US 5,965,614 AGranted

N-(aryl/heteroaryl) amino acid esters, pharmaceutical compositions comprising same, and methods for inhibiting .beta.-amyloid peptide release and/or its synthesis by use of such compounds

AssigneeAthena Neurosciences, Inc.

InventorsJames E. Audia, Beverly K. Folmer, Varghese John, Lee H. Latimer, Jeffrey S. Nissen, Jon K. Reel, Eugene D. Thorsett, Celia A. Whitesitt

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Abstract

Disclosed are compounds which inhibit .beta.-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits .beta.-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

Claims12

Dependent claims

A method for inhibiting .beta.-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of .beta.-amyloid peptide wherein said compounds are represented by formula I:

##STR10## wherein R1 is selected from the group consisting of:
(a) a substituted phenyl group of formula II:
##STR11## wherein R.sup.c is selected from the group consisting of acyl, alkyl, alkoxy, alkoxycarbonyl, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and where R.sup.b and R.sup.c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
R.sup.b and R.sup.b ' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that R.sup.b, R.sup.b ' and R.sup.c are not all hydrogen and with the further proviso that when R.sup.c is hydrogen, then neither R.sup.b nor R.sup.b ' are hydrogen;
(b) 2-naphthyl;
and
(c) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy;
R.sup.2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms and alkylthioalkoxy of from 1 to 4 carbon atoms;
and
R.sup.3 is selected from the group consisting of:
(a) --Y(CH.sub.2).sub.n CHR.sup.4 R.sup.5 wherein n is an integer of from 0 to 2, Y is selected from the group consisting of oxygen and sulfur, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, heteroaryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, and where R.sup.4 and R.sup.5 are joined to form a cycloalkyl group, a cycloalkenyl group or a heterocyclic group;
(b) --ON.dbd.C(NH.sub.2)R.sup.6 where R.sup.6 is selected from the group consisting of alkyl, aryl, cycloalkyl, and heteroaryl;
(c) --O(CH.sub.2).sub.p C(O)OR.sup.7 wherein p is an integer of from 1 to 2 and R.sup.7 is alkyl;
and
(d) --NR.sup.8 R.sup.9 wherein R.sup.8 and R.sup.9 are joined to form a pyrrolyl group;
and pharmaceutically acceptable salts thereof with the provisos that
1. when R.sup.1 is the substituted phenyl group of formula II above, R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.2 is methyl, then R.sup.3 is not --OCH(CH.sub.3)-.phi.;
2.

15 more elements

when R.sup.1 is the substituted phenyl group of formula II above, when R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.3 is --OCH.sub.2 CH.sub.3 then R.sup.2 is not hydrogen;

3. when R.sup.1 is the substituted phenyl group of formula II above, R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.3 is --OCH.sub.2 CH(CH.sub.3).sub.2 then R.sup.2 is not --CH(CH.sub.3)CH.sub.2 CH.sub.3 ;
and
4. when R.sup.1 is N-methylindol-5-yl and R.sup.2 is methyl, then R.sup.3
is not --OCH.sub.2 CH.sub.3. 2. A method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:
##STR12## wherein R.sup.1 is selected from the group consisting of:
(a) a substituted phenyl group of formula II:
##STR13## wherein R.sup.c is selected from the group consisting of acyl, alkyl, alkoxy, alkoxycarbonyl, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and where R.sup.b and R.sup.c are fused to form a heteroaryl or heterocylic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
R.sup.b and R.sup.b ' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that R.sup.b, R.sup.b ' and R.sup.c are not all hydrogen and with the further proviso that when R.sup.c is hydrogen, then neither R.sup.b nor R.sup.b ' are hydrogen;
(b) 2-naphthyl;
and
(c) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy;
R.sup.2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms and alkylthioalkoxy of from 1 to 4 carbon atoms;
and
R.sup.3 is selected from the group consisting of:
(a) --Y(CH.sub.2).sub.n CHR.sup.4 R.sup.5 wherein n is an integer of from 0 to 2, Y is selected from the group consisting of oxygen and sulfur, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, heteroaryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, and where R.sup.4 and R.sup.5 are joined to form a cycloalkyl group, a cycloalkenyl group or a heterocyclic group;
(b) --ON.dbd.C(NH.sub.2)R.sup.6 where R.sup.6 is selected from the group consisting of alkyl, aryl, cycloalkyl, and heteroaryl;
(c) --O(CH.sub.2).sub.p C(O)OR.sup.7 wherein p is an integer of from 1 to 2 and R.sup.7 is alkyl;
and
(d) --NR.sup.8 R.sup.9 wherein R.sup.8 and R.sup.9 are joined to form a pyrrolyl group;
and pharmaceutically acceptable salts thereof with the provisos that
1. when R.sup.1 is the substituted phenyl group of formula II above, R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.2 is methyl, then R.sup.3 is not --OCH(CH.sub.3)-.phi.;
2. when R.sup.1 is the substituted phenyl group of formula II above, when R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.3 is --OCH.sub.2 CH.sub.3 then R.sup.2 is not hydrogen;
3. when R.sup.1 is the substituted phenyl group of formula II above, R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.3 is --OCH.sub.2 CH(CH.sub.3).sub.2 then R.sup.2 is not --CH(CH.sub.3)CH.sub.2 CH.sub.3 ;
and
4. when R.sup.1 is N-methylindol-5-yl and R.sup.2 is methyl, then R.sup.3 is not --OCH.sub.2 CH.sub.3.

22 more elements

A method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

##STR14## wherein R.sup.1 is selected from the group consisting of:
(a) a substituted phenyl group of formula II:
##STR15## wherein R.sup.c is selected from the group consisting of acyl, alkyl, alkoxy, alkoxycarbonyl, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and where R.sup.b and R.sup.c are fused to form a heteroaryl or heterocyclic ring with the phenyl ring wherein the heteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 are heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
R.sup.b and R.sup.b ' are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that R.sup.b, R.sup.b ' and R.sup.c are not all hydrogen and with the further proviso that when R.sup.c is hydrogen, then neither R.sup.b nor R.sup.b ' are hydrogen;
(b) 2-naphthyl;
and
(c) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy;
R.sup.2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms and alkylthioalkoxy of from 1 to 4 carbon atoms;
and
R.sup.3 is selected from the group consisting of:
(a) --Y(CH.sub.2).sub.n CHR.sup.4 R.sup.5 wherein n is an integer of from 0 to 2, Y is selected from the group consisting of oxygen and sulfur, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, heteroaryl optionally substituted with from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy, and where R.sup.4 and R.sup.5 are joined to form a cycloalkyl group, a cycloalkenyl group or a heterocyclic group;
(b) --ON.dbd.C(NH.sub.2)R.sup.6 where R.sup.6 is selected from the group consisting of alkyl, aryl, cycloalkyl, and heteroaryl;
(c) --O(CH.sub.2).sub.p (O)OR.sup.7 wherein p is an integer of from 1 to 2 and R.sup.7 is alkyl;
and
(d) --NR.sup.8 R.sup.9 wherein R.sup.8 and R.sup.9 are joined to form a pyrrolyl group;
and pharmaceutically acceptable salts thereof with the provisos that
1. when R.sup.1 is the substituted phenyl group of formula II above, R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.2 is methyl, then R.sup.3 is not --OCH(CH.sub.3)-.phi.;
2. when R.sup.1 is the substituted phenyl group of formula II above, when R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.3 is --OCH.sub.2 CH.sub.3 then R.sup.2 is not hydrogen;
3. when R.sup.1 is the substituted phenyl group of formula II above, R.sup.b ' is hydrogen, R.sup.b and R.sup.c are chloro, and R.sup.3 is --OCH.sub.2 CH(CH.sub.3).sub.2 then R.sup.2 is not --CH(CH.sub.3)CH.sub.2 CH.sub.3 ;
and
4. when R.sup.1 is N-methylindol-5-yl and R.sup.2 is methyl, then R.sup.3 is not --OCH.sub.2 CH.sub.3.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/975,977Filed 21 Nov 1997
Granted: 12 Oct 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07C 259/10
Without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids: having carbon atoms of hydroxamic groups bound to…
A61K 31/216
Of carboxylic acids: of acids having aromatic rings, e.g. benactizyne, clofibrate
C07C 229/18
Having only one amino and one carboxyl group bound to the carbon skeleton: the nitrogen atom of the amino group being further bound to carbon…
C07C 257/14
With replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines: having carbon atoms of amidino groups bound to…