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1. WO1993016081 - PIPERIDINYL THIACYCLIC DERIVATIVES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WHAT IS CLAIMED IS:
1. A compound of the formula:


optical isomers or pharmaceutically acceptable salts thereof,
wherein
Y is -C(=O)-, -C(=CH2)-, -C(H)(OH)-, -C(OH)(phenyl)- or -C(B)(OH) wherein B is



Y is attached at the heterocycle position 2 or 3, and when Y is -C(B)(OH), B is attached at heterocycle
positions 2' or 3';
X and X' are the same or different and are carbon, CH
or nitrogen, provided that when Y is attached at
the 3 or 3 ' position X and X' are each carbon, and when Y is attached at the 2 or 2' position X and
X' are the same or different and are CH or
nitrogen;
R1 is -(CH2)n-Z-(CH2)rnCOR5, -C(O)R8 or

R2, R3, R2' and R3' are the same or different and are hydrogen or C1-4 alkyl, or when R2 and R3, and R2' and R3 ' are respectively taken together, with the atoms to which R2 and R3, and R2' and R3' are
respectively attached, each form a phenyl moiety respectively substituted with R4 or R4';
Z is a bond, O, or S;
R4 or R4' are the same or different and are hydrogen, chloro, fluoro, C1-4 alkyl, or C1-4 alkoxy;
R5 is OH, C1-4 alkoxy or -NR6R7;
R6 and R7 are the same or different and are H or C1-4 alkyl;
R8 is C1-4 alkyl, C1-4 alkoxy;
R9 is H, C1-4 alkyl, C1-4 alkoxy, OH, chloro, bromo, fluoro, -CF3, -NHC(O)R10, or CO2R11;
R10 is C1-4 alkyl or C1-4 alkoxy;
R11 is hydrogen or C1-4-alkyl;
n is an integer from 0-3 provided that when Z is not a bond, n is an integer from 2-3;
m is an integer from 1 to 3;
d is an integer from 1-5; and
e is zero or 1, provided that when e is 1:
d is an integer from 2 to 5; and
X is N, or R2 and R3, with the atoms to which R2
and R3 are attached, form a phenyl moiety; or X is N, and R2 and R3, with the atoms to which R2 and R3 are attached, form a phenyl moiety.

2. The compound of claim 1 wherein R2 and R3 together, with the atoms to which R2 and R3 are attached, form a phenyl moiety.

3. The compound of claim 1 wherein X is nitrogen.

4. The compound of claim 1 wherein R1 is


5. The compound of claim 4 wherein d is 2, e is 0 and R9 is CO2R11.

6. The compound of claim 1 wherein R2 and R3 together, with the atoms to which R2 and R3 are attached, form a phenyl moiety and X is nitrogen.

7. The compound of claim 1 wherein R2 and R3 together, with the atoms to which R2 and R3 are attached, form a phenyl moiety and X is CH or carbon.

8. The compound of claim 1 wherein X is CH or carbon.

9. The compound of claim 1 wherein Y is -C(=O)-.

10. The compound of claim 1 wherein Y is -C(H)(OH)-.

11. The compound of claim 1 which is [2-Benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone or any pharmaceutically acceptable addition salt thereof.

12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

13. Use of a compound according to any of claims 1-11 in the preparation of a medicine for the treatment of allergic disease.

14. Use of a compound according to any of claims 1-11 in the preparation of a medicine for treating a disease responsive to antagonism of the 5HT2 receptor.

15. Use of a compound according to any of claims 1-11 as a medicine.

16. A method of using a compound of formula (3):



to make a compound of Formula I


optical isomers or pharmaceutically acceptable addition salts thereof,
wherein Y is -C(=O)-, -C(=CH2)-, -C(H)(OH -C(OH)(phenyl)- or -C(B)(OH) wherein B is



Y is attached at the heterocycle position 2 or 3, and when Y is -C(B)(OH), Y is also attached at
heterocycle positions 2' or 3';
X and X' are the same or different and are carbon,
CH or nitrogen, provided that when Y is attached at the 3 or 3 ' position X and X1 are each carbon, and when Y is attached at the 2 or 2' position X and
X' are the same or different and are CH or
nitrogen;
R1 is -(CH2)n-Z-(CH2)mCOR5, -C(O)R8 or


R2, R3, R2' and R3' are the same or different and are hydrogen or C1-4 alkyl, or when R2 and R3, and R2' and R3 ' are respectively taken together, with the atoms to which R2 and R3 , and R2' and R3' are
respectively attached, each form a phenyl moiety substituted with R4 or R4';
Z is a bond, O, or S;
R4 or R4' are the same or different and are hydrogen, chloro, fluoro, C1-4 alkyl, or C1-4 alkoxy;
R5 is OH, C1-4 alkoxy or -NR6R7.
R6 and R7 are the same or different and are H or C1-4 alkyl;
R8 is C1-4 alkyl, C1-4 alkoxy;
R9 is H, C1-4 alkyl, C1-4 alkoxy, OH, chloro, bromo,
fluoro, -CF3, -NHC(O)R10f or CO2R11;
R10 is C1-4 alkyl or C1-4 alkoxy;
R11 is hydrogen or C1-4-alkyl;
n is an integer from 0-3 provided that when Z is not a bond, n is an integer from 2-3;
m is an integer from 1 to 3;
d is an integer from 1-5; and
e is zero or 1, provided that when e is 1:
d is an integer from 2 to 5; and
X is N, or R2 and R3, with the atoms to which R2 and R3 are attached, form a phenyl moiety; or X is N, and R2 and R3, with the atoms to which R2 and R3 are attached, form a phenyl moiety;

(a) by deprotecting the compound of formula (3) to
produce compound (4):


as previously defined;

(b) optionally reacting compound (4) with R1'-Hal in
the presence of an appropriate base to form
compound (6):


as previously defined and wherein Hal is Cl, Br or I;

(c) optionally reducing the carbonyl functionality of
compound (4) with a reducing agent to produce
compound (7):



as previously defined;

(d) optionally converting the carbonyl functionality of compound (4) to an ethenylene group by reacting
compound (7) with a suitable ylid to produce
compound (8):



as previously defined;

(e) optionally converting the carbonyl functionality of compound (6) to a phenyl teriary alcohol or
thiacyclic tertiary alcohol by reacting
phenyllithium or



to produce compound (9):
as previously defined, and wherein Y' is phenyl or



as previously defined; or

(f) optionally preparing pharmaceutically acceptable additon salts of Formula I.