US 5,512,575 AGranted

Methanoanthraceneyl methyl piperidinyl compounds

AssigneeZeneca Limited

InventorsRobert T. Jacobs, Michael T. Klimas, Cyrus J. Ohnmacht, Marc O. Terpko

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Abstract

Compounds of formula I or I', ##STR1## wherein X and Y are independently selected from hydrogen, halo, and (1-6C)alkoxy; R.sup.1 is selected from (A) (1-6C)alkyl; (B) phenyl and naphthyl or substituted versions thereof; (C) phenyl (1-3C)alkyl and naphthyl (1-3C) alkyl; (D) five- and six-membered heteroaryl rings; (E) heteroaryl (1-3C)alkyl and pharmaceutically acceptable salts thereof, useful in the treatment of neuropsychiatric disorders such as psychoses; pharmaceutical compositions comprising a compound of formula I or I' and a pharmaceutically acceptable diluent or carrier; and methods of treating neuropsychiatric disorders comprising administering to a mammal (including man) in need of such treatment an effective amount of a compound of formula I or I', or a pharmaceutically acceptable salt thereof are claimed. The invention also relates to novel processes for producing enantiomeric methanoanthracenyl sulfoxides.

Claims37

Dependent claims

A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein
X and Y are independently selected from hydrogen, halo, and (1-6C)alkoxy;
R.sup.1 is selected from
(A) phenyl and naphthyl each of which may bear 0-3 substituents independently selected from the group consisting of
(1-6C)alkyl, (1-6C)alkoxy, hydroxy, halo, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl,
aminosulfonyl having the formula SO.sub.2 NR.sup.a R.sup.b, and aminocarbonyl having the formula CONR.sup.c R.sup.d wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently selected from hydrogen, 2-pyrrolidinyl, and (1-6C)alkyl, or wherein R.sup.a and R.sup.b, and R.sup.c and R.sup.d, together with the nitrogen atom to which each is attached, form a 5-membered or 6-membered heterocyclic ring in which the said nitrogen is the only heteroatom, and
R.sup.h R.sup.i N(1-3C)alkyl wherein R.sup.h and R.sup.i are independently selected from hydrogen and (1-3C)alkyl;
(B) phenyl(1-3C)alkyl and naphthyl(1-3C)alkyl wherein the phenyl and naphthyl moieties may bear 0-3 substituents selected from the group of phenyl and naphthyl substituents given in A);
(C) five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and benz derivatives thereof, which may bear 0-2 substitutents selected from (1-6C)alkyl, hydroxy, (1-6C)alkoxy which may bear a trifluoromethyl group, (1-6C)alkoxycarbonyl, (1-6C)hydroxyalkyl, benzyloxy, halo, (1-3C)alkylaminocarbonyl(1-3C)alkyl, aminocarbonyl as defined in (A), R.sup.e S(O).sub.n R.sup.f NH, and R.sup.g S wherein R.sup.e and R.sup.f are independently selected from hydrogen and (1-6C)alkyl and n is 0, 1 or 2, and R.sup.g is selected from (1-3C)alkylcarbonylaminophenyl and di(1-3C)alkylamino(1-6C)-alkyl;
and
(D) heteroaryl(1-3C)alkyl wherein the heteroaryl moiety is a five- or six-membered ring as defined in (C) and wherein the heteroaryl moiety may bear 0-2 substituents selected from the group of heteroaryl substituents given in (C).

8 more elements

A pharmaceutical composition comprising a compound of formula I, ##STR4## or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from hydrogen, halo, and (1-6C)alkoxy;
R.sup.1 is selected from
(A) phenyl and naphthyl each of which may bear 0-3 substituents independently selected from the group consisting of (1-6C)alkyl, (1-6C)alkoxy, hydroxy, halo, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl,
aminosulfonyl having the formula SO.sub.2 NR.sup.a R.sup.b, and aminocarbonyl having the formula CONR.sup.c R.sup.d wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently selected from hydrogen, 2-pyrrolidinyl, and (1-6C)alkyl, or wherein R.sup.a and R.sup.b, and R.sup.c and R.sup.d, together with the nitrogen atom to which each is attached, form a 5-membered or 6-membered heterocyclic ring in which the said nitrogen is the only heteroatom, and
R.sup.h R.sup.i N(1-3C)alkyl wherein R.sup.h and R.sup.i are independently selected from hydrogen and (1-3C)alkyl;
(B) phenyl(1-3C)alkyl and naphthyl(1-3C)alkyl wherein the phenyl and naphthyl moieties may bear 0-3 substituents selected from the group of phenyl and naphthyl substituents given in (A);
(C) five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and benz derivatives thereof, which may bear 0-2 substitutents selected from (1-6C)alkyl, hydroxy, (1-6C)alkoxy which may bear a trifluoromethyl group, (1-6C)alkoxycarbonyl, (1-6C)hydroxyalkyl, benzyloxy, halo, (1-3C)alkylaminocarbonyl(1-3C)alkyl, aminocarbonyl as defined in (A), R.sup.e S(O).sub.n, R.sup.f NH, and R.sup.g S wherein R.sup.e and R.sup.f are independently selected from hydrogen and (1-6C)alkyl and n is 0, 1 or 2, and R.sup.g is selected from (1-3C)alkylcarbonylaminophenyl and di(1-3C)alkylamino(1-6C)-alkyl;
and
(D) heteroaryl(1-3C)alkyl wherein the heteroaryl moiety is a five- or six-membered ring as defined in (C) and wherein the heteroaryl moiety may bear 0-2 substituents selected from the group of heteroaryl substituents given in (C);
and a pharmaceutically acceptable diluent or carrier.

7 more elements

A method of treating psychoses, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I, ##STR5## or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from hydrogen, halo, and (1-6C)alkoxy;
R.sup.1 is selected from
(A) phenyl and naphthyl each of which may bear 0-3 substituents independently selected from the group consisting of (1-6C)alkyl, (1-6C)alkoxy, hydroxy, halo, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl,
aminosulfonyl having the formula SO.sub.2 NR.sup.a R.sup.b, and aminocarbonyl having the formula CONR.sup.c R.sup.d wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently selected from hydrogen, 2-pyrrolidinyl, and (1-6C)alkyl, or wherein R.sup.a and R.sup.b, and R.sup.c and R.sup.d, together with the nitrogen atom to which each is attached, form a 5-membered or 6-membered heterocyclic ring in which the said nitrogen is the only heteroatom, and
R.sup.h R.sup.i N(1-3C)alkyl wherein R.sup.h and R.sup.i are independently selected from hydrogen and (1-3C)alkyl;
(B) phenyl(1-3C)alkyl and naphthyl(1-3C)alkyl wherein the phenyl and naphthyl moieties may bear 0-3 substituents selected from the group of phenyl and naphthyl substituents given in (A);
(C) five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and benz derivatives thereof, which may bear 0-2 substitutents selected from (1-6C)alkyl, hydroxy, (1-6C)alkoxy which may bear a trifluoromethyl group, (1-6C)alkoxycarbonyl, (1-6C)hydroxyalkyl, benzyloxy, halo, (1-3C)alkylaminocarbonyl(1-3C)alkyl, aminocarbonyl as defined in (A), R.sup.e S(O).sub.n, R.sup.f NH, and R.sup.g S wherein R.sup.e and R.sup.f are independently selected from hydrogen and (1-6C)alkyl and n is 0, 1 or 2, and R.sup.g is selected from (1-3C)alkylcarbonylaminophenyl and di(1-3C)alkylamino(1-6C)-alkyl;
and
(D) heteroaryl(1-3C)alkyl wherein the heteroaryl moiety is a five- or six-membered ring as defined in (C) and wherein the heteroaryl moiety may bear 0-2 substituents selected from the group of heteroaryl substituents given in (C).

6 more elements

A compound of formula IIa, ##STR6## wherein X and Y are independently selected from hydrogen, halo, and (1-6C)alkoxy;

R.sup.1 is selected from
(A) phenyl and naphthyl each of which may bear 0-3 substituents independently selected from the group consisting of
(1-6C)alkyl, (1-6C)alkoxy, hydroxy, halo, cyano, nitro, phenyl, benzyloxy, benzoyl, trifluoromethyl,
aminosulfonyl having the formula SO.sub.2 NR.sup.a R.sup.b, and aminocarbonyl having the formula CONR.sup.c R.sup.d wherein R.sup.a, R.sup.b, R.sup.c and R.sup.d are independently selected from hydrogen, 2-pyrrolidinyl, and (1-6C)alkyl, or wherein R.sup.a and R.sup.b, and R.sup.c and R.sup.d, together with the nitrogen atom to which each is attached, form a 5-membered or 6-membered heterocyclic ring in which the said nitrogen is the only heteroatom, and
R.sup.h R.sup.i N(1-3C)alkyl wherein R.sup.h and R.sup.i are independently selected from hydrogen and (1-3C)alkyl;
(B) phenyl(1-3C)alkyl and naphthyl(1-3C)alkyl wherein the phenyl and naphthyl moieties may bear 0-3 substituents selected from the group of phenyl and naphthyl substituents given in (A);
(C) five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and benz derivatives thereof, which may bear 0-2 substitutents selected from (1-6C)alkyl, hydroxy, (1-6C)alkoxy which may bear a trifluoromethyl group, (1-6C)alkoxycarbonyl, (1-6C)hydroxyalkyl, benzyloxy, halo, (1-3C)alkylaminocarbonyl(1-3C)alkyl, aminocarbonyl as defined in (A), R.sup.e S(O).sub.n, R.sup.f NH, and R.sup.g S wherein R.sup.e and R.sup.f are independently selected from hydrogen and (1-6C)alkyl and n is 0, 1 or 2, and R.sup.g is selected from (1-3C)alkylcarbonylaminophenyl and di(1-3C)alkylamino(1-6C)-alkyl;
and
(D) heteroaryl(1-3C)alkyl wherein the heteroaryl moiety is a five- or six-membered ring as defined in (C) and wherein the heteroaryl moiety may bear 0-2 substituents selected from the group of heteroaryl substituents given in (C).

6 more elements

A process of producing chiral sulfinyl methanoanthracenyl compounds of formula I', ##STR7## wherein X and Y are independently selected from hydrogen, halogen and C1-6 alkoxy;

and
R.sup.1 is selected from:
Five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and benz derivatives thereof, which may bear 1-2 substituents selected from C1-6 alkyl, hydroxy, C1-6 alkoxy which may bear a trifluoromethyl group, C1-6 alkoxycarbonyl, C1-6 hydroxyalkyl, benzyloxy, halo, C1-3 alkylaminocarbonylC1-3alkyl, aminocarbonyl having the formula:
CONR.sup.c R.sup.d wherein R.sup.c and R.sup.d are independently selected from hydrogen, 2-pyrrolidinyl, and C.sub.1-6 alkyl or wherein R.sup.c and R.sup.d together with the nitrogen atom to which each is attached form a 5- or 6-membered heterocyclic ring in which said nitrogen is the only heteroatom, R.sup.e S(O).sub.n, R.sup.f NH, and R.sup.g S wherein R.sup.e and R.sup.f are independently selected from hydrogen and C.sub.1-6 alkyl and n is 0, 1 or 2 and R.sup.g is selected from C.sub.1-3 alkylcarbonylaminophenyl and di(C.sub.1-3)alkylamino(C.sub.1-6)alkyl wherein at least one of the substituents on the five- and/or six-membered heteroaryl ring is a chiral sulfoxide of the formula C.sub.1-4 alkylSO;
comprising the steps of (a) reacting a compound of formula I ##STR8## wherein X and Y are defined above and R.sup.1 includes a C.sub.1-4 alkylthio moiety with (b) an asymmetric oxidizing reagent selected from (1) titanium/tartrate/peroxide or (2) a chiral oxaziridine wherein the reaction proceeds enantioselectively to form an enantiomerically or diastereomerically enriched mixture of oxides of formula I'.

2 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/139,239Filed 19 Oct 1993 · continuation in part
Priority: GB 911763915 Aug 1991
Granted: 30 Apr 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 211/48
Attached in position 4: having an acyclic carbon atom attached in position 4
C07D 211/52
Attached in position 4: having an aryl radical as the second substituent in position 4
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms