US 5,346,907 AGranted

Amino acid analog CCK antagonists

AssigneeAbbott Laboratories

InventorsJames F. Kerwin, Jr., Mark W. Holladay, Michael J. Bennett

Life of this patent

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Abstract

Analogs of CCK-tetrapeptides, which analogs have the formula ##STR1## wherein A, B, D, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are specifically defined, having activity as CCK antagonists, useful in the treatment or prevention of disorders of the gastrointestinal, central nervous, appetite regulating or pain regulating systems.

Claims6

Dependent claims

A compound of the formula:

##STR8## or a pharmaceutically-acceptable salt, ester or amide thereof, wherein:
A is heteroaryl or substituted heteroaryl;
B is absent, or is O, N, S, ethylene, or substituted ethylene;
R.sup.1 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
R.sup.2 is:
(1) hydrogen,
(2) aryl-C.sub.1 -C.sub.3 -alkyl, or
(3) when R.sup.3 is hydrogen, additionally C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, or C.sub.2 -C.sub.6 -alkenyl;
or
R.sup.2 and D are linked together with the atoms to which they are attached to form:
(a) --C.sub.4 -C.sub.7 -alkylene, or
(b) --(CH.sub.2).sub.q -G-(CH.sub.2).sub.q -, wherein q is independently 1, 2 or 3 at each occurrence and G is O or S;
D is selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1 -C.sub.6 -alkyl,
(3) C.sub.2 -C.sub.6 -alkenyl,
(4) C.sub.3 -C.sub.7 -cycloalkyl,
(5) aryl,
(6) substituted aryl,
(7) Het,
(8) substituted Het,
(9) aryl-C.sub.1 -C.sub.6 -alkyl-,
(10) Het-C.sub.1 -C.sub.6 -alkyl-,
(11) substituted Het-C.sub.1 -C.sub.6 -alkyl-,
(12) aryl-(mono-substituted-C.sub.1 -C.sub.6 -alkyl)-,
(13) Het-(mono-substituted-C.sub.1 -C.sub.6 -alkyl)-,
(14) R.sup.6 -O-C.sub.1 -C.sub.6 -alkyl-, wherein:
R.sup.6 is:
(i) hydrogen,
(ii) C.sub.1 -C.sub.6 -alkyl,
(iii) aryl-C.sub.1 -C.sub.6 -alkyl-,
(iv) substituted aryl-C.sub.1 -C.sub.6 -alkyl-, or
(v) R.sup.7 --N--R.sup.8 --C(O)--, wherein
R.sup.7 is:
(a) C.sub.1 -C.sub.6 -alkyl,
(b) aryl,
(c) substituted aryl,
(d) Het,
(e) aryl-C.sub.1 -C.sub.6 -alkyl-,
(f) substituted aryl-C.sub.1 -C.sub.6 -alkyl-, or
(g) Het-C.sub.1 -C.sub.6 -alkyl-;
and R.sup.8 is:
(a) hydrogen,
(b) C.sub.1 -C.sub.6 alkyl,
(c) aryl,
(d) substituted aryl, or
(e) aryl-C.sub.1 -C.sub.6 -alkyl-;
or
R.sup.7 and R.sup.8 may be linked together with the atoms to which they are attached to form N--C.sub.4 -C.sub.7 -alkylene or N--(CH.sub.2).sub.q --G--(CH.sub.2).sub.q --, wherein q and G are as defined above;
(15) R.sup.9 --S--C.sub.1 -C.sub.6 -alkyl-, wherein:
R.sup.9 is:
(i) C.sub.1 -C.sub.6 -alkyl,
(ii) C.sub.2 -C.sub.6 -alkenyl,
(iii) aryl-C.sub.1 -C.sub.6 -alkyl-,
(iv) substituted aryl-C.sub.1 -C.sub.6 -alkyl-, or
(v) R.sup.7 --N--R.sup.8 --C(O)--, wherein R.sup.7 and R.sup.8 are as defined above;
(16) R.sup.10 --S(O).sub.n -C.sub.1 -C.sub.6 -alkyl-,
wherein:
n is 1 or 2, and
R.sup.10 is C.sub.1 -C.sub.6 -alkyl-, aryl-C.sub.1 -C.sub.6 -alkyl-, or substituted aryl-C.sub.1 -C.sub.6 -alkyl-;
and
(17) R.sup.11 --NH--C.sub.1 -C.sub.6 -alkyl-, wherein:
R.sup.11 is:
(i) hydrogen,
(ii) N-protecting group, or
(iii) R.sup.7 --J--CO--, wherein R.sup.7 is as defined above, and J is:
(a) absent,
(b) ethylene,
(c) substituted ethylene,
(d) O,
(e) O--CH.sub.2,
(f) s,
(f) S--CH.sub.2,
(h) NH, or
(i) N(C.sub.1 -C.sub.3 -alkyl);
or
(18) D is linked together with R.sup.2 and atoms to which they are attached to form C.sub.4 -C.sub.7 -alkylene or --(CH.sub.2).sub.q -G-(CH.sub.2).sub.q -, wherein q and G are as defined above;
or
(19) D is linked together with R.sup.3 and atoms to which they are attached to form --CO--N--C.sub.3 -C.sub.6 -alkylene or --CO--N--(CH.sub.2).sub.q --G--(CH.sub.2).sub.q --, wherein q and G are as defined above;
R.sup.3 is hydrogen or if R.sup.2 or D is hydrogen, then additionally:
(1) C.sub.1 -C.sub.6 -alkyl,
(2) C.sub.1 -C.sub.3 -alkyl--O--C.sub.1 -C.sub.3 -alkyl,
(3) C.sub.2 -C.sub.6 -alkenyl,
(4) aryl-C.sub.1 -C.sub.6 -alkyl-,
(5) C.sub.3 -C.sub.7 -cycloalkyl, or
(6) --C.sub.1 -C.sub.6 -alkylene-CO.sub.2 -R.sup.14, wherein R.sup.14 is C.sub.1 -C.sub.6 -alkyl or C.sub.3 -C.sub.7 -cycloalkyl;
or
R.sup.3 and D may be linked together to form --CO--N--C.sub.3 -C.sub.5 -alkylene or --CO--N--(CH.sub.2).sub.q --G--(CH.sub.2).sub.q --, wherein q and G are as defined above:
R.sup.4 is selected from the group consisting of:
(1) C.sub.1 -C.sub.3 -alkyl,
(2) C.sub.1 -C.sub.3 -alkyl-O--C.sub.1 -C.sub.3 -alkyl,
(3) C.sub.2 -C.sub.4 -alkenyl,
(4) aryl,
(5) aryl-C.sub.1 -C.sub.6 -alkyl-,
(6) C.sub.3 -C.sub.7 -cycloalkyl,
(7) cyano-C.sub.1 -C.sub.6 -alkyl, or
(8) --C.sub.1 -C.sub.3 -alkylene-CO.sub.2 -R.sup.14,wherein R.sup.14 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl, or aryl- C.sub.1 -C.sub.6 -alkylene;
or
if R.sup.2 is hydrogen, then R.sup.3 and R.sup.4 may be additionally linked to form:
##STR9## wherein:
r is independently at each occurrence 1 or 2, Q is CH.sub.2 or O, and
R.sup.17 represents one or two substituents independently selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1 -C.sub.6 -alkyl,
(3) aryl, and
(4) --C(O)--R.sup.18, wherein R.sup.18 is:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) aryl-C.sub.1 -C.sub.3 -alkyl-,
(v) substituted aryl-C.sub.1 -C.sub.3 -alkyl, or
(vi) N--R.sup.19 R.sup.20, wherein:
R.sup.19 is H or C.sub.1 -C.sub.3 alkyl, and
R.sup.20 is aryl, aryl-C.sub.1 -C.sub.6 -alkyl-, or heteroaryl-C.sub.1 -C.sub.6 alkyl-.

111 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/017,565Filed 16 Feb 1993 · continuation in part
Priority: 5 Apr 1988
Granted: 13 Sep 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification39 codes

C07D 213/82
Amides; Imides: in position 3
C07C 237/06
The carbon skeleton being acyclic and saturated: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon…
C07C 237/20
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton containing…
C07C 237/22
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: having nitrogen atoms of amino groups…

Family

Serial177,715Parent of this continuation-in-part · filed 5 Apr 1988
Serial582,896Parent of this continuation-in-part · filed 4 Apr 1989
Serial376,778Parent of this continuation-in-part · filed 7 Jul 1989
Serial793,414Parent of this continuation-in-part · filed 26 Jun 1990
US 5,346,907 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula:

##STR8## or a pharmaceutically-acceptable salt, ester or amide thereof, wherein:
A is heteroaryl or substituted heteroaryl;
B is absent, or is O, N, S, ethylene, or substituted ethylene;
R.sup.1 is hydrogen or C.sub.1 -C.sub.3 -alkyl;
R.sup.2 is:
(1) hydrogen,
(2) aryl-C.sub.1 -C.sub.3 -alkyl, or
(3) when R.sup.3 is hydrogen, additionally C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, or C.sub.2 -C.sub.6 -alkenyl;
or
R.sup.2 and D are linked together with the atoms to which they are attached to form:
(a) --C.sub.4 -C.sub.7 -alkylene, or
(b) --(CH.sub.2).sub.q -G-(CH.sub.2).sub.q -, wherein q is independently 1, 2 or 3 at each occurrence and G is O or S;
D is selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1 -C.sub.6 -alkyl,
(3) C.sub.2 -C.sub.6 -alkenyl,
(4) C.sub.3 -C.sub.7 -cycloalkyl,
(5) aryl,
(6) substituted aryl,
(7) Het,
(8) substituted Het,
(9) aryl-C.sub.1 -C.sub.6 -alkyl-,
(10) Het-C.sub.1 -C.sub.6 -alkyl-,
(11) substituted Het-C.sub.1 -C.sub.6 -alkyl-,
(12) aryl-(mono-substituted-C.sub.1 -C.sub.6 -alkyl)-,
(13) Het-(mono-substituted-C.sub.1 -C.sub.6 -alkyl)-,
(14) R.sup.6 -O-C.sub.1 -C.sub.6 -alkyl-, wherein:
R.sup.6 is:
(i) hydrogen,
(ii) C.sub.1 -C.sub.6 -alkyl,
(iii) aryl-C.sub.1 -C.sub.6 -alkyl-,
(iv) substituted aryl-C.sub.1 -C.sub.6 -alkyl-, or
(v) R.sup.7 --N--R.sup.8 --C(O)--, wherein
R.sup.7 is:
(a) C.sub.1 -C.sub.6 -alkyl,
(b) aryl,
(c) substituted aryl,
(d) Het,
(e) aryl-C.sub.1 -C.sub.6 -alkyl-,
(f) substituted aryl-C.sub.1 -C.sub.6 -alkyl-, or
(g) Het-C.sub.1 -C.sub.6 -alkyl-;
and R.sup.8 is:
(a) hydrogen,
(b) C.sub.1 -C.sub.6 alkyl,
(c) aryl,
(d) substituted aryl, or
(e) aryl-C.sub.1 -C.sub.6 -alkyl-;
or
R.sup.7 and R.sup.8 may be linked together with the atoms to which they are attached to form N--C.sub.4 -C.sub.7 -alkylene or N--(CH.sub.2).sub.q --G--(CH.sub.2).sub.q --, wherein q and G are as defined above;
(15) R.sup.9 --S--C.sub.1 -C.sub.6 -alkyl-, wherein:
R.sup.9 is:
(i) C.sub.1 -C.sub.6 -alkyl,
(ii) C.sub.2 -C.sub.6 -alkenyl,
(iii) aryl-C.sub.1 -C.sub.6 -alkyl-,
(iv) substituted aryl-C.sub.1 -C.sub.6 -alkyl-, or
(v) R.sup.7 --N--R.sup.8 --C(O)--, wherein R.sup.7 and R.sup.8 are as defined above;
(16) R.sup.10 --S(O).sub.n -C.sub.1 -C.sub.6 -alkyl-,
wherein:
n is 1 or 2, and
R.sup.10 is C.sub.1 -C.sub.6 -alkyl-, aryl-C.sub.1 -C.sub.6 -alkyl-, or substituted aryl-C.sub.1 -C.sub.6 -alkyl-;
and
(17) R.sup.11 --NH--C.sub.1 -C.sub.6 -alkyl-, wherein:
R.sup.11 is:
(i) hydrogen,
(ii) N-protecting group, or
(iii) R.sup.7 --J--CO--, wherein R.sup.7 is as defined above, and J is:
(a) absent,
(b) ethylene,
(c) substituted ethylene,
(d) O,
(e) O--CH.sub.2,
(f) s,
(f) S--CH.sub.2,
(h) NH, or
(i) N(C.sub.1 -C.sub.3 -alkyl);
or
(18) D is linked together with R.sup.2 and atoms to which they are attached to form C.sub.4 -C.sub.7 -alkylene or --(CH.sub.2).sub.q -G-(CH.sub.2).sub.q -, wherein q and G are as defined above;
or
(19) D is linked together with R.sup.3 and atoms to which they are attached to form --CO--N--C.sub.3 -C.sub.6 -alkylene or --CO--N--(CH.sub.2).sub.q --G--(CH.sub.2).sub.q --, wherein q and G are as defined above;
R.sup.3 is hydrogen or if R.sup.2 or D is hydrogen, then additionally:
(1) C.sub.1 -C.sub.6 -alkyl,
(2) C.sub.1 -C.sub.3 -alkyl--O--C.sub.1 -C.sub.3 -alkyl,
(3) C.sub.2 -C.sub.6 -alkenyl,
(4) aryl-C.sub.1 -C.sub.6 -alkyl-,
(5) C.sub.3 -C.sub.7 -cycloalkyl, or
(6) --C.sub.1 -C.sub.6 -alkylene-CO.sub.2 -R.sup.14, wherein R.sup.14 is C.sub.1 -C.sub.6 -alkyl or C.sub.3 -C.sub.7 -cycloalkyl;
or
R.sup.3 and D may be linked together to form --CO--N--C.sub.3 -C.sub.5 -alkylene or --CO--N--(CH.sub.2).sub.q --G--(CH.sub.2).sub.q --, wherein q and G are as defined above:
R.sup.4 is selected from the group consisting of:
(1) C.sub.1 -C.sub.3 -alkyl,
(2) C.sub.1 -C.sub.3 -alkyl-O--C.sub.1 -C.sub.3 -alkyl,
(3) C.sub.2 -C.sub.4 -alkenyl,
(4) aryl,
(5) aryl-C.sub.1 -C.sub.6 -alkyl-,
(6) C.sub.3 -C.sub.7 -cycloalkyl,
(7) cyano-C.sub.1 -C.sub.6 -alkyl, or
(8) --C.sub.1 -C.sub.3 -alkylene-CO.sub.2 -R.sup.14,wherein R.sup.14 is C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, aryl, or aryl- C.sub.1 -C.sub.6 -alkylene;
or
if R.sup.2 is hydrogen, then R.sup.3 and R.sup.4 may be additionally linked to form:
##STR9## wherein:
r is independently at each occurrence 1 or 2, Q is CH.sub.2 or O, and
R.sup.17 represents one or two substituents independently selected from the group consisting of:
(1) hydrogen,
(2) C.sub.1 -C.sub.6 -alkyl,
(3) aryl, and
(4) --C(O)--R.sup.18, wherein R.sup.18 is:
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) aryl-C.sub.1 -C.sub.3 -alkyl-,
(v) substituted aryl-C.sub.1 -C.sub.3 -alkyl, or
(vi) N--R.sup.19 R.sup.20, wherein:
R.sup.19 is H or C.sub.1 -C.sub.3 alkyl, and
R.sup.20 is aryl, aryl-C.sub.1 -C.sub.6 -alkyl-, or heteroaryl-C.sub.1 -C.sub.6 alkyl-.

111 more elements

Facts

Application

08/017,565Filed 16 Feb 1993 · continuation in part

Priority

5 Apr 1988

Granted

13 Sep 1994

Term ends

Not estimatedThe source records don’t support an estimate.

Classification39 codes

C07D 213/82
Amides; Imides: in position 3
C07C 237/06
The carbon skeleton being acyclic and saturated: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon…
C07C 237/20
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: the carbon skeleton containing…
C07C 237/22
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: having nitrogen atoms of amino groups…

Family

Serial177,715Parent of this continuation-in-part · filed 5 Apr 1988

Serial582,896Parent of this continuation-in-part · filed 4 Apr 1989

Serial376,778Parent of this continuation-in-part · filed 7 Jul 1989

Serial793,414Parent of this continuation-in-part · filed 26 Jun 1990

US 5,346,907 AThis patent

From the US filing history. Foreign family members aren’t listed.