modulators of the
chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-
3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
The utility of the compounds in accordance with the present
invention as modulators of chemokine receptor activity may be
demonstrated by methodology known in the art, such as the assay for
CCR-1 and/or CCR-5 binding as disclosed by Van Riper, et ai., .J Exg_
Med., 177, 851-856 ( 1993), and the assay for CCR-2 and/or CCR-3 binding
as disclosed by Daugherty, et al., J. Ex~. Med., 183, 2349-2354 (1996). Cell
lines for expressing the receptor of interest include those naturally
expressing the receptor, such as EOL-3 or THP-l, or a cell engineered to
express a recombinant receptor, such as CHO, RBL-2H3, HEK-293. For
example, a CCR3 transfected AML14.3D10 cell line has been placed on
restricted deposit with American Type Culture Collection in Rockville,
Maryland as ATCC No. CRL-12079, on April 5, 1996. The utility of the
compounds in accordance with the present invention as inhibitors of the
spread of HIV infection in cells may be demonstrated by methodology
known in the art, such as the HIV quantitation assay disclosed by
Nunberg, et al., J. Virology, 66 (9), 4887-4892 (1991).
In particular, the compounds of the following examples had
activity in binding to either the CCR-5 receptor or the CCR-3 receptor in
the aforementioned assays, generally with an IC50 of less than about 10
p,M. Such a result is indicative of the intrinsic activity of the compounds
in use as modulators of chemokine receptor activity.
Mammalian chemokine receptors provide a target fOr
interfering with or promoting eosinophil and/or lymphocyte function in
a mammal, such as a human. Compounds which inhibit or promote
chemokine receptor function, are particularly useful for modulating
eosinophil and/or lymphocyte function for therapeutic purposes.
Accordingly, the present invention is directed to compounds which are
useful in the prevention and/or treatment of a wide variety of
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inflammatory and immunoregulatory disorders and diseases, including
asthma and allergic diseases, as well as autoimmune pathologies such
as rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one or
more functions of a mammalian chemokine receptor (e.g., a human
chemokine receptor) may be administered to inhibit (i.e., reduce or
prevent) inflammation. As a result, one or more inflammatory
processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of
enzymes, histamine) or inflammatory mediator release, is inhibited.
For example, eosinophilic infiltration to inflammatory sites (e.g., in
asthma) can be inhibited according to the present method.
Similarly, an instant compound which promotes one or
more functions of a mammalian chemokine receptor (e.g., a human
chemokine) is administered to stimulate (induce or enhance) an
inflammatory response, such as leukocyte emigration, chemotaxis,
exocytosis (e.g., of enzymes, histamine) or inflammatory mediator
release, resulting in the beneficial stimulation of inflammatory
processes. For example, eosinophils can be recruited to combat parasitic
infections.
In addition to primates, such as humans, a variety of other
mammals can be treated according to the method of the present
invention. For instance, mammals including, but not limited to, cows,
sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine,
equine, canine, feline, rodent or murine species can be treated.
However, the method can also be practiced in other species, such as
avian species (e.g., chickens).
Diseases and conditions associated with inflammation and
infection can be treated using the method of the present invention. In a
preferred embodiment, the disease or condition is one in which the
actions of eosinophils and/or lymphocytes are to be inhibited or
promoted, in order to modulate the inflammatory response.
Diseases or conditions of humans or other species which
can be treated with inhibitors of chemokine receptor function, include,
but are not limited to: inflammatory or allergic diseases and conditions,
including respiratory allergic diseases such as asthma, allergic
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rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis,
eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic
eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung
diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated
with rheumatoid arthritis, systemic lupus erythematosus, ankylosing
spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or
dermatomyositis); systemic anaphylaxis or hypersensitivity responses,
drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies;
autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,
juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,
Behcet's disease; graft rejection (e.g., in transplantation), including
allograft rejection or graft-versus-host disease; inflammatory bowel
diseases, such as Crohn's disease and ulcerative colitis;
spondyloarthropathies; scleroderma; psoriasis (including T-cell
mediated psoriasis) and inflammatory dermatoses such an dermatitis,
eczema, atopic dermatitis, allergic contact dermatitis, urticaria;
vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);
eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte
infiltration of the skin or organs. Other diseases or conditions in which
undesirable inflammatory responses are to be inhibited can be treated,
including, but not limited to, reperfusion injury, atherosclerosis, certain
hematologic malignancies, cytokine-induced toxicity (e.g., septic shock,
endotoxic shock), polymyositis, dermatomyositis.
Diseases or conditions of humans or other species which
can be treated with promoters of chemokine receptor function, include,
but are not limited to: immunosuppression, such as that in individuals
with immunodeficiency syndromes such as AIDS, individuals
undergoing radiation therapy, chemotherapy, therapy for autoimmune
disease or other drug therapy (e.g., corticosteroid therapy), which
causes immunosuppression; immunosuppression due congenital
deficiency in receptor function or other causes; and infectious diseases,
such as parasitic diseases, including, but not limited to helminth
infections, such as nematodes (round worms); (Trichuriasis,
Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis,
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filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis),
cestodes (tape worms) (Echinococcosis, Taeniasis saginata,
Cysticercosis); visceral worms, visceral larva migrans (e.g., Toxocara),
eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.),
cutaneous larva migrans (Ancylostona braziliense, Ancylostoma
caninum).
The compounds of the present invention are accordingly
useful in the prevention and treatment of a wide variety of inflammatory
and immunoregulatory disorders and diseases.
In another aspect, the instant invention may be used to
evaluate putative specific agonists or antagonists of chemokine
receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4,
CCR-5, CXCR-3, and CXCR-4. Accordingly, the present invention is
directed to the use of these compounds in the preparation and execution
of screening assays for compounds which modulate the activity of
chemokine receptors. For example, the compounds of this invention are
useful for isolating receptor mutants, which are excellent screening
tools for more potent compounds. Furthermore, the compounds of this
invention are useful in establishing or determining the binding site of
other compounds to chemokine receptors, e.g., by competitive inhibition.
The compounds of the instant invention are also useful for the
evaluation of putative specific modulators of the chemokine receptors,
including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5,
CXCR-3, and CXCR-4. As appreciated in the art, thorough evaluation of
specific agonists and antagonists of the above chemokine receptors has
been hampered by the lack of availability of non-peptidyl (metabolically
resistant) compounds with high binding affinity for these receptors.
Thus the compounds of this invention are commercial products to be
sold for these purposes.
The present invention is further directed to a method for the
manufacture of a medicament for modulating chemokine receptor
activity in humans and animals comprising combining a compound of
the present invention with a pharmaceutical carrier or diluent.
The present invention is further directed to the use of these
compounds in the prevention or treatment of infection by a retrovirus, in
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particular, the human immunodeficiency virus (HIV) and the
treatment of, and delaying of the onset of consequent pathological
conditions such as AIDS. Treating AIDS or preventing or treating
infection by HIV is defined as including, but not limited to, treating a
wide range of states of HIV infection: AIDS, ARC (AIDS related
complex), both symptomatic and asymptomatic, and actual or potential
exposure to HIV. For example, the compounds of this invention are
useful in treating infection by HIV after suspected past exposure to HIV
by, e.g., blood transfusion, organ transplant, exchange of body fluids,
bites, accidental needle stick, or exposure to patient blood during
surgery.
In a preferred aspect of the present invention, a subject
compound may be used in a method of inhibiting the binding of a human
immunodeficiency virus to a chemokine receptor, such as CCR-5 and/or
CXCR-4, of a target cell, which comprises contacting the target cell with
an amount of the compound which is effective at inhibiting the binding
of the virus to the chemokine receptor.
The subject treated in the methods above is a mammal,
preferably a human being, male or female, in whom modulation of
chemokine receptor activity is desired. "Modulation" as used herein is
intended to encompass antagonism, agonism, partial antagonism
and/or partial agonism. The term "therapeutically effective amount"
means the amount of the subject compound that will elicit the biological
or medical response of a tissue, system, animal or human that is being
sought by the researcher, veterinarian, medical doctor or other
clinician.
The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the specified
amounts. By "pharmaceutically acceptable" it is meant the carrier,
diluent or excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the
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invention or a prodrug of a compound of the invention to the individual
in need of treatment.
Combined therapy to modulate chemokine receptor activity
and thereby prevent and treat inflammatory and immunoregulatory
disorders and diseases, including asthma and allergic diseases, as well
as autoimmune pathologies such as rheumatoid arthritis and
atherosclerosis, and those pathologies noted above is illustrated by the
combination of the compounds of this invention and other compounds
which are known for such utilities.
For example, in the treatment or prevention of
inflammation, the present compounds may be used in conjunction with
an antiinflammatory or analgesic agent such as an opiate agonist, a
lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a
cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an
interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA
antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of
nitric oxide, a non-steroids! antiinflammatory agent, or a cytokine-
suppressing antiinflammatory agent, for example with a compound
such as acetaminophen, asprin, codiene, fentanyl, ibuprofen,
indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam,
a steroids! analgesic, sufentanyl, sunlindac, tenidap, and the like.
Similarly, the instant compounds may be administered with a pain
reliever; a potentiator such as caffeine, an H2-antagonist, simethicone,
aluminum or magnesium hydroxide; a decongestant such as
phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,
ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-
desoxy-ephedrine; an antiitussive such as codeine, hydrocodone,
caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a
sedating or non-sedating antihistamine.
The present invention is further directed to combinations of
the present compounds with one or more agents useful in the prevention
or treatment of AIDS. For example, the compounds of this invention
may be effectively administered, whether at periods of pre-exposure
and/or post-exposure, in combination with effective amounts of the AIDS
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antivirals, immunomodulators, anti-infectives, or vaccines known to
those of ordinary skill in the art.
ANTIVIRALS
Drug Name Manufacturer Indication
097 HoechstlBayer HIV infection,
AIDS, ARC
(non-nucleoside
reverse
transcriptase
inhibitor)
141 W94 Glaxo Wellcome HIV infection,
AIDS, ARC
(protease inhibitor)
1592U89 Glaxo Wellcome HIV infection,
AIDS, ARC
Acemannan Carrington Labs ARC
(Irving, TX)
Acyclovir Burroughs Wellcome HIV infection,
AIDS,
ARC, in
combination with
AZT
AD-439 Tanox Biosystems HIV infection,
AIDS,
ARC
AD-519 Tanox Biosystems HIV infection,
AIDS,
ARC
Adefovir dipivoxilGilead Sciences HIV infection
AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Alpha InterferonGlaxo Wellcome Kaposi's sarcoma,
HIV in combination
w/Retrovir
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Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH)
Erbamont
(Stamford, CT)
Antibody which Advanced BiotherapyAIDS, ARC
neutralizes pH Concepts
labile alpha aberrant(Rockville, MD)
Interferon
AR177 Aronex Pharm HIV infection, AIDS,
ARC
beta-fluoro-ddA Nat'1 Cancer InstituteAIDS-associated
diseases
(-) 6-Chloro-4(S)-Merck HIV infection,
cyclopropylethynyl- AIDS, ARC
4(S)-trifluoro- (non-nucleoside
methyl-1,4-dihydro- reverse
2H-3,1-benzoxazin- transcriptase
2-one inhibitor)
CI-1012 Warner-Lambert HIV-1 infection
Cidofovir Gilead Science CMV retinitis, herpes,
papillomavirus
Curdlan sulfate AJI Pharma USA HIV infection
Cytomegalovirus MedImmune CMV retinitis
immune globin
Cytovene Syntex sight threatening
Ganciclovir CMV
peripheral CMV
retinitis
Delaviridine Pharmacia-Upjohn HIV infection,
AIDS, ARC
(protease inhibitor)
Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. (Osaka, positive asymptomatic
Japan)
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ddC Hoffman-La Roche HIV infection, AIDS,
Dideoxycytidine ARC
ddI Bristol-Myers SquibbHIV infection, AIDS,
Dideoxyinosine ARC; combination
with AZT/d4T
DMP-450 AVID HIV infection,
(Camden, NJ) AIDS, ARC
(protease inhibitor)
EL10 Elan Corp, PLC HIV infection
(Gainesville, GA)
Efavirenz, DMP- DuPont-Merck HIV infection,
266 Pharmaceuticals AIDS, ARC
(non-nucleoside
reverse
transcriptase
inhibitor)
Famciclovir Smith HIine herpes zoster,
herpes simplex
FTC Emory University HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor)
GS 840 Gilead HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor)
GW 141 Glaxo Welcome HIV infection,
AIDS, ARC
(protease inhibitor)
GW 1592 Glaxo Welcome HIV infection,
AIDS, ARC
(reverse transcriptase
inhibitor}
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HBY097 Hoechst Marion HIV infection,
Roussel AIDS, ARC
(non-nucleoside
reverse transcriptase
inhibitor)
Hypericin VIMRx Pharm. HIV infection,
AIDS,
ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's
Interferon Beta (Almeda, CA) sarcoma, ARC
Interferon alfa-n3Interferon Sciences ARC, AIDS
Indinavir Merck HIV infection,
AIDS,
ARC, asymptomatic
HIV positive,
also in
combination with
AZT/ddI/ddC
ISIS 2922 ISIS PharmaceuticalsCMV retinitis
KNI-272 Nat'1 Cancer InstituteHIV-assoc.
diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection,
AIDS, ARC
(reverse
transcriptase
inhibitor); also
with AZT
Lobucavir Bristol-Myers SquibbCMV infection
Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC
(protease inhibitor)
Nevirapine Boeheringer HIV infection,
Ingleheim AIDS, ARC
(protease inhibitor)
Novapren Novaferon Labs, Inc.HIV inhibitor
(Akron, OH)
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Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA)
Sequence
Trisodium Astra Pharm. CMV retinitis,
HIV
Phosphonoformate Products, Inc infection, other
CMV
infections
PNU-140690 Pharmacia Upjohn HIV infection,
AIDS, ARC
(protease inhibitor)
Probucol Vyrex HIV infection,
AIDS
RBC-CD4 Sheffield Med. HIV infection,
Tech (Houston TX) AIDS, ARC
Ritonavir Abbott HIV infection,
AIDS, ARC
(protease inhibitor)
Saquinavir Hoffmann- HIV infection,
LaRoche AIDS, ARC
(protease inhibitor)
Stavudine; d4T Bristol-Myers SquibbHIV infection,
AIDS,
Didehydrodeoxy- ARC
thymidine
Valaciclovir Glaxo Wellcome genital HSV & CMV
infections
Virazole ViratekJICN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS,
ARC
VX-478 Vertex HIV infection,
AIDS,
ARC
Zalcitabine Hoffmann-La Roche HIV infection,
AIDS,
ARC, with AZT
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Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS,
ARC, Kaposi's
sarcoma, in
combination with
other therapies
IMMUNO-MODULATORS
Drug Name Manufacturer Indication
AS-101 Wyeth-Ayerst AID S
Bropirimine Pharmacia Upjohn advanced AIDS
Acemannan Carrington Labs, AIDS, ARC
Inc.
(Irving, TX)
CL246,738 American Cyanamid AIDS, Kaposi's
Lederle Labs sarcoma
EL10 Elan Corp, PLC HIV infection
(Gainesville, GA)
Gamma Interferon Genentech ARC, in combination
w/TNF (tumor
necrosis factor)
Granulocyte Genetics Institute AIDS
Macrophage ColonySandoz
Stimulating
Factor
Granulocyte Hoeschst-Roussel AIDS
Macrophage ColonyImmunex
Stimulating
Factor
Granulocyte Schering-Plough AIDS, combination
Macrophage Colony w/AZT
Stimulating Factor
HIV Core ParticleRorer seropositive HIV
Immunostimulant
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IL-2 Cetus AIDS, in combination
Interleukin-2 w/AZT
IL-2 Hoffman-La Roche AIDS, ARC, HIV, in
Interleukin-2 Immunex combination w/AZT
IL-2 Chiron AIDS, increase in
CD4
Interleukin-2 cell counts
(aldesiukin)
Immune Globulin Cutter Biological pediatric AIDS, in
Intravenous (Berkeley, CA) combination w/AZT
(human)
IMREG-1 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
IMREG-2 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
Imuthiol Diethyl Merieux Institute AIDS, ARC
Dithio Carbamate
Alpha-2 Schering Plough Kaposi's sarcoma
Interferon w/AZT, AIDS
Methionine- TNT PharmaceuticalAIDS, ARC
Enkephalin (Chicago, IL)
MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide
Granulocyte Amgen AIDS, in combination
Colony Stimulating w/AZT
Factor
Remune Immune Response immunotherapeutic
Corp.
rCD4 Genentech AIDS, ARC
Recombinant
Soluble Human CD4
rCD4-IgG AIDS, ARC
hybrids
Recombinant Biogen AIDS, ARC
Soluble Human CD4
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Interferon Hoffman-La Roche Kaposi's sarcoma
Alfa 2a AIDS, ARC, in
combination w/AZT
SK&F10652$ Smith Kline HIV infection
Soluble T4
Thymopentin Immunobiology HIV infection
Research Institute
(Annandale, NJ)
Tumor Necrosis Genentech ARC, in combination
Factor; TNF w/gamma Interferon
ANTI-INFECTIVES
Drua Name Manufacturer Indication
Clindamycin withPharmacia Upjohn PCP
Primaquine
Fluconazole Pfizer cryptococcal
meningitis,
candidiasis
Pastille Squibb Corp. prevention
of
Nystatin Pastille oral candidiasis
Ornidyl Merrell Dow PCP
Eflornithine
Pentamidine LyphoMed PCP treatment
Isethionate (IM (Rosemont, IL)
& IV)
Trimethoprim antibacterial
Trimethoprim/sulfa antibacterial
Piritrexim Burroughs Wellcome PCP treatment
Pentamidine Fisons Corporation PCP prophylaxis
isethionate for
inhalation
Spiramycin Rhone-Poulenc cryptosporidial
diarrhea
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Intraconazole- Janssen Pharm. histoplasmosis;
851211 cryptococcal
meningitis
Trimetrexate Warner-Lambert PCP
Drug Name Manufacturer indication
Daunorubicin NeXatar, Sequus Karposi's sarcoma
Recombinant Human Ortho Pharm. Corp.severe anemia
Erythropoietin assoc. with AZT
therapy
Recombinant Human Serono AIDS-related wasting,
Growth Hormone cachexia
Megestrol Acetate Bristol-Myers Squibbtreatment of
anorexia assoc.
w/AIDS
Testosterone Alza, Smith Kline AIDS-related wasting
Total Enteral Norwich Eaton diarrhea and
Nutrition Pharmaceuticals malabsorption
related to AIDS
It will be understood that the scope of combinations of the
compounds of this invention with AIDS antivirals, immunomodulators,
anti-infectives or vaccines is not limited to the list in the above Table, but
includes in principle any combination with any pharmaceutical
composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating
treatments of with a compound of the present invention and an inhibitor
of HIV protease and/or a non-nucleoside inhibitor of HTV reverse
transcriptase. An optional fourth component in the combination is a
nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC,
ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is
the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-
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hydroxy-5-( 1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarbo-xamido)-
piperazinyl))-pentaneamide ethanolate, and is synthesized according to
U.S. 5,413,999. Indinavir is generally administered at a dosage of 800
mg three times a day. Other preferred inhibitors of HTV protease
include nelfinavir and ritonavir. Preferred non-nucleoside inhibitors of
HIV reverse transcriptase include (-) 6-chloro-4(S)-cyclopropylethynyl-
4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, which may be
prepared by methods disclosed in EP 0,582,455. The preparation of ddC,
ddI and AZT are also described in EPO 0,484,071. These combinations
may have unexpected e~'ects on limiting the spread and degree of
infection of HIV. Preferred combinations with the compounds of the
present invention include the following (1) indinavir, with efavirenz or
(-) 6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-
3,1-benzoxazin-2-one, and, optionally, AZT and/or 3TC and/or ddI and/or
ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC.
In such combinations the compound of the present
invention and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of other
agent(s).
The compounds of the present invention may be
administered by oral, parenteral (e.g., intramuscular, intraperitoneal,
intravenous, ICV, intracisternal injection or infusion, subcutaneous
injection, or implant}, by inhalation spray, nasal, vaginal, rectal,
sublingual, or topical routes of administration and may be formulated,
alone or together, in suitable dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers, adjuvants
and vehicles appropriate for each route of administration. In addition to
the treatment of warm-blooded animals such as mice, rats, horses,
cattle, sheep, dogs, cats, monkeys, ete., the compounds of the invention
are effective for use in humans.
The pharmaceutical compositions for the administration of
the compounds of this invention may conveniently be presented in
dosage unit form and may be prepared by any of the methods well known
in the art of pharmacy. All methods include the step of bringing the
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active ingredient into association with the carrier which constitutes one
or more accessory ingredients. In general, the pharmaceutical
compositions are prepared by uniformly and intimately bringing the
active ingredient into association with a liquid carrier or a finely divided
solid carrier or both, and then, if necessary, shaping the product into the
desired formulation. In the pharmaceutical composition the active
object compound is included in an amount sufficient to produce the
desired effect upon the process or condition of diseases. As used herein,
the term "composition" is intended to encompass a product comprising
the specified ingredients in the specified amounts, as well as any
product which results, directly or indirectly, from combination of the
specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain
the active ingredient in admixture with non-toxic pharmaceutically
acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be for example, inert diluents, such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, corn
starch, or alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be coated by
known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as glyceryl
monostearate or glyceryl distearate may be employed. They may also be
coated by the techniques described in the U.S. Patents 4,256,108;
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4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control
release.
Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredient is mixed
with water or an oil medium, for example peanut oil, liquid paraffin, or
olive oil.
Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose, hydroxy-
propylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents may be a
naturally-occurring phosphatide, for example lecithin, or condensation
products of an alkylene oxide with fatty acids, for example
polyoxyethylene stearate, or condensation products of ethylene oxide
with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
with partial esters derived from fatty acids and a hexitol such as
polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives, for example
ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one
or more flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
Oily suspensions may be formulated by suspending the
active ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The
oily suspensions may contain a thickening agent, for example beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
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Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent, suspending
agent and one or more preservatives. Suitable dispersing or wetting
agents and suspending agents are exemplified by those already
mentioned above. Additional excipients, for example sweetening,
flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also
be in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral oil, for
example liquid paraffin or mixtures of these. Suitable emulsifying
agents may be naturally- occurring gums, for example gum acacia or
gum tragacanth, naturally-occurring phosphatides, for example soy
bean, lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension. This suspension
may be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally-acceptable
diluent or solvent, for example as a solution in 1,3-butane diol. Among
the acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils axe conventionally employed as a solvent or suspending
medium. For this purpose any bland fixed oil may be employed
including synthetic mono- or diglycerides. In addition, fatty acids such
as oleic acid find use in the preparation of injectables.
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The compounds of the present invention may also be
administered in the form of suppositories for rectal administration of the
drug. These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the rectum
to release the drug. Such materials are cocoa butter and polyethylene
glycols.
For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the compounds of The present invention
are employed. (For purposes of this application, topical application shall
include mouth washes and gargles.)
The pharmaceutical composition and method of the present
invention may further comprise other therapeutically active compounds
as noted herein which are usually applied in the treatment of the above
mentioned pathological conditions.
In the treatment or prevention of conditions which require
chemokine receptor modulation an appropriate dosage level will
generally be about 0.01 to 500 mg per kg patient body weight per day
which can be administered in single or multiple doses. Preferably, the
dosage level will be about 0.1 to about 250 mg/kg per day; more preferably
about 0.5 to about i40 mg/kg per day. A suitable dosage level may be
about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about
0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5,
0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the
compositions are preferably provided in the form of tablets containing 1.0
to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0,
15Ø 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,
600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient
for the symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day.
It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied and
will depend upon a variety of factors including the activity of the specific
compound employed, the metabolic stability and length of action of that
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compound, the age, body weight, general health, sex, diet, mode and
time of administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
Several methods for preparing the compounds of this
invention are illustrated in the following Schemes and Examples.
Starting materials are made from known procedures or as illustrated.
Several methods for preparing the compounds of this
invention are illustrated in the following Schemes and Examples.
SCHEME 1
RCHO, [H]
R2
R1X RZ
R3 ~ n N~ )m R3 )m
I H ~N II
R2 R1
RCO R3 ~ )m Strong [H]
N
O~ R
The compounds of the present invention are prepared by
alkylating heterocycle I under appropriate conditions to provide
compound II (Scheme 1). The required starting materials for preparing
heterocycle I are available commercially or can be prepared using the
methods given below.
Thus, heterocycle I is combined with the appropriate
aldehyde and the intermediate imine or iminium species is reduced to
the tertiary amine chemically (e.g, using sodium cyanoborohydride,
sodium borohydride, or sodium triacetoxyborohydride) or catalytically
(e.g. using hydrogen and palladium on carbon or Raney nickel catalyst)
(Scheme 1). The aldehyde needed for this reaction can be prepared by
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methods generally known in the chemical literature; for the purposes of
the present invention one preparation of a representative aldehyde is
described in Hale, J.J.; Finke, P.E.; MacCoss, M. Bioorganic &
Medicinal Chemistry Letters 1993,3, 319-322.
In an alternative embodiment of the present
invention, heterocycle I can be alkylated with an alkyl halide or alkyl
sulfonate ester (with or without an added base to neutralize the mineral
acid or sulfonic acid by-product) to give the desired compound (Scheme
1). The alkyl halide or alkyl sulfonate needed for this reaction can be
prepared by methods generally known in the chemical literature; for the
purposes of the present invention an aldehyde, prepared as described
above, can be reduced to an alcohol with sodium borohydride,
diisobutylaluminum hydride or lithium aluminum hydride, and the
product alcohol converted to either the alkyl halide using methods
described in March J. "Advanced Organic Chemistry", 4th ed., John
Wiley & Sons, New York, pp. 431-433 (1992), or alkyl sulfonate ester using
methods described in March J. "Advanced Organic Chemistry", 4th ed.,
John Wiley & Sons, New York, p. 49$-499 (1992).
In an alternative embodiment of the present invention, I
can be acylated to give a tertiary amide; subsequent reduction with a
strong reducing agent (e.g. diborane; borane in THF; borane
dimethylsulfide, or lithium aluminum hydride) will give the desired
compound (Scheme 1). The acylating agent needed for this reaction can
be prepared by methods generally known in the chemical literature; for
the purposes of the present invention an aldehyde, prepared as described
above, can be oxidized using such commonly used reagents as
permanganate in acid or silver oxide, and the resulting acid activated as
an acid chloride or mixed anhydride which can be used to acylate I. The
product amide can in and of itself be a chemokine receptor modulator or
can be reduced as noted above to give the tertiary amine.
Optionally, compound II may be further modified in
subsequent reactions, as illustrated below.
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SCHEME 2
HO~ /OH Ph3P-Br2 Br
- Br\
CH3CN -
1 ) ArS02N(CH3)Na, DMF
R2 m Me ~ Rs
,r
w
2 m N\ ,N~'S RT
2) R 'NH R3 "
R3 ~ III
R2 vYm
(nBu)3SnH, THF N
PdCl2(Ph3P)2 R3 "
~ Rs
R IV (nBu)3Sn Me I ~~~ Rr
Ry~~ ~ \ Br R2 m
'N
Rz R3 " O~ ,O
PdCl2(Ph3)2, dioxane, O ~ N'S
Rs
PdCI Ph R / Me
2( 3)2~
N-methylpyrrolidinone, 0 "~ ~ R-r
or R i~.l V
Pd(dba), P(furan)3, K2C03, Y Rz
N-methylpyrrolidinone, 0
R2 ~llm
N
Rs " O, ,O
H~/ 10% Pd/C, MeOH or N~S
s
H2/ Pd(OH)2/C, MeOH, HOAc RX / Me I ~~1 R
V I R i. '~
R
z
In an alternative embodiment of the present invention,
compounds of interest can be prepared by activating the hydroxyl groups
of 1,4-dihydroxy-2-butyne, for example by treatment with triphenyl-
phosphine dibromide in acetonitrile, to give 1,4-dibromo-2-butyne
(Scheme 2). Displacement of one bromide with the sodium salt of an
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arylsulfonamide (wherein Rs and Rt are substituents on the phenyl or
Ar as defined herein), followed by displacement of the other bromide
with a suitable cyclic secondary amine, provides the acetylene derivative
III. Palladium-catalysed hydrostannylation preferentially forms the 3-
tributylstannyl olefin IV. The minor product from this reaction can also
isolated and carried through the sequence described below. Compound
IV can be converted to the corresponding 3-aryl derivative V by
treatment with an aryl bromide (wherein Rx, Ry and Rz are substituents
on the phenyl or heteroaryl as defined herein) in the presence of a
suitable palladium catalyst at or above room temperature. Suitable
catalysts include palladium acetate and triphenylphosphine,
bis(triphenylphosphine) palladium (II) chloride, or palladium (0)
bis(dibenzylidineacetone) in the presence of triphenylphosphine or tri-2-
furylphosphine. Suitable solvents include 1,4-dioxane, DMF, and N-
methylpyrrolidinone. A base such as potassium carbonate or potassium
phosphate may also be employed. Compound V may be employed as a
chemokine receptor modulator itself or it can be reduced to saturated
derivative VI by standard conditions, for example catalytic
hydrogenation with palladium on carbon or with palladium hydroxide
in the presence of a mild acid such as acetic acid.
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SCHEME 3
O EDAC O
\ HOST-H20 \ ~OMe
OH HN(Me)(OMe)~HCI N RLi, -78°C or
- Me
/ I Rx l \ I RMgBr, rt
Rx l~ W
R ~~Rz VII RY ~z VI11
Y
O R6NH3CI R
\ R Na~ \ N~H ArS02Cl
R6 TEA
Rx ~ ~ Rx /
L \
Ry ~ Rz IX Ry ~ Rz X
1 ) Os04
R O O NMO R O O
\ N~S~' acetone/ tBuOH/H20 H ~S~~
R6 ( \ RS 2:1:1 O R6 ~ \jRs
/ RT 2) Na104 R / ~\ RT
Rx ~ THF:H O x h \
2
RY/~Rz XI 3:1 RY/~Rz XII
R2 N H R2 )m R O, ~ O
N ~S,
R~ R3 ~ R6 ~ \jRs
NaBH3CN / ~ ~\ RT
MeOH Rx L~ \
Ry "Rz XIII
In an alternative embodiment of the present invention, the
allyl acid VII (prepared, for example, as described in Hale et al; see
above) can be converted into the N-methyl-N-methoxy amide VIII, which
is then treated with an alkyl or aryl metal reagent, for example
methyllithium or butyllithium, to provide the ketone IX (Scheme 3). The
ketone can be converted into an imine which can then be reduced to
secondary amine X chemically, (e.g using sodium cyanoborohydride or
sodium borohydride), or catalytically (e.g. using hydrogen and
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palladium on carbon or Raney nickel catalyst). Acylation under
standard conditions, for example with an acid chloride, provides the
corresponding amide. Alternatively, amine X can be sulfonylated, for
example with a alkyl or aryl sulfonyl chloride or an alkyl or aryl sulfonic
anhydride, to give (for aryl substituted sulfonylating reagents)
sulfonamide XI. The allyl group in XI can be oxidatively cleaved to
aldehyde XII with osmium tetroxide followed by sodium periodate or
with ozone at low temperature. Reductive amination of aldehyde XII
with azacycle I can then be carried out under the conditions described
above to give the desired product XIII.
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SCHEME 4
Ry ~~~.~ Z R v .. Rz
RX I 1 ) (COCI)2 R r~
\ CH2CI2, r.t.
O
/ OH 2) N-lithio-2S-benzyl
XIV oxazolidinone / N O
XV ~/
Ph
KHMDS, THF, 1 ) LiBH4, MeOH,
trisyl azide ~ THF, 0°C
HOAc N O 2) PPh3, THF/H20 OH
XVI N3 L.w~"'J 65°C XVII NH2
R R Ph 1 ) Os04, Na104 R
RX yr~'~/ Z tBuOH, H20 R R ~\~/ z
1 ) triphosgene \ I " \
2), NaCNBH3,
THF, r.t. MeOHlTHF R2 m
2) NaH, Mel N
m
DMF, 70°C / v ~~O R2 NH R3 ~ ,N O
XVIII Me ~ R3 " R XIX Me
RX ~~
1 ) 1 M KOH,
EtOH, 85°C m \ Me ~~R
R2 N~ \ v
2) ArS02Cl, Et3N, N = ~S~ RT
CH2CI2, 0°C R3 ~ HO' O O XX
Preparation of hydroxymethyl derivatives of the target
compounds is outlined in Scheme 4. The oxazolidinone imide XV is
prepared from acid XIV, by formation of the corresponding acid chloride
(by treatment with oxalyl chloride or thionyl chloride) and addition of N-
lithio 2(S)-benzyl oxazolidinone. The enolate azidation can be
accomplished by a variety of methods, such as the procedure of Evans, D.
A.; et. al. J. Am. Chem. Soc. 1990,112, 4011-4030. Reduction of the
oxazolidinone moiety of XVI can be carried out by a variety of metal
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SUBSTITUTE SHEET (RULE 26)

CA 02296314 2000-O1-13
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hydride reagents (e.g. LiBH4JMeOH, LiAlH4, etc.). The azide is then
reduced by treatment with PPh3/H20 to provide alcohol XVII.
Formation of cyclic carbamate XVIII is accomplished by literature
methods; i.e. phosgene, triphosgene or carbonyl diimidazole, followed by
N-alkylation with sodium hydride and methyl iodide. The target
compounds are prepared by oxidative cleavage of the olefin to the
aldehyde followed by reductive amination with an amine salt as
described for Scheme 1, to provide XIX. Hydrolysis of the cyclic
carbamate under basic conditions (for example, potassium hydroxide in
ethanol at elevated temperature) followed by selective amide formation at
0°C by combining with an acylating agent or a sulfonating agent such as
an arylsulfonyl chloride gives the corresponding hydroxyamides or
hydroxysulfonamides (i.e. XX).
SCHEME 5
R ~% z
AgN03
R X ~ ~ 1 ) (COCI)2
H20
OH 2) CH2N2, Et20
N2
VII O O
Ry~~Rz 1) (COCI)2 R Ry~ j z
/ x
Rx ~ / 2) / O \
OH \ I ~ Rs
1 / /
O Me. N I / RS XXI Me
XIV H
R ~~/R z
1 ) Os04, HzO, tBuOH Rx i
N-Me-morpholine-N-oxide / O \
Rs
2) Na104, H20, THF O ~ N f /
XXII Me
Compounds with alternate arrangements of an amide bond
are prepared as shown in Scheme 5. Acid VII can be homologated
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under Arndt-Eistert conditions to give the chain-extended acid XTV,
which can be derivatized under standard acylating conditions with, for
example, an aniline derivative, to give the amide XXI. Oxidative
cleavage of the olefin with osmium tetroxide or ozone then provides
aldehyde XXII as an intermediate suitable for coupling as described
earlier.
SCHEME 6
Rv\ %Rz
RX i 1 ) (COCI)2
OH
2) CH2N2
/ OH
O 3) AgN03, H20
XIV
~c~cm O
Rv\%Rz ( \ Rs
1 ) (COCI)2 RX i / '
BrMg
2) HN(Me)OMe Me
/ N~ OMe THF
1 ) Os04, H20, tBuOH
N-Me-morphofine-N-oxide
2) Na104, H20, THF
- Rs
O
O XXVI
In addition, ketone derivatives are prepared by an extension
of the chemistry given above, as shown in Scheme 6. An Arndt-Eistert
chain extension of acid XIV provides heptenoic acid XXIII, which after
conversion into N-methoxy-N-methyl amide XXIV, can be reacted with
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CA 02296314 2000-O1-13
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an aryl organometallic reagent, such as an aryl magnesium bromide, to
provide ketone XXV. Routine oxidative cleavage then gives the desired
aldehyde XXVI, which can be coupled with an appropriate amine as
described above.
SCHEME 7
O
\ OH \ N, Me
R ~ 1 ) (COCI)2
~OMe
z L~ VII 2 HN Me OMe Rz
.. ) C )
RI R
v x Rv Rx
1 ) Os04,H20, tBuOH O~ N\ Me R2 "'
N-Me-morpholine-N-oxide ~ OMe + nNH
R3
2) Na104, H20, THF Rz L
R I~-~ XXVII
v Rx
O ATMgCI
MeOH, NaBH3CN R2 ' N ~Me
mol. sieves R3 n N~
j OMe
Rz
XXVI I I R I''
v Rx
R2 "' O R2 m OH
R3 nN \ NaBH4 nN \
R3
Rz L I Rs Rz : I Rs
l~
XXIX R I'' R XXX I
v x Rv Rx
Alcohol containing compounds are prepared according to
procedures given in Scheme 7. Formation of the N-methyl-N-methoxy
amide of acid VII followed by oxidative cleavage of the olefin provides
intermediate aldehyde XXVII. Coupling with an appropriate amine
provides amide XXVIII. Addition of an organometallic reagent to
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compound XXVIII provides illustrated ketone XXIX. Treatment with a
hydride reducing agent, such as sodium borohydride, then yields the
desired alcohol X~.
SCHEME 8
O
OH LiA~ IH~~ OH (CFsS
THF , 2,6-lutidine
R ~ Rz
z ' v XXX I
VII R
R y Rx \
v Rx I 1 R
/ s
n
HN ,N ~ N ~N
/ Rz l~ XXXII
\v Rl..v \
R y Rx I / Rs
s
1 ) Os04, H20, tBuOH ~ ~ w
N-Me-morpholine-N-oxide
~/
2) Na104, H20, THF Rz l
R /v~R XXXI I I
Y x
Formation of heterocycle compounds is carried out
according to the procedure given in Scheme 8 for substituted imidazoles.
Reduction of allyl acid VII with a strong reducing agent such as lithium
aluminum hydride provides alcohol XX~~I. In situ formation of the
trifluoromethanesulfonate ester of the formed alcohol allows for
displacement of the triflate with a nucleophile such as 2-phenyl-
imidazole, to give imidazole XXXII. Oxidative cleavage under standard
conditions provides the aldehyde XXXIII which can then be coupled
under the conditions described above to the appropriate amine.
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SCHEME 9
O
OH ~iAh~ OH NaH
THF , DMF
Rz
Rz ~ ' ~ VII I~~ XXXI
R ~~ R \ Rv Rx
x I 'R
s 1 ) Os04, H20, tBuOH
N-Me-morpholine-N-oxide
X ~ O 2) Na104, H20, THF
/ ~ Rs Rz l ~ XXXIV
\
Rv Rx
\ ~\
Rs ~ / R2 m Rs-.r.
NH
O~ R3 " R2 ~Ym
O ~N O
NaBH3CN , R3
Rz ~ ~ XXXV mol. sieves RZ /
XXXVI
RI R Rw
x v Rx
Compounds with ether substituents are prepared by the
route shown in Scheme 9. Thus, allyl acid VII can be reduced to alcohol
X~~XI with, for example, lithium aluminum hydride. This alcohol can
be alkylated by a Williamson ether synthesis, by deprotonation with a
strong base such as sodium hydride or sodium hexamethyldisilazide
followed by reaction with a benzyl halide such as benzyl bromide. The
resulting ether XXXIV can be processed through the oxidative cleavage
steps described earlier to provide aldehyde XXXV. This aldehyde can
then be coupled with an appropriate amine under reductive amination
conditions to give XX~~VI. Alternatively, reduction of X~~XV to the
corresponding alcohol followed by conversion to the bromide allows for
alkylation with an amine to provide XXXVI.
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SCHEME 10
O ~ 1 ) HOBT, EDAC O
N N
HO OIBu 2) ROH R''O OtBu
XXXVI I XXXVI II
O ~ 1 ) HOBT, EDAC O
N N
HO OtBu 2) RR'NH R'N OtBu
XXXVII R' XXXIX
\
O ~ 1 ) HOBT, EDAC O
N N
HO OtBu 2) Me0(Me)NH Me0-N OIBu
XXXVII Me XL
O ~ RMgX or RLi O
N N
Me0-N OtBu R OtBu
MQ XL . XLI
O TFA, CH2CI2 O
R~ N-~ R' N H~TFA
O ~/ OtBu O ~/
XXXVI I I XLII
O TFA, CH2C1 O
N 2 R' N N H~TFA
OtBu R' XLIII
R' XXXIX
O TFA, CH2CI2 O
N H~TFA
N R
R U ptgu XLIV
XLI
The substituted amines employed in the preceding Schemes
can be obtained commercially in many cases or are prepared by a
number of procedures. For example, as shown in Scheme 10, compound
X~~VII, the N-t-butoxycarbonyl protected form of isonipecotic acid (4-
piperidinecarboxylic acid) can be activated under standard conditions,
for example with a carbodiimide, and converted into ester X~~VIII or
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SUBSTITUTE SHEET (RULE 26)

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amide ~. Alternatively, acid XXXVII can be converted into the N-
methyl-N-methoxy amide, XL, which upon reaction with
organomagnesium and organolithium reagents forms the ketone XLI.
The Boc group of ~O~XVIII, XXXIX and XLI can be removed under
acidic conditions to provide secondary amines XLII, XLIII and XLIV,
respectively.
SCHEME 11
O O 1 ) Oxalyl Chloride O
N ,N N
HO ~ 2) NaN3; toluene, C ' OBn
OBn acetone p'
XLV 3) heat XLVI
O R~ ~ O
N N-~ R~ O N N-
O.C OBn H OBn
XLVI XLVI1
O , R~ ~ O
N ~N- ~ R~ N N N--
C OBn R' H OBn
XLVI
XLVIII
R\ O H2; Pd/C
O N N R
H ~OBn MeOH O N NH
H XLIX
XLVII
O H2; Pd/C
R,
N N N R
H ~Bn MeOH N N NH
R R, H
XLVIII L
Alternatively, CBZ-protected piperidine XLV can be allowed
to react with oxalyl chloride and then sodium azide, to provide the
corresponding acyl azide, which can then be thermally rearranged to
isocyanate XLVI (Scheme 11). Compound XLVI can be treated with an
alcohol ROH or an amine RR'NH to form carbamate XLVII or urea
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XLVIII, respectively, each of which can be deprotected with hydrogen in
the presence of palladium on carbon to secondary amines XLIX or L.
SCHEME~.~
O
O NaH ~ O
O N ~N-~ ~ O N ~N-
(CH2 x H OBn DMF CH ~ OBn
~--CI XLVII' (x = 1-3) { 2)x LI
R\ ~ O NaH, DMF R, ~ O
O H ~N~ R~X O N 'N
OBn R' OBn
XLVII LII
O O
O H2; Pd/C
O N 'N-~ O N N H
(CH2) ~ OBn MeOH (CH2)
LI LIII
R, ~ O R.
O N ~N-.~ H2; Pd/C O N 'NH
R' OBn MeOH R~
LII LIV
If the carbamate XLVII has R = -(CH2)XCH2C1, where x = 1-
3, then treatment with a suitable base, such as sodium hydride, lithium
hexamethyldisilazide or potassium t-butoxide, can induce cyclizatian to
compound LI (Scheme 12). For other R groups, carbamate XLVII can be
treated with an alkylating agent R'X,where R' = primary or secondary
alkyl or alkyl-cycloalkyl, while X = bromide, iodide, tosylate, mesylate or
trifluoromethanesulfonate, in the presence of a suitable base, such as
sodium hydride, lithium hexamethyldisilazide or potassium t-butoxide,
to give derivative LII. In each case, removal of the CBZ protecting group
under standard conditions provides the secondary amines LIII and
LIV.
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SCHEME 13
Me O
~ fI O
O t-BuOH; CuC1 Me~O~ N N
,N N~ H
C OBn
O, Ogn DMF
XLVI LV
TFA O
LV -~ TFA~NH2~N-
CH2CI2 OBn
LVI O
~ O RCOCI, CH2CI2 ~ ~O
TFA~NH2~N~ R N N
OBn Pyridine H _~,/
OBn
LVI
O LV I I
ROCOCI, CH2CI2 II O
LVI R~O~ N N-
Pyndine H~/
OBn XLVII
RR'NCOCI, CH2CI2 O
Pyridine .. R' N~ N N- ~O
LVI or
RNCO (R' = H) R~ H OBn XLVIII
RS02C1 , CH2CI2 ~' ~~ O
LVI ~S~
pyridine R H~N
OBn LVlll
Additional derivatives of a piperidine with nitrogen
functionality at C4 can be carried out as shown in Scheme 13. For
example, if the ring nitrogen is protected with a CBZ group, as with
isocyanate XLVI, treatment with tert-butyl alcohol in the presence of
copper(I) chloride, provides Boc derivative LV. This compound can be
selectively deprotected to the free amine LVI. This amine can be
acylated with an acid chloride, a chloroformate, an isocyanate, or a
carbamyl chloride, to provide compounds LVII, XLVII or XLVIII.
Alternatively, amine LVI can be sulfonated with an alkyl or arylsulfonyl
chloride, to give sulfonamide LVIII.
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SCHEME 14
O O
O H ; Pd/C
R N IV-~ 2 R N ~N H
H OBn MeOH H
LVII LIX
OII H2; Pd/C
O
R~O~N N--~ R~O N NH
H OBn MeOH
XLVII XLIX
O
O H2; Pd/C O
R~N ~ N N-~ R,
R' H OBn MeOH N N NH
R~ H
XLVIII L
O H2; Pd/C
R H N OBn MeOH R~ S~ N NH
H
LVIII
LX
In each case, removal of the CBZ group under reductive
conditions gives the desired secondary amines LIX, XLIX, L, and LX
(Scheme 14).
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SCHEME 15
Me 'Me O
Me O H ' II
Me~ ~ O 2, Pd/C Me~O~ N NH
Me O ~ N~ MeOH H
OBn
LV LX I
Me 'MIe O H ~S ~O
Me~O~ N NH + ~~ Rs I j Rs
H O / .~ R
T
LXI R" l~~\~
Ry ~RZ
Me O
NaBH3CN, MeOH Me~ ~ O, ,O
Me O ~ N N,S
mol. sieves
Rs I JRs
~~ R
T
LXII Rx
Ry ~'RZ
MeCOCI HCI~NH2 N OS°O
Rs I \jRs
MeOH j ~~ R
T
LXIII
Ry ~RZ
Functionalization of the piperidine can also be carried out
after it has been coupled with an N1 substituent. For example, as shown
in Scheme 15, reductive deprotection of CBZ derivative LV yields
secondary amine LXI. Reductive amination with an appropriate
aldehyde fragment (as described above) provides piperidine LXII.
Removal of the Boc group under acidic conditions then gives primary
amine LXIII. This primary amine can then be functionalized by
analogy to the chemistry given in Scheme 13. Compound LXI can also
be alkylated as described above in Scheme 12, and then carried through
the remaining sequence given in Scheme 15.
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scHEIVIE 1s
R
Ry R /'/ Y
Rz\ ~% Rx 1 ) NaH, THF z~ ~ Rx
2) Bra
CN ~ CN LXV
LXIV
RY 1 ) RNH2, NaBH3CN
DIBAL-H Rz~~/~ Rx mol, sieves
2) ArS02Cl, pyr
CHO RY
/, Ry LXVI Rz ~~~ Rx
Rz~ // Rx
f / 1 ) 9-BBN, THF / R
N, , r 2) NaOH, H202 H4 N,S,Ar
A
O O
O O LXVIII
LXVI I
R ~ / j Rx R2 NH
Ph3P-Br2 ~ / n
R R3
CH3CN Br N, ~Ar
DIEA, CH3CN, 0
~~ ~O
R O
Y
Rz~ ~j Rx
R2 '~' R A LXIX
~N N, S, r
R3 O~ ~O
A method of preparing a backbone with an alternate
spacing from the one described above is given in Scheme 16.
Deprotonation of a suitable phenylacetonitrile derivative LXIV with
sodium hydride followed by addition of allyl bromide provides the allyl
nitrile LXV. Reduction to the corresponding aldehyde LXVI is carried
out with diisobutylaluminum hydride in THF. Reductive amination
with a primary amine followed by sulfonylation then provides
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sulfonamide LXVII. Selective hydroboration of the terminal position of
the olefin, for example with 9-BBN, followed by oxidation with basic
hydrogen peroxide, then gives primary alcohol LXVIII. Conversion of
this alcohol to the corresponding bromide with triphenylphosphine-
dibromide complex followed by alkylation with a cyclic secondary amine
then gives the desired product LXIX.
SCHEME 1?
Rz ~~Ry R R ~/Ry R
/ x mCPBA z\ / X RNH2
/ /
LXX LXX I
O
Rz\ ~~ RX Rz\ /~ Rx
ArS02Cl
/ /
H DIEA, THF R
HO N~R HO N,S-Ar
O ~O
LXXI I LXXI I I
Ry
1 ) MeS02Cl, Et3N Rz I ~j RX
EtOAc
R3 R
2) R2 "' N,S,Ar
R3 NH R m O O
LXXIV
Another backbone variation is prepared according to
Scheme 17. Epoxidation of a suitably substituted styrene derivative LXX
with an oxidizing agent such as mCPBA provides the epoxide LXXI
which is converted to the aminoalcohol LXXII by treatment with a
primary amine RNH2. Treatment of T_XXTI with an acylating agent or a
sulfonylating agent under mild conditions (as shown for the conversion
to compound LXXIII) produces the corresponding neutral alcohol.
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Activation of the hydroxy group with, for example, methanesulfonyl
chloride, followed by treatment with a secondary cyclic amine yields the
aminosulfonamide LXXIV.
~,CI-~EME 18
Ry Ry
Rz~ /j Rx RZ\~/j Rx
/ O Ac20
toluene LXXVI
HO OH
LXXV R
y O O O
Rz\~/% Rx
RNH2 O I / O LiAIH4
THF
HO N-R THF
Ry LXXVII H Ry
RZ~ / j Rx RZ\~/j Rx
/ ArS02Cl /
O~ ~~
O
DIEA HO N~S~Ar
HO H~R R
LXXVI I I LXXIX
R
1 ) MsCI, Et3N Rz~ / j Rx
2) R2 ' NH R2 "' ~g\O
R3 n ~N NR Ar
Na2C03, Me2CHCN R3 LXXX
Another backbone variation is prepared according to
Scheme 18. Treatment of 3-arylpentane-1,5-dioic acid LXXV with acetic
anhydride in toluene provides anhydride LXXVI. Addition of an amine
RNHZ yields amidoacid LXXVII, which can be reduced with a strong
reducing agent like lithium aluminum hydride to give aminoalcohol
LXXVIII. Selective sulfonylation on nitrogen can be accomplished by
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treatment with a suitable arylsulfonyl chloride, to produce sulfonamide
LXXI~~. Activation of the hydroxy group with methanesulfonyl chloride
in the presence of triethylamine followed by addition of a cyclic
secondary amine in isobutyronitrile in the presence of sodium carbonate
at elevated temperatures then provides the desired sulfonamidoamine
LXXX.
SCHEME 19
RZ~ ~j Rx R ~~j Rx
LiAIH4
HO OH HO OH
O O LXXXI R LXXXII
v
Rzi ~jRx
NaH, t-BuSi(Me)2C1 / ArS02NHR
THF TBDMSO OH DEAD, Ph3P, THF
LXXX I I I R
Y
~ R
1) Bu4NF, THF R~~~ x
R
,Ar 2) MeS02Cl, EtOAc Ms0 N,S,Ar
,, ,, ,.
LXXXIV O O LXXXV O O
R
R2 NH Rz i ~j Rx
R3 ~ R2 ~ R LXXXVI
'Ym
Na2C03, Me2CHCN N N.S,Ar
R3 '' ''
O O
Another backbone variation is prepared according to
Scheme 19. Reduction of 2-arylmalonic acid derivative LXXXI with
lithium aluminum hydride provides diol LXXXII, which upon
treatment with sodium hydride and t-butyldimethylsilyl chloride in THF
produces selectively the monosilyl ether LXXXIII. Exposure of this
compound to an N-substituted arylsulfonamide in the presence of DEAD
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and triphenylphosphine in THF provides the sulfonamide LXXXIV.
Removal of the silyl group, for example with tetrabutylammonium
fluoride in THF, followed by treatment with methanesulfonyl chloride in
ethyl acetate, yields the mesylate LXX~~V. Treatment of this mesylate
with a cyclic secondary amine then provides the desired product
LXXXVI .
SCHEME 20
RNH2, MeOH ArS02Cl, Et2NEt
O
NaBH3CN THF
3 H
LXXXViI
\
/
CH
LXXXVI I I \ LXXXIX
R2 NH I / R
R3 ~ R2 m N~S ~ Ar
N
R3 ~ CH3
NaBH3CN, THF
XC
Another backbone variation is prepared according to
Scheme 20. Reductive alkylation of the commercially available aldehyde
LXXXVII with a suitable primary amine followed by sulfonylation
provides sulfonamide LXXXVIII. Treatment of this olefin with osmium
tetroxide followed by sodium periodate provides aldehyde LXXXIX.
Reductive amination with a cyclic secondary amine then provides the
target compound XC.
/ R I /
1 ) Os04, NMMO, tBuOH
N,S,Ar
/ CH3 O~ ~O 2) Na104, THF/H20 O ~ CH3 oSO r
In some cases the order of carrying out the foregoing
reaction schemes may be varied to facilitate the reaction or to avoid
unwanted reaction products.
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The following examples are provided for the purpose of
further illustration only and are not intended to be limitations on the
disclosed invention.
EXAMPLE 1
(R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide
Step A: (R,S)-N-(2-Phenylpent-4-en-I-yl)-N-methylbenzene-
sulfonamide
A solution of 2.0 g (11.4 mmol) of (R,S)-4-phenyl-5-
methylamino-1-pentene (prepared as described by J. Hale et ad.,
Bioorganic acnd Medicinal Chemistry Letters, 1893, 3, 319-322) and 6.0
mL (34 mmol) of diisopropylethylamine (DIPEA) in 25 mL of methylene
chloride was cooled in an ice/ethanol bath. To this was added 2.2 mL (17
mmol) of benzenesulfonyl chloride and after 5 min the ice bath was
removed. After stirring for I6 h, the reaction mixture was diluted with
methylene chloride and washed with water containing 20 mL of 2 N HCl.
The aqueous layer was reextracted with methylene chloride and the
organic layers were washed with brine, combined, dried over sodium
sulfate and concentrated in vacuo. The residue was purified by flash
column chromatography (FCC) eluting with 5% ethyl acetate/hexanes to
afford 3.2 g of the title compound.
1H NMR (400 MHz, CDCl3): 8 2.3$ (p, J = 8, 1H), 2.55 (m, 1H), 2.57 (s,
3H), 2.94 (m, 2H), 3.41 (m, 1H), 4.95 (m, 2H), 5.62 (m, 1H), 7.1-7.3 (m, 5H),
7.45 {m, 2H), 7.52 (m, 1H), 7.69 (dd, J = 1.5 and 6, 2H).
Step B: (R,S)-N-(2-Phenyl-4-oxobut-1-yl)-N-methylbenzene-
sulfonamide
To a solution of 1.0 g (3.2 mmol) of (R,S)-N-(2-phenylpent-4-
en-1-yl)-N-methylbenzenesulfonamide from Step A in 7 mL of acetone,
3.5 mL of t-butanol and 3.5 mL of water was added 413 mg (3.5 mmol) of
N-methylmorpholine-N-oxide followed by 0.14 mL of 4% osmium
tetroxide in water. The reaction was stirred at rt for 16 h and was then
quenched with aqueous sodium bisulfite and concentrated in vacuo. The
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residue was diluted with water and extracted twice with ether. The
ether layers were each washed with brine, combined, dried over sodium
sulfate and concentrated in vacuo. The residue was purified by FCC
eluting with 5% methanol in methylene chloride to afford the diol
intermediate. The above product was taken up in 10 mL of THF and 755
mg (3.5 mmole) of sodium periodate in 3 mL of water was added. The
mixture was stirred at rt for 3 h, poured into water and extracted twice
with ether. The ether layers were each washed with brine, combined,
dried over sodium sulfate and concentrated in vacuo to afford 940 mg of
the title compound. 1H NMR (400 MHz, CDC13): b 2.62 (s, 3H), 2.75-2.9
(m, 2H), 3.14 (dd, J = 6 and 17, 1H), 3.39 (m, 1H), 3.55 (m, 1H), 7.15-7.35 (2
m, 5H), 7.46 (m, 2H), 7.53 (m, 1H), 7.70 (dd, J = 1.5 and 7, 2H), 9.78 (d, J =
1.2, 1H).
Step C: (R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide hydrochloride salt
To a solution of 0.020 g (0.063 mmol) of (R,S)-N-(2-phenyl-4-
oxobut-1-yl)-N-methylbenzenesulfonamide from Step B in 1.2 mL of THF
were added 31 mg {0.19 mmol) of 4-phenylpiperidine, 3 ~ molecular
sieves and 0.011 mL of acetic acid. After stirring the mixture for 20 min,
27 mg (0.126 mmol) of sodium triacetoxy-borohydride was added. After
16 h the mixture was filtered through a pad of celite and the reaction
flask and the pad were rinsed with water and ethyl acetate. The layers
were separated and the aqueous layer was extracted twice more with
ethyl acetate. The organic layers were each washed with brine,
combined, dried over sodium sulfate and concentrated in vacuo. The
residue was purified by prep TLC using 5% methanol in methylene
chloride to isolate 25 mg of the free amine of the title compound as an oil.
1H NMR (400 MHz, CDC13): 8 1.80 (m, 5H), 1.9-2.3 {3 m, 5H), 2.4-2.5 (m,
1H), 2.59 (s, 3H), 2.9-3.1 (m, 4H), 3.35-3.45 (m, 1H), 7.1-?.3 (m, lOH), 7.4-
7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.70 (dd, J = 1.5 and 7.0, 2H). Mass spectrum
(NH3/CI): m/z 463 (M+1, 100%). The hydrochloride salt of the title
compound was prepared by dissolving the above oil in ether/methanol
and addition of 2-3 equivalents of 1 M ethereal HCI. Evaporation of the
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volatiles and drying in vacuo afforded 26 mg of the title salt as a white
solid after trituration with ether.
The following Examples were prepared following the
procedure described in Example 1, Step C but using the appropriate
substituted amine in the reductive amination.
EXAMPLE 2
(R,S)-N-[2-Phenyl-4-(4-benzylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 477 (M+1, 100%).
EXAMPLE 3
(R, S )-N- [2-Phenyl-4-(4-dimethylami nocarbonyl-4-phenylpiperidin-1-
yl~lbut-1-vll-N-methylbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 534 (M+1, 100%).).
EXAMPLE 4
(R,S)-N-[2-Phenyl-4-(4-aminocarbonyl-4-phenylpiperidin-1-yl)but-1-yl]-
N-methylbenzenesuifonamide
Mass spectrum (NH3/CI): m/z 50fi (M+1), 249 (100%).
EXAMPLE 5
(R,S)-N-[2-Phenyl-4-(4-hydroxymethyl-4-phenylpiperidin-1-yl)but-1-yl]-
N-meth~lbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 493 (M+1, 100%).
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EXAMPLE 6
(R, S )-N- [2-Phenyl-4-(4-methoxycarbonyl-4-phe nylpiperidin-1-yl)but-1-
yll-N-meth~benzenesulfonamide
Mass spectrum (NH3/CI): m/z 521 (M+1, 100%).
EXAMPLE 7
(R,S)-N-[2-Phenyl-4-(piperidin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide
Mass spectrum (NH3/CI): m/z 387 (M+1, 100%).
EXAMPLE 8
(R, S )-N- [2-Phenyl-4-(4-pentylaminocarbonylpiperidin-1-yl )but-1-yl] -N-
methYlbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 500 (M+1, 100%).
EXAMPLE 9
(R,S)-N-[2-Phenyl-4-(4-isopropylaminocarbonylpiperidin-1-yl)but-1-yl]-
N-met vlbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 472 (M+1, 100%).
EXAMPLE 10
35
(R,S)-N-[2-Phenyl-4-(4-methylaminocarbonylmethylene-4-
phenylpi~eridin-1-~~l)but-1-yll-N-meth~lbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 534 (M+1, 100%).
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CA 02296314 2000-O1-13
WO 99!04794 PCT/US98l14990
EXAMPLE 11
(R,S)-N-[2-Phenyl-4-(4-methylaminocarbonyl(methylamino)methylene-4-
phenvlnineridin 1 vl)but-1=yll-N-methvlbenzenesulfonamide
Mass spectrum (ESI): m/z 563 (M+1, 100%).
EXAMPLE 12
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminomethylene-4-
~henvluineridin 1 yl)but-1-vll-N-methylbenzenesulfonamide
Mass spectrum (ESI): m/z 550 (M+1, 100%).
EXAMPLE 13
(R,S)-N-[2-Phenyl-4-(4-methylaminocarbonylaminomethylene-4-
phen~~nineridin-1-xl)but-1-yll-N-methylbenzenesulfonamide
Mass spectrum (ESI): m/z 549 (M+1, 100%).
EXAMPLE 14
(R,S)-N-[2-Phenyl-4-(4-(2-methyl)phenylpiperidin-1-yl)but-1-yl]-N-
~~eth,~enzenesulfonamide
Mass spectrum (NH3/CI): m/z 477 (M+1, 100%).
EXAMPLE 15
35
(R,S)-N-[2-Phenyl-4-(4-morpholinocarbonylpiperidin-1-yl)but-1-yl]-N-
methvlbenz~nesulfonamide
Mass spectrum (NH3/CI): m/z 500 (M+1, 100%).
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The following Examples were prepared following the
procedure described in Example 1, Step A-C but starting with (R,S)-4-(2-
chlorophenyl), (3,5-dichlorophenyl), (2-thienyl), (3-thienyl), or
(cyclohexyl)-5-methylamino-1-pentene (prepared as described by J. Hale
et al., Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and
using the appropriate substituted piperidine in the reductive amination.
EXAMPLE 16
(R,S)-N-[2-(2-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide
Mass spectrum (NH3/CI): m/z 497 (M+1, 100%).
EXAMPLE 17
(R,S)-N- [2-(2-Thienyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenes~lfonamide
Mass spectrum (ESI): m/z 469 (M+1, 100%).
EXAMPLE 18
(R,S)-N-[2-(3-Thienyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
meth,~~lbenzenesulfonamide
Mass spectrum (ESI): m/z 469 (M+1, 100%).
EXAMPLE 19
(R,S)-N-[2-(3-Thienyl)-4-(4-benzylpiperidin-1-yl)but-I-yl]-N-
meth~benzenesulfonamide
Mass spectrum (ESI): m/z 483 (M+1, 100%).
EXAMPLE 20
(R,S)-N-[2-Cyclohexyl-4-(4-phenylpiperidin-1-yI)but-1-yl]-N-
rr~Pthylbenzenes~lfonamide
Mass spectrum (NH3/CI): m/z 469 (M+1, 100%).
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EXAMPLE 21
(R,S)-N-[2-(3,5-Dichlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 531 (M+1, 100%).
EXAMPLE 22
(R,S)-N-[2-(3-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-ylJ-N-
methylbenzenesulfonamide
Step A: N-[4-(4-Phenylpiperidin-1-yl)but-2-yn-1-yl]-N-
methylbenzenesulfonamide
To a suspension of triphenylphosphine dibromide at 0 °C
(prepared by addition of bromine to 53.5 g (210 mmol) of
triphenylphosphine in 200 mL of acetonitrile at 0 °C) was added 8.0 g
(93
mmol) of 2-butyne-1,4-diol. The reaction was stirred for 10 min, the ice
bath was removed, the mixture was stirred for 2 hr, and then
concentrated in vacuo. The residue was triturated with ether and
filtered to remove the precipitated triphenylphosphine oxide. The filtrate
was washed with water and brine, dried over sodium sulfate and
concentrated. The residue of crude dibromide was taken up in 50 mL of
DMF under nitrogen and cooled in an ice bath.
A solution of the sodium salt of N-methylbenzene-
sulfonamide in 50 mL of DMF was prepared at 0 °C under nitrogen by
portionwise addition of 3.2 g (80 mmol) of 60% sodium hydride over 0.5 h
and then stirred with cooling for 0.5 h. This salt solution was added via
canula over 15 min with cooling to the above dibromide solution. After
0.5 h, 18.0 g (110 mmol) of 4-phenylpiperidine was added and the reaction
was stirred a further 2 h at rt. The reaction was diluted with water and
extracted three times with ether. The ether layers were each washed
with a portion of brine, dried over sodium sulfate, combined and
concentrated in vacuo. The residue was purified by FCC eluting with 30
to 50% ethyl acetate/hexanes to afford 11.3 g of title compound.
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1H NMR (400 MHz, CDC13): b 1.65-1.85 (m, 4H), 2.07 (dt, J = 3 and 8, 2H),
2.4 (m, 1H), 2.78 (br d, J = 11, 2H), 2.84 (s, 3H), 3.09 (t, J = 2, 2H), 4.07
(t, J
= 2, 2H), 7.1-7.3 (2 m, 5H), 7.45-7.6 (m, 3H), 7.82 (dd, J = 1.5 and 7, 2H).
Mass spectrum (NH3-CI): m/z 383 (M+1, 100%).
Step B: N-[4-(4-Phenylpiperidin-1-yl)-2-tributylstannylbut-2-en-1-yl]-
N-methylbenzenesulfonamide and N-[4-(4-Phenylpiperidin-
1-yl)-3-tributylstannylbut-2-en-1-yl]-N-methylbenzene-
aulfonamid~
To a solution of 11.0 g (29 mmol) of N-[4-(4-phenyl-piperidin-
1-yl)but-2-yn-1-yl]-N-methylbenzenesulfonamide from Step A in 75 mL of
THF under nitrogen was added 400 mg (0.58 mmol) of
dichlorobis(triphenylphosphine)palladium (II) and then 13.7 mL (51
mmol) of tributylstannane was added drapwise via syringe over 0.5 h.
After a further 0.5 h, the dark reaction (from precipitated palladium)
was concentrated in vacuo. The residue was purified by FCC eluting
with 20% ethyl acetate/hexanes to give 2.5 g of the higher R f 3-stannyl
title product. Elution with 30-40% ethyl acetate/hexanes afforded 10.8 g
of the lower Rf 2-stannyl title compound. Further elution with 50-70%
ethyl acetate/hexanes afforded 3.5 g of recovered starting material.
higher Rf product:
1H NMR (400 MHz, CDC13): 8 0.8-0.9 (m, 6H), 0.87 (t, J = 7, 9H), 1.25-1.35
(m, 6H), 1.35-1.5 (m, 6H), 1.6-1.85 (2 m, 4H), 1.94 (dt, J = 3 and 8, 2H),
2.43
(m, 1H), 2.69 (s, 3H), 3.01 (br t, JH_Sn = 25, 2H), 3.78 (d, J = 6, 2H), 5.44
(br
ttt, J = 1.5 and fi, JH~n = 34, 1H), 7.1-7.3 (2 m, 5H), 7.5-7.65 (m, 3H), 7.77
(dd, J = 1.5 and 7.0, 2H).
Lower R f product:
1H NMR (400 MHz, CDC13): S 0.87 (t, J = 7, 9H), 0.95-1.05 (m, 6H), 1.25
1.4 (m, 6H), 1.45-1.6 (m, 6H), 1.7-1.85 (m, 4H), 1.92 (dt, J = 3 and 8, 2H),
2.42 (m, 1H), 2.48 (s, 3H), 2.96 (m, 2H), 3.74 (br t, JH_Sn = 23, 2H), 5.88
(br
tt, J = 6, JH-sn = 32,1H), 7.1-7.3 (2 m, 5H), 7.5-7.65 (m, 3H),, 7.77 (dd, J =
1.5
and 7.0, 2H).
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Step C: N-[2-(3-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-2-en-
yll-N-methvlbenzenesulfonamide
To 250 mg (0.37 mmol) of N-[4-(4-phenylpiperidin-1-yl)-2-
tributylstannylbut-2-en-1-yl]-N-methylbenzenesulfonamide from Step B
in 0.4 mL of N-methylpyrrolidinone under argon was added 77 mg (0.55
mmol) of potassium carbonate, 8 mg (catalytic) of dichlorobis(triphenyl
phosphine)palladium {II) and 0.067 mL (0.55 mmol) of 3-methylbromo
benzene. The mixture was heated at 70 °C for 24 h, cooled, treated with
aqueous sodium fluoride for 10 min, and partitioned between water and
ether. The water layer was reextracted with ether and each organic
layer was washed with brine, dried over sodium sulfate, combined and
concentrated in vacuo. The residue was purified by FCC eluting with 25-
50% ethyl acetate/hexanes to give 57 mg of product contaminated with
stannane biproduct. The product was further purified by prep TLC (50%
ethyl acetate/hexanes) to afford 53 mg of title compound.
1H NMR (400 MHz, CDCl3): 8 1.7-1.9 (m, 4H), 2.0-2.2 (m, 2H), 2.32 (s,
3H), 2.6-2.6 (m, 1H), 2.50 (s, 3H), 3.05 {m, 2H), 3.20 (m, 2H), 4.12 (s, 2H),
6.11 (br t, J = 7, 1H), 7.07 (m, 1H), 7.15-7.35 (m, 8H), 7.52 (m, 2H), 7.60
(m,
1H), 7.74 (dd, J = 1.5 and 7, 2H).
Step D: (R,S)-N-[4-(4-Phenylpiperidin-1-yl)-2-(3-methylphenyl)-but-1-
y11-N-methvlbenzenesulfonamide
A mixture of 46 mg (0.097 mmol) of N-[4-(4-phenylpiperidin-
1-yl)-2-(3-methylphenyl)but-2-en-I-yl]-N-methylbenzenesulfonamide
from Step C, 12 mg of 20% palladium hydroxide/C (50% water), and 2
drops of acetic acid in 3 mL of methanol was hydrogenated at 40 psi for
24 h. The catalyst was removed by filtration and the filtrate concentrated
in vacuo. The residue was purified by prep TLC (50% ethyl
acetate/hexanes) to afford 20 mg of title compound. A major biproduct
was cleavage of the 4-phenylpiperidine to give N-[2-(3-methylphenyl)but-
I-yl]-N-methylbenzenesulfonamide.
1H NMR (400 MHz, CDC13): b 1.8-2.0 (m, 5H), 2.1-2.3 (m, 3H), 2.32 (s,
3H), 2.38 (m, 1H), 2.51 (m, 2H), 2.61 (s, 3H), 2.88 (m, 2H), 3.21 (m, 2H),
3.32 (dt, J = 3 and 9, 1H), 6.96 (br s, 2H), ?.05 (d, J = 8, 1H), 7.15-7.3 (m,
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6H), 7.46 (m, 2H), 7.54 (m, 1H), 7.70 (dd, J = 1.5 and 7, 2H). Mass
spectrum (NH3-CI): m/z 477 (M+1, 100%).
The following Examples were prepared following the
procedure described in Example 22, Steps C-D but using the appropriate
substituted bromobenzene in Step C.
EXAMPLE 23
(R,S)-N-[2-(3-Ethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 491 (M+l, 100%).
EXAMPLE 24
(R,S)-N-[2-(3-Carboethoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 535 (M+1, 100%).
EXAMPLE 25
(R,S)-N-[2-(3-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide hvdrochloride salt
Mass spectrum (NH3-CI): m/z 481 (M+l, 100%).
EXAMPLE 26
(R,S)-N-[2-(3-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide hvdrochloride salt
Mass spectrum (NH3-CI): m/z 493 (M+1, 100%).
EXAMPLE 27
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(R,S)-N-[2-(3,4-Difluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 499 (M+1, I00%).
EXAMPLE 28
(R,S)-N-(2-(3-Biphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
meth~ilbenzenesulfonamide vdrochloride salt
Mass spectrum (NH3-CI): m/z 539 (M+1, 100%).
EXAMPLE 29
(R,S)-N-[2-(3-Pyridyl)-4-(4-phenylpiperidin-1-yI)but-1-yl]-N-
m~thylbenzenesulfonamide hydrochloride salt
Mass spectrum {NH3-CI): m/z 464 (M+1, I00%).
EXAMPLE 30
(R,S)-N-(2-(Naphthalen-2-yl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 513 (M+1, 100%).
EXAMPLE 31
(R,S)-N-[2-(4-Methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N
methylbenzenesulfonamide hydrochloride salt ___
Mass spectrum (NH3-CI): m/z 553 (M+1, 100%).
EXAMPLE 32
(R,S)-N-(2-(2-Pyridyl)-4-{4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 464 (M+1, 100%).
EXAMPLE 33
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(R,S)-N-[2-(3-Fluoro-4-methylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-
yll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 495 (M+1, 100%).
EXAMPLE 34
(R,S)-N-[2-(3,4-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl)-
N-meth~ilbenzenesulfonamide hydrochloride salt _
Mass spectrum (NH3-CI): m/z 491 (M+1, 100%).
EXAMPLE 35
(R,S)-N-[2-(3,5-Dimethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-
N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 491 (M+1, 100%).
EXAMPLE 36
(R,S)-N-[2-(4-Methoxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
~nethvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 493 (M+1, 100%).
EXAMPLE 37
(R,S)-N-[2-(3-Trifluoromethylphenyl)-4-(4-phenylpiperidin-1-yl)but-1-
vll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 531 (M+1, 100%).
EXAMPLE 38
(R,S)-N-[2-(3-Methyl-4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-
yll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 495 (M+1, 100%).
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EXAMPLE 39
(S)-N-[2-(3-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide hydrochloride salt
Step A: (S)-N-[2-(3-Chlorophenyl)pent-4-en-1-yl]-N-
methylbenzenesulfonamide
A solution of 2.0 g (9.53 mmol) of (S)-4-(3-chorophenyl)-5-
methylamino-1-pentene (prepared as described by J. Hale et al.,
Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) and 5.0
mL (28.6 mmol) of diisopropylethylamine (DIPEA) in 20 mL of methylene
chloride was cooled in an ice%thanol bath. To this was added 1.46 mL
(11.4 mmol) of benzenesulfonyl chloride and after 5 min the ice bath was
removed. After stirring for 16 h, the reaction mixture was diluted with
methylene chloride and washed with water containing 20 mL of 2 N HCI.
The aqueous layer was reextracted with methylene chloride and the
organic layers were washed with brine, combined, dried over sodium
sulfate and concentrated in vacuo. The residue was purified by flash
column chromatography (FCC) eluting with 15% ethyl acetate/hexanes
to afford 3.44 g of the title compound.
1H NMR (400 MHz, CDC13): 8 2.38 (p, J = 8, 1H), 2.55 (m, 1H), 2.59 (s,
3H), 2.94 (m, 2H), 3.37 (m, 1H), 4.95 (m, 2H), 5.60 (m, 1H), 7.05-7.3 (m,
4H), 7.46 (m, 2H), 7.55 (m, 1H), 7.69 (dd, J = 1.5 and 6, 2H).
Step B: (S)-N-[2-(3-Chlorophenyl)-4-oxo-but-1-yl]-N-methylbenzene-
sulfonamide
To a solution of 3.33 g (9.53 mmol) of (S)-N-[2-(3-
chlorophenyl)pent-4-en-1-yl]-N-methylbenzenesulfonamide from Step A
in 16 mL of acetone, 8 mL of t-butanol and 8 mL of water was added 1.22
g (10.4 mmol) of N-methylmorpholine-N-oxide followed by 0.50 mL of 4%
osmium tetroxide in water. The reaction was stirred at rt for 16 h and
was then quenched with aqueous sodium sulfite and concentrated in
vacuo after 20 min. The residue was diluted with water and extracted
twice with ethyl acetate. The organic layers were each washed with
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brine, combined, dried over sodium sulfate and concentrated in vacuo to
afford the crude diol intermediate.
The above product was taken up in 30 mL of THF and 2.45 g
(11.4 mmole) of sodium periodate in 10 mL of water was added. The
mixture was stirred at rt for 2 h, poured into water and extracted twice
with ether. The ether layers were each washed with brine, combined,
dried over sodium sulfate and concentrated in vacuo. The residue was
purified by FCC (20% ethyl acetate/hexanes) to afford 2.57 g of the title
compound. 1H NMR (400 MHz, CDC13): 8 2.63 (s, 3H), 2.75-2.9 (m, 2H),
3.14 (dd, J = 6 and 16, 1H), 3.35 (dd, J = 10 and 14, 1H), 3.55 (m, 1H), 7.15-
7.35 (2 m, 4H), 7.46 (m, 2H), 7.53 (m, 1H), 7.70 (dd, J = 1.5 and 7, 2H), 9.78
(s, 1H).
Step C: (S)-N-[2-(3-Chlorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-
N-methylbenzenesulfonamide hvdrochloride salt
To a solution of 20 mg (0.057 mmol) of (S)-N-[2-(3-
chlorophenyl)-4-oxo-but-1-yl]-N-methylbenzenesulfonamide from Step B
in 1.0 mL of THF were added 27 mg (0.17 mmol) of 4-phenylpiperidine, 3
E~ molecular sieves and 0.010 mL of acetic acid. After stirring the
mixture for 20 min, 24 mg (0.113 mmol) of sodium triacetoxyborohydride
was added. After 16 h the reaction was quenched with aqueous sodium
bicarbonate, the mixture was filtered through a pad of celite and the
reaction flask and the pad were rinsed with water and ethyl acetate. The
layers were separated and the aqueous layer was extracted twice more
with ethyl acetate. The organic layers were each washed with brine,
combined, dried aver sodium sulfate and concentrated in vacuo. The
residue was purified by prep TLC using 2% triethylamine in 5%
methanol/ethyl acetate to isolate 20 mg of the free amine of the title
compound as an oil.
1H NMR (400 MHz, CDC13): 8 1.80 (m, 5H), 1.9-2.3 (3 m, 5H), 2.4-2.5 (m,
1H), 2.61 (s, 3H), 2.9-3.1 (m, 4H), 3.35-3.45 (m, 1H), 7.1-7.3 (m, 9H), 7.4-
7.5
(m, 2H), 7.5-7.6 (m, 1H), 7.70 (dd, J = 1.5 and 7.0, 2H). Mass spectrum
(ESI): m/z 497 (M+1, 100%).
The hydrochloride salt of the title compound was prepared
by dissolving the above oil in ether/methanol and addition of 2-3
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equivalents of 1 M ethereal HCI. Evaporation of the volatiles and drying
in vacuo afforded 21 mg of the title salt as a white solid after trituration
with ether.
The following Examples were prepared following the
procedure described in Example 39, Step C but using the appropriate
substituted piperidine in the reductive amination.
EXAMPLE 40
(S)-N-[4-(4-Benzylpiperidin-1-yl)-2-(3-chlorophenyl)but-1-yl]-N-
methylbenzenesuifonamide hydrochloride salt
Mass spectrum (ESI): m/z 511 (M+1, 100%).
EXAMPLE 41
(S)-N-[4-(4-(3-Phenylprop-1-yl)piperidin-1-yl)-2-(3-chlorophenyl)but-
1-yll-N-methvlbenzen~sul~'o_~~a_raide hydrochloride salt
Mass spectrum (ESI): m/z 539 (M+1, 100%).
EXAMPLE 42
(S)-N-[2-(3-Chlorophenyl)-4-(4-t-butylpiperidin-1-yl)but-1-yl]-N-
~nethvlbenzenesulfonamide hvdroc ~loride salt
Mass spectrum (NH3-CI): m/z 477 (M+1, 100%).
EXAMPLE 43
(S)-N-[2-(3-Chlorophenyl)-4-(4-(cas-octahydro-2H-benzimidazol-2-on-1-
yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride
salt
Mass spectrum (ESI): m/z 559 (M+1, 100%).
EXAMPLE 44
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(S)-N-[2-(3-Chlorophenyl)-4-(4-(1,2,3,4-tetrahydro-2H-quinazolin-2-on-1-
yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride
salt
Mass spectrum (ESI): m/z 567 (M+1, 100%).
EXAMPLE 45
(S)-N-[2-(3-Chlorophenyl)-4-(3-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 497 (M+1, 100%).
EXAMPLE 46
(S)-N-(2-(3-Chlorophenyl)-4-(4-hydroxy-4-phenylpiperidin-I-yl)but-I-yl]-
N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 513 (M+1, 100%).
EXAMPLE 47
(S)-N-[2-(3-Chlorophenyl)-4-(4-(2,3-dihydro-2H-benzimidazol-2-on-I-
yl)piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride
salt
Mass spectrum (NH3-CI): m/z 553 (M+1, 100%).
EXAMPLE 48
( S )-N- (2-( 3-Chlorophenyl )-4- [4,4-diphenylpiperidin-1-yl] -butyl }-N-
xnethylbenzenesulfonamide l~,vdrochloride salt
Mass spectrum (NH3-CI): m/z 573 (M+1, 100%).
EXAMPLE 49
(S)-N-[4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-2-(3-chlorophenyl)-
but-1-yll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 547 (M+1, 100%).
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EXAMPLE 50
(S)-N-(4-(4-Acetyl-4-phenylpiperidin-1-yl)-2-{3-chlorophenyl)but-1-yl]-N-
meth3rlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 539 (M+1, 100%).
EXAMPLE 51
(S)-N-[4-[4-(4-Chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl]-2-
{3-chlorophenyl)but-1-yl]-N-methylbenzenesulfonamide hydrochloride
salt
Mass spectrum (NH3-CI): m/z 614 (M+1, 100%).
EXAMPLE 52
(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-methoxycarbonylphenyl)piperidin-1-yl]-
~3~t-1-yll-N-met~ylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 555 (M+1, 100%).
EXAMPLE 53
( S )-N- [2-( 3-Chlorophenyl)-4-[4-hydroxy-4-( 3-trifluoromethyl )phenyl-piper-
Mass spectrum (NH3-CI): m/z 581 (M+1, 100%).
EXAMPLE 54
(S)-N-[2-(3-Chlorophenyl)-4-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-
vllbut-1- ly 1-hj-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 531 (M+1, 100%).
EXAMPLE 55
(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piper-
idin-1-~~llbut-1-yll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 568 (M+1, 100%).
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EXAMPLE 56
(S)-N-[2-(3-Chlorophenyl)-4-[4-(2-oxo-3H-benzo[d] (1,4]oxazin-1-yl)piper-
idin-1-yllbut-hull-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NHS-CI): m/z 568 (M+1, 100%).
EXAMPLE 57
(S)-N-[4-(4-Benzoylpiperidin-1-yl)-2-(3-chlorophenyl)but-1-yl]-N-
methylbenzenesulfonamide hvdroch~oride salt
Mass spectrum (NH3-CI): m/z 525 (M+1, 100%).
EXAMPLE 58
(S)-N-(2-(3-Chlorophenyl)-4-[4-(2-methoxy)phenylpiperidin-1-yl]but-1-
yll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 527 (M+1, 100%).
EXAMPLE 59
(S)-N-(2-(3-Chlorophenyl)-4-(4-piperidin-1-ylpiperidin-1-yl)but-1-yl]-N-
methylbenze~esulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 504 (M+1, 100%).
The following Examples were prepared using the procedure
described in Example 39 but utilizing the appropriate substituted 4-
phenyl pentene derivative (prepared as described by J. Hale et al.,
Bioorganic and Medicinal Chemistry Letters, 1993, 3, 319-322) as the
starting material.
EXAMPLE 60
(S)-N-[2-(3,4-Methylenedioxyphenyl)-4-(4-phenylpiperidin-1-yl)but-1-
yll-N-met~ylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 507 (M+1, 100%).
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EXAMPLE 61
(S)-N-[2-(4-Fluorophenyl)-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
met ~Tlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3-CI): m/z 481 (M+1, 100%).
EXAMPLE 62
(S)-N-[2-(3,4-Dichlorophenyl)-4-{4-phenylpiperidin-1-yl)-but-1-yl]-N-
ethylbenzenesulfonamide hydrochloride salt
Following essentially the same procedure as described in
Example 39 but utilizing (S)-4-(3,4-dichorophenyl)-5-ethylamino-1-
pentene (prepared as described by J. Hale et al., Bioorganic and
Medicinal Chemistry Letters, 1883, 3, 319-322) as the starting material,
the title compound was prepared.
1H IVMR (400 MHz, CDC13): 8 0.955 (t, J = 8, 3H), 1.5-1.9 (3 m, 5H), 1.9-2.3
(2 m, 5H), 2.4-2.6 (m, 1H), 2.8-3.05 (m, 3H), 3.05-3.2 (m, 3H) 3.44 (dd, J = 8
and 13, 1H), 7.03 (br d, J = 7, 1H), 7.15-7.4 (m, 7H), 7.45 (t, J = 7, 2H),
7.52
(br t, J = 7, 1H), 7.70 (dd, J = 1.5 and 7, 2H).
Mass spectrum (NH3-CI): m/z 545 (M+1, 100%).
EXAMPLE 63
(R,S)-N-[2-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-methylphenyl-
acetamide
The title compound was prepared following the procedure
described in Example 1, Steps A-C but substituting phenylacetyl chloride
in Step A. Mass spectrum (NH3-CI): m/z 441 (M+1, 100%).
EXAMPLE 64
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(R,S)-N-[2-Phenyl-4-[4-acetyl(ethylamino)piperidin-1-yl]but-1-yi)-N-
methvlbenzenesulfonamide
Step A: ~ Ben~lox~carbonvlniDeridin-4- l~~yanate
To a solution of 9.72 g (34.8 mmol) of 1-benzyloxycarbonyl-4-
carboxypiperidine in 100 mL of methylene chloride was added 2 drops of
DMF and then slowly 3.34 mL (38.3 mmol) of oxalyl chloride. The
reaction was stirred at rt for 1 h (gas evolution had stopped) and the
volatiles were removed in vacuo followed by evaporation of a portion of
toluene.
The above residue was taken up in 100 mL of acetone and
slowly added to a solution of 5.66 g (87 mmol) of sodium azide in 25 mL of
water and 25 mL of acetone while stirred in an ice bath. The reaction
was stirred at 0 °C for 1.5 h and then diluted with ice water and
extracted twice with 2x150 mL of toluene. The organic layers were each
washed with a portion of brine, dried over sodium sulfate, combined and
concentrated to about 100 mL in vacuo with a minimum of heating. The
remaining solution was slowly heated to 85 °C for 1.5 h and then
concentrated to dryness in vacuo to afford about 9.5 g of crude title
product which can be used directly in subsequent reactions.
Step B: 1-Benzes c~~"yl-4-t-butox, cy arbo~~ylaminopiperidine
A solution of 3.2 g (12.3 mmol) of (1-benzyloxycarbonyl-
piperidin-4-yl)isocyanate from Step A in 25 mL of DMF was slowly added
to a suspension of CuCl3 in 25 mL of DMF and 12 mL of t-butanol. The
reaction was stirred for 24 h and then diluted with water and extracted
twice with 1:1 ether:ethyl acetate. The organic layers were each washed
with a portion of water and brine, dried over sodium sulfate, combined
and concentrated. The residue was purified by FCC eluting with 20%
ethyl acetate/hexanes to afford 685 mg of title compound. 1H NMR (400
MHz, CDC13): 8 1.26 (m, 2H), 1.42 (s, 9H), 1.90 (br d, J = 12, 2H), 2.90 {br
t,
2H), 3.58 (m, 1H), 4.08 (m, 2H), 4.42 (br s, 1H), 5.09 (s, 2H), 7.33 (m, 5H).
Step C: 1-Benzyloxycarbonyl-4-t-butoxycarbonyl(ethylamino)-
~peridine
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To a solution of 476 mg ( 1.42 mmol) of 1-benzyloxycarbonyl-4-
t-butoxycarbonylaminopiperidine and 0.24 mL (2.8 mmol) of ethyl iodide
in 10 mL of DMF was added 85 mg (2.1 mmol) of 60% sodium hydride in
mineral oil. The reaction was stirred for 16 h and was then poured into
water and extracted three times with ether. The organic layers were
each washed with a portion of water and brine, dried over sodium
sulfate, combined and concentrated. The residue was purified by FCC
eluting with 15% ethyl acetate/hexanes to afford 409 mg of title
compound. 1H NMR (400 MHz, CDC13): b 1.06 (t, J = 7, 3H), 1.44 (s, 9H),
1.5-1.7 (2 m, 4H), 2.78 (m, 2H), 3.1 (m, 2H), 4.10 (m, 1H), 4.25 (m, 2H), 5.10
(s, 2H), 7.33 (m, 5H).
Step D: 4-t-Butoxycarbon, l~vlamino)pineridine
A solution of 400 mg (1.1 mmol) of 1-benzyloxycarbonyl-4-t
butoxycarbonyl(ethylamino)piperidine from Step C in 4 mL of methanol
was hydrogenated with 40 mg of 10% Pd/C under a hydrogen balloon for
16 h. The reaction was filtered and concentrated in vacuo to give the title
compound which was used directly in the next step.
Step E: (R,S)-N-[2-Phenyl-4-[4-t-butoxycarbonyl(ethylamino)-
pigeridin-1;vllbut-1-yll-N-meth, l~zenesulfonamide
Using essentially the same procedure as Example 1, Step C,
235 mg (1.0 mmol) of 4-t-butoxycarbonyl(ethylamino)piperidine from Step
D and 212 mg of {R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-
methylbenzenesulfonamide from Example 1, Step B afforded 360 mg of
title compound. 1H NMR (400 MHz, CDC13): S 1.06 (t, J = 7, 3H), 1.43 (s,
9H), 1.5-2.2 (5 m, lOH), 2.56 (s, 3H), 2.90 (m, 4H), 3.10 (m, 2H), 3.38 (m,
1H), 3.83 (m, 1H), 7.1-7.3 (m, 5H), 7.45 (m, 2H), 7.54 (m, 1H). Mass
spectrum (ESI): m/z 530 (M+I, 100%).
Step F: (R,S)-N-(2-Phenyl-4-(4-(ethylamino)piperidin-1-yl]but-1-yl]-
N-methylbenzenesulfonamide hydrochloride salt
A solution of 10 mmol of HCl in 10 mL of methanol was
prepared by slowly adding 0.70 mL ( 10 mmol) of acetyl chloride with ice
bath cooling. To this was added 251 mg (0.489 mmol) of (R,S)-N-[2-
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phenyl-4-[4-t-butoxycarbonyl(ethylamino)piperidin-1-yl]but-1-yl]-N-
methylbenzenesulfonamide. After stirring at rt for 16 h, the volatiles
were removed in vacuo to give the title compound.
Mass spectrum (ESI): m/z 430 (M+1, 100%).
Step G: (R,S)-N-[2-Phenyl-4-[4-acetyl(ethylamino)piperidin-1-yl]but-
1-yll-N-methylbenzenesulfonamide hydrochloride salt
To a solution of 45 mg (0.089 mmol) of (R,S)-N-[2-phenyl-4-[4-
(ethylamino)piperidin-1-yl]but-1-yl]-N-methylbenzenesulfonamide
hydrochloride salt in 2 mL of methylene chloride at 0 °C was added
0.067
mL (0.38 mmol) of DIPEA and 0.014 mL (0.19 mmol) of acetyl chloride.
The reaction was stirred at rt for 16 h and then was quenched with
aqueous sodium carbonate and extracted three times with methylene
chloride. The organic layers were each washed with a portion of brine,
dried over sodium sulfate, combined and concentrated. The residue was
purified by prep TLC eluting with 10% methanol in methylene chloride
and converted to the hydrochloride salt to afford 40 mg of title compound.
Mass spectrum (ESI): m/z 472 (M+1, 100%).
EXAMPLE 65
(R, S )-N- [2-Phenyl-4- [4-( oxazolidin-2-on-3-yl )piperidin-1-yl] but-1-yl] -
N-
methvlbenzenesulfonamide hydrochloride salt
Step A: 1-Benzylczx;Yc~rhonyl-4-(oxazolidin-2-on-3-~piperidine
To a solution of 0.53 g (2.0 mmol) of (1
benzyloxycarbonylpiperidin-4-yl)isocyanate from Example 64, Step A in
10 mL of methylene chloride was added 690 mg (2.0 mmol) of 2-
chloroethanol and 5 mg {cat) of DMAP. The reaction was stirred under
nitrogen at rt for 24 h and then evaporated to dryness to give the crude 2-
chloroethylcarbamate intermediate.
The above residue was taken up in 10 mL of DMF under
nitrogen and 197 mg {4.93 mmol) of 60% sodium hydride in mineral oil
was added. The reaction was stirred at rt for 1 h and then poured into
water containing 3 mL of 2 N hydrochloric acid and extracted twice with
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ether. The organic layers were each washed with a portion of brine,
dried over sodium sulfate, combined and concentrated. The residue was
purified by FCC eluting with 70% ethyl acetate/hexanes to afford 533 mg
of title compound. 1H NMR (400 MHz, CDC13): b 1.55 (m, 2H), 1.76 (br d,
J = 10, 2H), 2.83 (m, 2H), 3.46 (t, J = 8, 2H), 3.87 (m, 1H), 4.27 (m, 2H),
4.31
(t, J = 8, 2H), 5.10 (s, 2H), 7.35 (m, 5H).
Step B: 4-(Oxazolidin-2-on-3-~~'lneridine
Using essentially the same procedure as in Example 64,
Step D, 525 mg (1.72 mmol) of 1-benzyloxycarbonyl-4-(oxazolidin-2-on-3-
yl)piperidine from Step A was hydrogenated to afford 250 mg of the title
compound.
Step C: (R,S)-N-[2-Phenyl-4-[4-(oxazolidin-2-on-3-yl)piperidin-1-
vllbut-1-yll-N-methvlbenzenesulfonamide hydrochloride salt
Using essentially the same procedure as in Example 1, Step
C, the piperidine derivative from Step B was utilized to reductively
alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to
provide the title compound.
Mass spectrum (ESI): m/z 472 (M+1, 100%).
EXAMPLE 66
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(ethylamino)piperidin-1-yl)but-1-
yll-N-methvlbenzenesulfonamide hydrochloride salt
Step A: 1-Benz~ycarbonyl-4-(methoxycarbonylamino)piperidine
To a solution of 1.0 g (3.9 mmol) of (1-benzyloxycarbonyl-
piperidin-4-yl)isocyanate from Example 64, Step A in 10 mL of methanol
was added 5 mg (cat) of DMAP. The reaction was stirred under nitrogen
at rt for 24 h and then poured into water containing 2 mL of 2 N
hydrochloric acid and was extracted twice with ethyl acetate. The
organic layers were each washed with a portion of brine, dried over
sodium sulfate, combined and concentrated to give 1.4 g of the crude title
compound which can be used directly in subsequent reactions. 1H NMR
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(400 MHz, CDC13): 8 1.32 (m, 2H), 1.92 (br d, J = 10, 4H), 2.91 (v br t, 2H),
3.66 (br s, 3H + 1H), 4.10 (m, 2H), 4.58 (br s, 1H), 5.09 (s, 2H), .7.33 (m,
5H).
Step B: 1-Benzyloxycarbonyl-4-jmethoxycarbonyl(ethylamino)]-
piperidine
To 82 mg (0.28 mmol) of 1-benzyloxycarbonyl-4-
(methoxycarbonylamino)piperidine from Step A and 0.045 mL (0.56
mmol) of ethyl iodide in 4 mL of DMF under nitrogen was added 22 mg
(0.56 mmol) of 60% sodium hydride in mineral oil. The reaction was
stirred at rt for 1 h and was then poured into water containing 1 mL of 2
N hydrochloric acid and extracted twice with ether. The organic layers
were each washed with a portion of brine, dried over sodium sulfate,
combined and concentrated. The residue was purified by FCC eluting
with 50% ethyl acetate/hexanes to afford 87 mg of title compound. 1H
NMR (400 MHz, CDC13): S 1.07 (t, J = 7, 3H), 1.5-1.8 (m, 4H), 2.79 (m, 2H),
3.15 (m, 2H), 3.68 (s, 3H), 4.10 (m, 1H), 4.26 (m, 2H), 5.10 (s, 2H), 7.34 (m,
5H).
Step C: 4-fMethoxycarbonyl(ethylamino)lpiperidine
Using essentially the same procedure as in Example 64,
Step D, 85 mg (0.27 mmol) of 1-benzyloxycarbonyl-4-[methoxycarbonyl-
(ethylamino)] piperidine from Step B was hydrogenated to afford 37 mg of
the title compound.
Step D: (R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(ethylamino)-
piperidin-1-yl)but-1-yl]-N-methylbenzenesulfonamide
hydrochloride salt
Using essentially the same procedure as in Example 1, Step
C, the piperidine derivative from Step C was utilized to reductively
alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to
provide the title compound. Mass spectrum (ESI): m/z 488 (M+1, 100%).
EXAMPLE 67
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(R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonylaminopiperidin-1-yl)but-1-
yll-N-methylbenzenesulfonamide
Step A: 1-Benzyloxycarbonyl-4-(dimethylaminocarbonylamino)-
piperidine
To 0.83 g (3.2 mmol) of (1-benzyloxycarbonylpiperidin-4-
yl)isocyanate from Example 64, Step A in 10 mL was added 16 mL (32
mmol) of 2 M dimethylamine in THF. The reaction was stirred under
nitrogen at rt for 24 h and then poured into water containing 20 mL of 2
N hydrochloric acid and was extracted twice with ethyl acetate. The
organic layers were each washed with a portion of brine, dried over
sodium sulfate, combined and concentrated to give 0.95 g of the crude
title compound which can be used directly in subsequent reactions.
1H NMR (400 MHz, CDC13): 8 1.25 (m, 2H), 1.95 (br d, J = 10, 2H), 2.86 (br
s, 6H + 2H), 3.79 (m, 1H), 4.0-4.25 (m, 3H), 5.09 (s, 2H), 7.35 (m, 5H).
Step B: 4-(Dimethylaminocarbonylamino)pineridine
Using essentially the same procedure as in Example 64,
Step D, 1.4 g (4.6 mmol) of 1-benzyloxycarbonyl-4-
(dimethylaminocarbonylamino)piperidine from Step A was
hydrogenated to afford 690 mg of the title compound.
Step C: (R,S)-N-[2-Phenyl-4-(4-dimethylaminocarbonylamino-
piperidin-1-yl)but-1-yll-N-methylbenzenesulfonamide
Using essentially the same procedure as in Example 1, Step
C, the piperidine derivative from Step C was utilized to reductively
alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to
provide the title compound.
Mass spectrum (ESI): m/z 473 (M+1, 100%).
EXAMPLE 68
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(prop-1-ylamino)piperidin-1-
yl)but-1-vll-N-meth~benzenesulfonamide hydrochloride salt
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Step A: 4-Azido-1-t-buto~carbonvluineridine
To a solution of 45.3 g (172 mmol) of 4-bromo-1-t-
butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol)
of sodium azide and 2.5 g (17 mmol) of sodiun iodide. The reaction was
stirred at rt for 24 h and then at 60 °C for 4 h. The mixture was
poured
into water containing 20 mL of sodium bicarbonate and extracted twice
with 1:1 ether:hexanes. The organic layers were each washed with a
portion of water and brine, dried over sodium sulfate, combined and
concentrated. The residue was purified by FCC eluting with 5 - 10%
ethyl acetate/hexanes to afford 39 g of title compound having a trace of
elimination biproduct.
1H NMR (400 MHz, CDCl3): 8 1.43 (s,9H), 1.52 (m, 2H), 1.85 (m, 2H), 3.07
(m, 2H), 3.55 (m, 1H), 3.78 (m, 2H).
Step B: 4-Amino-1-t-butoxvcarbonYlpi~eridine
A solution of 4.05 g ( 17.9 mmol) of 4-azido-1-t-
butoxycarbonylpiperidine from Step A in 50 mL of methanol was
hydrogenated with 350 mg of IO% Pd/C under a hydrogen balloon for 16 h
when the reaction was complete by TLC (10% ethyl acetate/hexanes).
The catalyst was filtered off and the volatiles removed in vacuo to give 3.5
g of title compound which was used directly in subsequent reactions.
Step C: 4-Benzyloxycarbonylamino-1-t-butox'~carbonvlniperidine
To a solution of 1.2 g (6.0 mmol) 4-amino-1-t-
butoxycarbonylpiperidine from Step B in 40 mL of methylene chloride
was added 3.15 mL (18 mmol) of DIPEA and 1.03 mL (7.2 mmol) of benzyl
chloroformate while cooled in an ice bath. After 0.5 h the reaction was
quenched with aqueous sodium carbonate and extracted three times
with methylene chloride. The organic layers were each washed with a
portion of brine, dried over sodium sulfate, combined and concentrated.
The residue was purified by FCC eluting with 25% ethyl acetate/hexanes
to afford 1.94 g of title compound.
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1H NMR (400 MHz, CDC13): 8 1.26 (m, 2H), 1.42 (s, 9H), 1.90 (br d, J = 12,
2H), 2.90 (br t, 2H), 3.58 (m, 1H), 4.08 (m, 2H), 4.42 (br s, 1H), 5.09 (s,
2H),
7.33 (m, 5H).
Step D: 4-Benzyloxycarbonyl(prop-1-ylamino)-1-t-
butoxvcarbonylpineridine
To 110 mg (0.32 mmol) 4-benzyloxycarbonylamino-1-t-
butoxycarbonylpiperidine from Step C and 0.16 mL (1.6 mmol) of n-
propyl iodide in 2 mL of DMF under nitrogen was added 26 mg (0.65
mmol) of 60% sodium hydride in mineral oil. The reaction was stirred
at rt for 16 h and was then poured into water and extracted twice with
ether. The organic layers were each washed with a portion of brine,
dried over sodium sulfate, combined and concentrated. The residue was
purified by FCC eluting with 20% ethyl acetate/hexanes to afford 90 mg of
title compound.
Step E: 4-Benzyloxycarbonyl(prop-1-ylamino)piperidine
hydrochloride salt
To a solution of 2.4 mmol of HCl in 2 mL of methanol
(prepared by the addition of 0.17 mL of acetyl chloride at 0 °C and
stirring
for 10 min) was added 90 mg of 4-benzyloxycarbonyl(prop-1-ylamino)-1-t-
butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at
which time the reaction was complete by TLC (20% ethyl
acetate/hexanes) and was evaporated to dryness in vacuo to afford 75 mg
of the title compound as the hydrochloride salt.
Step F: (R,S)-N-I2-Phenyl-4-(4-benzyloxycarbonyl(prop-1-
ylamino)piperitiin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide hydrochloride salt
Using essentially the same procedure as in Example 1, Step
C, the piperidine derivative from Step E was utilized to reductively
alkylate (R,S)-N-(2-phenyl-4-oxobut-1-yl)-N-methylbenzenesulfonamide to
provide the title compound. Mass spectrum (NH3/CI): m/z 578 (M+1,
100%).
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The following Examples were prepared following the
procedure described in Example 1, Step C but using the appropriate
substituted piperidine in the reductive amination step (prepared by
analogy to the piperidine derivatives in Examples 64-68).
EXAMPLE 69
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonylaminopiperidin-1-yl)but-1-yl]-
N-methvlbenzenesulfonamide
Mass spectrum (ESI): m/z 460 (M+1, 100%).
EXAMPLE 70
(R,S)-N-[2-Phenyl-4-(4-aminocarbonylaminopiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide
Mass spectrum (ESI): m/z 445 (M+1, 100%).
EXAMPLE 71
(R,S)-N-[2-Phenyl-4-(4-aminopiperidin-1-yl)but-1-yl]-N-methylbenzene-
sulfonamide hydrochloride silt
Mass spectrum (ESI): m/z 402 (M+1, 100%).
EXAMPLE 72
(R,S}-N-[2-Phenyl-4-(4-acetylaminopiperidin-1-yl)but-1-yl]-N
methylbenzenesulfonamide hvdrochlori~de salt _
Mass spectrum (ESI): m/z 444 (M+1, 100%).
EXAMPLE 73
(R,S)-N-[2-Phenyl-4-(4-isopropylcarbonylaminopiperidin-1-yl)but-1-
yll-N-methvlbenzgnesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 472 (M+1, 100%).
EXAMPLE 74
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(R,S)-N-[2-Phenyl-4-(4-methylsulfonylaminopiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 480 (M+1, 100%).
EXAMPLE 75
(R,S)-N-[2-Phenyl-4-(4-isopropylcarbonyl(ethylamino)piperidin-1-
1 but-1-yll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 500 (M+1, 100%).
EXAMPLE 76
(R,S)-N-[2-Phenyl-4-(4-methylsulfonyl(ethylamino)piperidin-1-yl)but-
1-yll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 508 (M+1, 100%).
EXAMPLE 77
(R,S)-N-[2-Phenyl-4-(4-t-butoxycarbonylaminopiperidin-1-yl)but-1-yl]-
N-met lbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 502 (M+1, 100%).
EXAMPLE 78
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(methylamino)piperidin-1-yl)but-
1- l~meth l~nzgnesulfonamide hydrochloride salt
Mass spectrum (PB-EI): m/z 474 (M+1), 211 (100%).
EXAMPLE 79
(R,S )-N- [2-Phenyl-4-(4-(pyrrolidin-2-on-1-yl )piperi din-1-yl )but-1-yl] -N-
methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (PB-EI): m/z 470 (M+1), 160 (100%).
EXAMPLE 80
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(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclobutylmethylamino)-
piperidin-1-vl)but-1-vll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (PB-EI): m/z 528 (M+1), 160 (100%).
EXAMPLE 81
(R,S)-N-[2-Phenyl-4-(4-ethoxycarbonyl(ethylamino)piperidin-1-yl)but-1-
vll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (PB-EI): m/z 502 (M+1), 160 (100%).
EXAMPLE 82
(R,S)-N-[2-Phenyl-4-(4-isobutyloxycarbonyl(ethylamino)piperidin-1-
yl)but-1-vll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (PB-EI): m/z 530 (M+1), 160 (100%).
EXAMPLE 83
(R,S)-N-[2-Phenyl-4-(4-piperidin-2-on-1-ylpiperidin-1-yl)but-1-yl]-N-
m~thylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 484 (M+1), 347 (100%).
EXAMPLE 84
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(benzylamino)piperidin-1-yl)but-
1 vll N methylbenzenesulfonamide hydrochloride salt
Mass spectrum (ESI): m/z 550 (M+1, 100%).
EXAMPLE 85
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(prop-1-ylamino)piperidin-1-
but-1-yll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): m/z 502 (M+1), 118 (100%).
EXAMPLE 86
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(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(but-1-ylamino)piperidin-1-
Mass spectrum (NH3/CI): m/z 516 (M+1), 132 (100%).
EXAMPLE 87
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclohexylmethylamino)-piper-
idin-1-ail)but-1-~N-meth~~lbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): m/z 556 (M+1, 100%).
EXAMPLE 88
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(cyclopropylmethylamino)-piper-
idin-1-yl)but-1-vll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): m/z 514 (M+1, i00%).
EXAMPLE 89
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(pent-1-ylarnino)piperidin-1-
vl)but-1-vll-N-meth~rlbenzenesulfonamide h dv rochloride salt
Mass spectrum (NH3/CI): m/z 530 (M+1, 100%).
EXAMPLE 90
(R,S)-N-[2-Phenyl-4-(4-methoxycarbonyl(pent-1-ylamino)piperidin-1-
yl but-1-yll-N-meth~lbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/Ci): m/z 530 (M+1, 100%).
EXAMPLE 91
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(methylamino)piperidin-1-
yl)but-1-yll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): m/z 550 (M+1, 100%).
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EXAMPLE 92
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(ethylamino)piperidin-1-yl)but-
1-yll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (PB-EI): m/z 564 (M+1), 160 (100%).
EXAMPLE 93
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbony!(but-1-ylamino)piperidin-1-
)but-1-yll-N-methylbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): rn/z 592 (M+1, 100%).
EXAMPLE 94
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbony!(pent-1-ylamino)piperidin-1-
yl)but-1-vll-N-methvlbenzenesulfonamide hvdrochloride salt
Mass spectrum (NH3/CI): m/z 606 (M+1, 100%).
EXAMPLE 95
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(cyclobutylmethylamino)-piper-
idin-1-vl)but-1-yll-N-methvlbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): m/z 604 (M+1, 100%).
EXAMPLE 96
(R,S)-N-[2-Phenyl-4-(4-benzyloxycarbonyl(cyclohexylmethylamino)-piper-
idin-1-yl)but-1-vll N meth~lbenzenesulfonamide hydrochloride salt
Mass spectrum (NH3/CI): m/z 632 (M+1, 100%).
EXAMPLE 97
(S)-N-(2-(3-Chlorophenyl-4-(4-benzyloxycarbonyl(ethylamino)-piperidin-1-
vl)but-1-vll-N-methylbenzenesulfonamide hvdrochloride salt
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The title compound was prepared using essentially the same
procedure as in Example 39, Step C. The piperidine subunit was
prepared by analogy to the procedure given in Example 68.
Mass spectrum (NH3/CI): m/z 598 (M~-1, 100%).
EXAMPLE 98
(R,S)-N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methvlbenzenesulfonamide h drochloride salt
Step A: N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-2-en-1-yl]-N-
methylbenzenesulfonamide _
To 250 mg (0.37 mmol) of N-[4-(4-phenylpiperidin-1-yl)-3
tributylstannylbut-2-en-1-yl]-N-methylbenzenesulfonamide from
Example 21, Step B (isomeric higher Rf product) in 0.5 mL of N-
methylpyrrolidinone under argon was added 75 mg (0.55 mmol) of
potassium carbonate, 8 mg (2% cat) of dichlorobis(triphenylphosphine)-
palladium (II) and 90 mg (0.55 mmol) of bromobenzene. The mixture
was heated at 70 °C for 24 h, cooled, treated with aqueous sodium
fluoride for 10 min, and partitioned between water and ether. The water
layer was reextracted with ether and each organic layer was washed
with brine, dried over sodium sulfate, combined and concentrated in
vacuo. The residue was purified by FCC eluting with 20-25% ethyl
acetate/hexanes to give 120 mg of title product as an oil.
1H NMR (400 MHz, CDC13): b 1.55-1.6 (m, 2H), 2.75 (br d, J = 11, 2H), 2.00
(br dt, J= 2 and 14, 2H), 2.42 (m, 1H), 2.78 (s, 3H), 2.93 (br d, J = 11, 2H),
3.33 (s, 2H), 4.05 (d, J = 6.5, 2H), 5.78 (t, J = 6.5, 1H), 7.1-7.4 (3 m, 5H),
7.5-
7.65 (m, 3H), 7.84 (dd, J = 1.5 and 7, 2H).
Mass spectrum (ESI): m/z 461 (M+l, 100%).
Step B: (R,S)-N-[3-Phenyl-4-(4-phenylpiperidin-1-yl)but-1-yl]-N-
methylbenzenesulfonamide
A mixture of 90 mg (0.20 mmol) of N-[3-phenyl-4-(4-
phenylpiperidin-1-yl)but-2-en-1-yl]-N-methylbenzenesulfonamide from
Step A, 12 mg of 20% palladium hydroxide/C (50% water), and 2 drops of
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acetic acid in 3 mL of methanol was hydrogenated at 40 psi for 24 h. The
catalyst was removed by filtration and the filtrate concentrated in vacuo.
The residue was purified by prep TLC (50% ethyl acetate/ hexanes) to
afford 20 mg of title compound. A major biproduct was cleavage of the 4-
phenylpiperidine to give N-(3-phenylbut-1-yl)-N-
methylbenzenesulfonamide. 1H NMR (400 MHz, CDC13): S 1.5-1.8 (m,
5H), 1.95 (br t, J = 11, 1H), 2.1-2.25 (2 m, 2H), 2.45 (m, 2H), 2.57 (m, 1H),
2.6-2.7 (m, 2H), 2.68 (s, 3H), 2.9 (m, 2H), 3.0-3.2 (2 m, 2H), 7.1-7.3 (m,
5H),
7.45 (m, 2H), 7.54 (m, 1H), 7.69 (dd, J = 1.5 and 7, 2H). Mass spectrum
(ESI): m/z 463 (M+1, 100%).
EXAMPLE 99
(R,S )-N-Methyl-N- (2-methyl-2-phenyl-4-(4-phenylpiperidin-1-yl)but-1-
yllbenzenesulfonamide hydrochloride
Step A: (R S)-N-Methyl(2 5-dimethyl-2-~henvlhex-4-envl)amine
Methylamine hydrochloride (500 mg, 7.41 mmol),
triethylamine ( 1.00 mL, 725 mg, 7.17 mmol), and 3 ~ molecular sieve
pellets (1.05 g) were added to a stirred solution of 2,5-dimethyl-2-
phenylhex-4-enal (500 mg, 2.47 mmol) in 5.0 mL of methanol at room
temperature. After 1 h, the mixture was cooled in an ice bath and acetic
acid (0.29 mL, 0.30 g, 5.1 mmol) was added followed by sodium
cyanoborohydride (310 mg, 4.93 mmol). The mixture was allowed to
slowly come to room temperature and stirred 16 h before being diluted
with ethyl acetate (50 mL) and washed with saturated aqueous sodium
bicarbonate (30 mL) and saturated aqueous sodium chloride (30 mL).
The aqueous layers were extracted with ethyl acetate (30 mL) and the
combined organic layers were dried over sodium sulfate, decanted, and
evaporated. The residue was purified by flash column chromatography
on silica gel, eluting with 5% methanol in ethyl acetate to give 415 mg the
title compound. 1H NMR (400 MHz, CD30D): 81.34 (s, 3H), 1.54 (s, 3H),
1.59 (s, 3H), 2,27 (s, 3H), 2.30 (dd, J = 14 and 8, 1H), 2.39 (dd, J = 14 and
7.5, 1H), 2.66 (d, J = 12, 1H), 2.87 (d, J = 12, 1H), 4.88 (t, J = 7.5, 1H),
7.18 (t,
J = 7, 1H), 7.28-7.36 (m, 4H).
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Mass spectrum (NH3/CI): m/z 218 (M+1, 100%).
Step B: (R,S)-N-Methyl-N-(2,5-dimethyl-2-phenylhex-4-en-1-
lv )benzenesulfonamide
Using essentially the same procedure as in Example 1 (Step
A), (R,S)-N-methyl(2,5-dimethyl-2-phenylhex-4-enyl)amine from Step A
above was allowed to react with benzenesulfonyl chloride in THF to give
the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 8 1.42
(s, 3H), 1.59 (s, 6H), 2.09 (s, 3H), 2.33 (dd, J = 15 and 8, 1H), 2.50 (dd, J
= 15
and 6, 1H), 2.94 (d, J = 13, 1H), 3.40 (d, J = 13, 1H), 4.83 (bt, J = 7, 1H),
7.17,
t, J = 7, 1H), 7.23-7.33 (m, 4H), 7.48 (t, J = 7.5, 2H), ?.55 (t, J = 7.5,
1H), 7.72
(d, J = 7.5, 2H). Mass spectrum (NH3/CI): m/z 358 (M+1, 100%).
Step C: (R,S)-N-Methyl-N-(2-methyl-2-phenyl-4-oxobut-1-
yl)benzenesulfonamide
To a solution of (R,S)-N-methyl-N-(2,5-dimethyl-2-
phenylhex-4-en-1-yl)benzenesulfonamide (300 mg, 0.839 mmol) from Step
B in 6.0 mL of acetone, 3.0 mL of t-butanol and 1.5 mL of water was
added 0.145 mL (118 mg, 0.012 mmol) of 2.5% osmium tetroxide in t-
butanol followed by 433 mg (3.70 mmol) of N-methylmorpholine-N-oxide.
The reaction was stirred at room temperature for 18 h and was then
quenched with 3 g of aqueous sodium bisulfate and concentrated in
vacuo. The residue was partitioned between dichloromethane (20 mL)
and water (10 mL). The aqueous layer was extracted with
dichloromethane (2 x 20 mL) and the combined organic layers were
dried over sodium sulfate, decanted, and evaportated to give the diol
intermediate. The above product was dissolved in 9.0 mL of THF and 3.0
mL of water, and treated with 323 mg (1.51 mmol) of sodium periodate.
After 2 h, additional sodium periodate (150 mg, 0.70 mmol) was added
and the mixture was stirred 1 h longer. Most of the THF was removed in
vacuo and the residue was patitioned between ethyl acetate (20 mL) and
water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x
20 mL) and the combined organic layers were dried (sodium sulfate),
decanted, and evaporated. The residue was re-dissolved in 9.0 mL of
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THF and 3.0 mL of water, and sodium periodate (450 mg, 2.1 mmol) was
added in three equal portions at 1.5 h intervals. The mixture was stirred
for 1.5 h after the addition of the last portion, and then worked up as
before. Flash column chromatography on silica gel, eluting with 20%
ethyl acetate in hexane gave 210 mg of the title compound as a colorless
syrup. 1H NMR (400 MHz, CDC13): b 1.64 (s, 3H), 2.21 (s, 3H), 2.78 (dd, J
= 16 and 2.5, 1H), 3.15 (d, J = 13, 1H), 3.19 (dd, J = 16 and 2.5, 1H), 3.23
(d,
J = 13, 1H), 7.23-7.28 (m, 1H), 7.32-7.40 (m, 4H), 7.52 (t, J = 7.5, 2H), 7.59
(t,
J = 7.5, 1H), 7.74 (d, J = 7.5, 2H), 9.62 (t, J = 2.5, 1H). Mass spectrum
(ESI): m/z 332 (M+1, 100%).
Step D: (R,S)-N-Methyl-N-[2-methyl-2-phenyl-4-(4-phenyl-piperidin
1- 1 but-1-vllbenzenesulfonamide hvdrochloride
Using essentially the same procedure as in Example 1 (Step
C), (R,S)-N-methyl-N-(2-methyl-2-phenyl-4-oxobut-1-yl)benzene-
sulfonamide from Step C above was allowed to react with 4-phenyl-
piperidine to give the free amine of the title compound as a colorless
film. 1H NMR (400 MHz, CD30D): b 1.50 (s, 3H), 1.70-1.93 (m, 5H), 2.06-
2.23 (m, 3H), 2.11 (s, 3H), 2.29 (td, J = 12 and 4, 1H), 2.40-2.59 (m, 2H),
3.03
{d, J = 14, 1H), 3.03-3.15 (m, 2H), 3.41 (d, J = 14, 1H), 7.15 (t, J = 7, 1H),
7.19-7.29 (m, 5H), 7.34 (t, J = 7.5, 2H), 7.42 (d, J = 8, 2H), 7.57 (t, J =
7.5,
2H), 7.64 (t, J = 7.5, 1H), 7.76 (d, J = 8, 2H).
Mass spectrum (ESI): m/z 477 (M+1, 100%). The hydrochloride salt of
the title compound was prepared by dissolving the free base in ethanol
and adding 1.5 equivalents of aqueous 2 N HCl. Evaporation of the
solvent gave the title salt as a white solid.
EXAMPLE 100
(R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-methyl-2-
~envlbut-1-vll-N-methylbenzenesulfonamide hydrochloride
Using essentially the same procedure as in Example 1 (Step
C), (R,S)-N-methyl-N-(2-methyl-2-phenyl-4-oxobut-1-yl)benzene-
sulfonamide (from Example 99, Step B) was allowed to react with 4-
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benzyloxycarbonyl(ethylamino)piperidine (prepared by analogy to
Example 68) to give the free amine of the title compound as a colorless
film. 1H NMR (400 MHz, CD30D): S 1.11 (t, J = 7, 3H), 1.47 (s, 3H), 1.60-
1.70 (m, 2H), 1.72-1.86 (m, 3H), 1.91-2.06 (m, 3H), 2.10 (s, 3H), 2.20 (td, J
=
12 and 3, 1H), 2.28-2.38 (m, 1H), 2.90-3.02 (m, 2H), 3.00 (d, J = 14, 1H),
3.24
(t, J = 7, 2H), 3.99 (d, J = 14, 1H), 3.78-3.90 (b, 1H), 5.11 (s, 2H), 7.21
(t, J =
7, 1H), 7.27-7.42 (m, 9H), 7.56 (t, J = 7, 2H), 7.63 (t, J = 7.5, 1H), 7.75
(d, J =
7.5, 2H). Mass spectrum (NH3/CI): m/z 578 (M+1, 100%). The
hydrochloride salt of the title compound was prepared by dissolving the
free base in ethanol and adding 1.5 equivalents of aqueous 2 N HCI.
Evaporation of the solvent gave the title salt as a clear glass.
EXAMPLE 101
(R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-2-ethyl-2-
nhenylbut-1-vll-N-meth3rlbenzenesulfonamide hydrochloride
Step A: (R,S)-2-Eth~rl-2-~henylnent-4-enenitrile
A solution of 2-phenylpent-4-enenitrile (500 mg, 3.18 mmol)
in THF (6.5 mL) was stirred in an ice bath and 1.5 M lithium
diisopropylamide monotetrahydrofuran complex in cyclohexane (2.16
mL, 3.23 mmol) was added. After 10 min, the ice bath was removed and
the solution was stirred at room temperature for 1 h. The solution was
cooled in a dry ice/isopropanol bath and iodoethane (0.280 mL, 546 mg,
3.50 mmol) was added. The reaction was allowed to warm to -20 °C over
min, and was then stirred 2 h at room temperature. The mixture was
partitioned between ethyl acetate (50 mL) and saturated aqueous
ammonium chloride (30 mL). The organic layer was washed with
saturated aqueous sodium chloride (30 mL), dried over sodium sulfate,
30 decanted, and evaporated. The residue was purified by flash column
chromatography on silica gel, eluting with 5% ether in hexane to give
the title compound as 537 mg of yellow oil.
1H NMR (400 MHz, CDC13): b 0.93 (t, J = 7.5, 3H), 1.94 (dq, J = 14 and 7,
1H), 2.08 (dq, J = 14 and 7, 1H), 2.68 (d, J = 7, 2H), 5.12 (d, J = 10, 1H),
5.13
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(d, J = 16, 1H), 5.65 (ddt, J = 16, 10, and 7, 1H), 7.28-7.35 (m, 1H}, 7.35-
7.42
(m, 4H).
Step B: (R,S)-2-Et vl-2-2-y~~ent-4-enal
A solution of 500 mg (2.70 mmol) of (R,S)-2-ethyl-2-
phenylpent-4-enenitrile from Step A in 2.0 mL of ether was cooled in an
ice bath and 1.5 M diisobutylaluminum hydride in toluene (2.65 mL, 3.97
mmol) was added. The solution was stirred for 2 h at 0 °C, then
quenched by the addition of 15 mL of 2 N aqueous HCl and stirred for 1 h.
The mixture was extracted with ether (2 x 50 mL). The combined
organic layers were washed with saturated aqueous sodium bicarbonate
(50 mL) and saturated aqueous sodium chloride (50 mL), dried over
sodium sulfate, decanted, and evaporated to give 410 mg of the title
compound. 1H NMR (400 MHz, CDC13): 8 0.80 (t, J = 7.5, 3H), 1.94-2.05
(m, 2H), 2.67 (dd, J = 14 and 7, 1H), 2.74 (dd, J = 14 and 7, 1H), 5.03 (d, J
=
10, 1H), 5.07 (d, J = 16, 1H), 5.53 (ddt, J = 16, 10, and 7, 1H), 7.22 (d, J =
8,
2H), 7.29 (t, J = 8, 1H), 7.39 (t, J = 8, 2H).
Step C: (R.S)-N-Methyl(2-eth~phenylpent-4-enyl)amine
Using essentially the same procedure as in Example 99
(Step A), the crude (R,S)-2-ethyl-2-phenylpent-4-enal from Step B above
gave the title compound as an amber liquid. 1H NMR (400 MHz,
CD30D): 8 0.69 (t, J = 7.5, 3H), 1.74 (q, J = 7.5, 2H), 2.27 (s, 3H), 2.48
(dd, J
= 14 and 7, 1H), 2.56 (dd, J = 14 and 7, 1H), 2.77 (s, 2H), 5.00 (dm, J = 10,
1H), 5.07 dm, J = 16, 1H), 5.61 (ddt, J = 16, 10, and 7, 1H), 7.16-?.22 (m,
1H), 7.30-?.37 (m, 4H). Mass spectrum (ESI): m/z 204 (M+1, 100%).
Step D: (R,S)-N-(2-Ethyl-2-phenylpent-4-enyl)-N-methylbenzene-
sulronarniae
Using essentially the same procedure as in Example 1 (Step
A), (R,S)-N-methyl(2-ethyl-2-phenylpent-4-enyl)amine from Step A above
was allowed to react with benzenesulfonyl chloride in THF to give the
title compound as an amber syrup. 1H NMR (440 MHz, CDC13): 8 0.82
(t, J = 7.5, 3H), 1.85 (q, J = 7.5, 2H), 1.94 (s, 3H), 2.59 (dd, J = 14 and 7,
1H),
2.73 (dd, J = 14 and 7, 1H}, 3.08 (d, J = 14, 1H), 3.25 (d, J = 14, 1H), 5.10
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(dm, J = 10, 1H), 5.16 (bd, J = 16, 1H), 5.89 (ddt, J = 16, 10, and ?, 1H),
7.20
(d, J = 7, 1H), 7.27-7.36 (m, 4H), ?.51 (t, J = 7, 2H), 7.58 (t, J = 7, 1H),
?.73
(d, J = 7, 2H).
Mass spectrum (ESI): m/z 344 (M+1, 33%), 361 (M+NH3+1, 100%).
Step E: (R,S)-N-(2-Ethyl-2-phenyl-4-oxobut-1-yl)-N-methyl-
benzenesulfonamide
Using essentially the same procedure as in Example 1 (Step
B), (R,S)-N-(2-ethyl-2-phenylpent-4-enyl)-N-methylbenzenesulfonamide
from Step D above was oxidized to give the title compound as a syrup.
IH NMR (400 MHz, CDC13): 8 0.79 (t, J = 7.5, 3H), 1.92-2.07 (m, 2H), 2.06
(s, 3H), 2.94 (d, J = 14, 1H), 2.96 (dd, J = 17 and 3, 1H), 3.22 (bd, J = 17,
1H),
3.65 (d, J = 14, IH), 7.22-7.38 (m, 5H), 7.53 (t, J = 7, 2H), 7.60 (t, J = 7,
1H),
7.74 (d, J = 7, 2H), 9.92 (dd, J = 3 and 2, 1H).
Mass spectrum (ESI): m/z 346 (M+1, 85%), 363 (M+NH3+1, 100%).
Step F: (R,S)-N-[4-(4-Benzyloxycarbonyl(ethylamino)piperidin-1-yl)-
2-ethyl-2-phenylbut-1-yl]-N-methylbenzenesulfonamide
hydrochloride
Using essentially the same procedure as in Example 1 (Step
C), (R,S)-N-(2-ethyl-2-phenyl-4-oxobut-1-yl)-N-methylbenzene-
sulfonamide from Step E above was allowed to react with 4-
benzyloxycarbonyl(ethylamino)piperidine (prepared by analogy to
Example 68) to give the free amine of the title compound as a colorless
film. IH NMR (400 MHz, CD30D): 8 0.87 (t, J = 7, 3H), 1.12 (t, J = 7, 3H),
1.63-2.24 (m, 11H), 1.89 (s, 3H), 2.50-2.60 (m, 1H), 3.04 (bd, J = 10, 1H),
3.11
(bd, J = 10, 1H), 3.16 (d, J = 14, 1H), 3.22 (d, J = 14, 1H), 3.26 (q, J = 7,
2H),
3.82-3.96 (b, 1H), 5.12 (s, 2H), ?.20 (t, J = 7, 1H), 7.28-7.42 (m, 4H), 7.58
ft, J
= 7, 2H), 7.65 (t, J = 7, 1H), 7.74 (d, J = 7, 2H). Mass spectrum (ESI): m/z
592 (M+1, 100%). The hydrochloride salt of the title compound was
prepared by dissolving the free base in ethanol and adding 1.5
equivalents of aq. 2 N HCl. Evaporation of the solvent gave the title salt
as a white glass.
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While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled in the
art will appreciate that various adaptations, changes, modifications,
substitutions, deletions, or additions of procedures and protocols may be
made without departing from the spirit and scope of the invention. For
example, effective dosages other than the particular dosages as set forth
herein above may be applicable as a consequence of variations in the
responsiveness of the mammal being treated for any of the indications
with the compounds of the invention indicated above. Likewise, the
specific pharmacological responses observed may vary according to and
depending upon the particular active compounds selected or whether
there are present pharmaceutical carriers, as well as the type of
formulation and mode of administration employed, and such expected
variations or differences in the results are contemplated in accordance
with the objects and practices of the present invention. It is intended,
therefore, that the invention be defined by the scope of the claims which
follow and that such claims be interpreted as broadly as is reasonable.
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