IP Library › Granted Patent US 8,987,295

Granted Patent B2

US 8,987,295 · App. 13/707,265 · Granted Mar 24, 2015

Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof

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Quick Facts

Patent No.: US 8,987,295
App. No.: 13/707,265
Granted: Mar 24, 2015
Kind: B2

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Abstract

The present invention is directed to substituted azoanthracene derivatives or pharmaceutically acceptable salts thereof that modulate the human GLP-1 receptor and that may be useful in the treatment of diseases, disorders, or conditions in which modulation of the human GLP-1 receptor is beneficial, such as diabetes mellitus type 2. The invention is also directed to pharmaceutical compositions comprising these compounds and to the use of these compounds and compositions in the treatment of such diseases, disorders, or conditions in which modulation of the human GLP-1 receptor is beneficial.

Claims (211)

1. A method of treating diabetes mellitus type 2comprising administering to a human a compound selected from the group consisting of:

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4-pyridin-4-yl-phenyl)-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3-Chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(4-Chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-(4-Cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,3-Dimethyl-butoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-3-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-2-{[(3S,8S)-3-(4-isobutoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(Bicyclo[2.2.1]hept-2-yloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dimethyl-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]propionic acid;

(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-thiazol-2-ylmethyl-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(1-methyl-cyclobutylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(1,1-dimethyl-propylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(2,5-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(4-Chloro-cyclohexyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(5-Chloro-pyridin-3-ylmethoxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-({(3S,8S)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-{4-[2-(3,4-Dichloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2-methyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid; and

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2,4-dimethyl-oxazole-5-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid; or

a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound is

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4-pyridin-4-yl-phenyl)-propionic acid or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is

4. The method of claim 1 , wherein the compound is

5. The method of claim 1 , wherein the compound is

6. The method of claim 1 , wherein the compound is (S)-2-{[(3S,8S)-3-[4-(3,5-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound is (S)-2-{[(3S,8S)-3-{4-[2-(3,4-Dichloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is (S)-2-{[(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

9. A method to lower blood glucose in a human, to increase glucose-dependent insulin secretion by a human pancreatic beta-cell, to suppress glucagon secretion in a human, or to slow gastric emptying in a human comprising administering to a human a compound selected from the group consisting of:

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4-pyridin-4-yl-phenyl)-propionic acid;

(S)-3-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-2-{[(3S,8S)-3-(4-isobutoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid;

(S)-2-{[(3S,8S)-3-[4-(3,5-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid; p 1 (S)-2-{[(3S,8S)-3-{4-[2-(3,4-Dichloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;

a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the compound is

(S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4-pyridin-4-yl-phenyl)-propionic acid or a pharmaceutically acceptable salt thereof.

11. The method of claim 9 , wherein the compound is

12. The method of claim 9 , wherein the compound is

13. The method of claim 9 , wherein the compound is

14. The method of claim 9 , wherein the compound is (S)-2-{[(3S,8S)-3-[4-(3,5-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

15. The method of claim 9 , wherein the compound is (S)-2-{[(3S,8S)-3-{4-[2-(3,4-Dichloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

16. The method of claim 9 , wherein the compound is (S)-2-{[(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

17. The method of claim 9 , wherein the method lowers blood glucose in a human.

18. The method of claim 9 , wherein the method increases glucose-dependent insulin secretion by a human pancreatic beta-cell.

19. The method of claim 9 , wherein the method suppresses glucagon secretion in a human.

20. The method of claim 9 , wherein the method slows gastric emptying in a human.

21. A method of treating diabetes mellitus type 2comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein

W and Z are an oxygen atom;

X is —CH 2 —;

Y is —CH(R 5 )—;

wherein

R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

G 3 is 1,4-phenylene optionally substituted 1 to 4 times with substituents independently selected from halogen, methyl, ethyl, isopropyl, —CF 3 , —CH 2 CF 3 , —CN, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCH 2 CF 3 , —S(O) 2 —CH 3 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , and —C(O)—CH 3 ;

L 2 is —O—;

L 3 is a direct bond;

Q 2 is —CH 2 —,

G 4 is phenyl optionally substituted 1 to 4 times with substituents independently selected from halogen, methyl, ethyl, isopropyl, —CF 3 , —CH 2 CF 3 , —CN, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCH 2 CF 3 , —S(O) 2 —CH 3 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , and —C(O)—CH 3 ;

R 1 is —CO 2 H;

R 2 is hydrogen;

R 3 is selected from the group consisting of:

a) —CO 2 -tert-butyl,

b) —CO 2 -n-hexyl,

c) —CO 2 -isopropyl,

d) —CO 2 -(tert-butylcyclohexyl)

e) —CO 2 -tetrahydrofuran-2-yl,

f) —CO 2 -tetrahydropyran-4-yl,

g) —CO 2 —CH 2 -cyclopropyl,

h) —C(O)NH-(tert-butylphenyl),

i) —C(O)-piperidin-2-yl,

j) —C(O)—NH-(trifluoromethoxyphenyl),

k) —C(O)—NH-(1,1-diphenylmethyl),

l) —C(O)-isopropyl,

m) —C(O)-phenyl,

n) —C(O)-(fluorophenyl),

o) —C(O)-(chlorophenyl),

p) —C(O)-(cyanophenyl),

q) —C(O)-pyridin-2-yl,

r) —C(O)-pyrimidin-4-yl,

s) —C(O)-furan-2-yl,

t) —C(O)-cyclobutyl,

u) —C(O)-cyclopentyl,

v) —C(O)-cyclohexyl,

w) —C(O)-thiophene-2-yl,

x) —C(O)-benzyl,

y) —C(O)-(fluorobenzyl),

z) —C(O)-(chlorobenzyl),

aa) —C(O)-(cyanobenzyl),

bb) —C(O)-(2,5-dimethyl-oxazol-4-yl),

cc) —CH 2 -oxazol-2-yl,

dd) —CH 2 -(1-methylimdiazol-2-yl),

ee) —CH 2 -pyridin-2-yl,

ff) —CH 2 -furan-2-yl,

gg) —CH 2 -thiazol-2-yl,

hh) —CH 2 —C≡C-pyrimidin-2-yl,

ii) —CH 2 —C≡C-phenyl,

jj) —CH 2 -thiophene-2-yl,

kk) —(R)-1-(phenyl)-propyl, and

ll) —(S)-1-(phenyl)-propyl;

R is —(CH 2 ) p -G 1 -L 1 -G 2 ;

wherein

p is 1;

L 1 is a direct bond or —O—;

G′ is 1,4-phenylene; and

G 2 is 2,3-dimethyl-pyridine-4-yl; and

R q is hydrogen.

22. A method to lower blood glucose in a human, to increase glucose-dependent insulin secretion by a human pancreatic beta-cell, to suppress glucagon secretion in a human, or to slow gastric emptying in a human comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein

W and Z are an oxygen atom;

X is —CH 2 —;

Y is —CH(R 5 )—;

wherein

R 5 is -G 3 -L 2 -Q 2 -L 3 -G 4 , wherein

L 2 is —O—;

L 3 is a direct bond;

Q 2 is —CH 2 —,

R 1 is —CO 2 H;

R 2 is hydrogen;

R 3 is selected from the group consisting of:

a) —CO 2 -tert-butyl,

b) —CO 2 -n-hexyl,

c) —CO 2 -isopropyl,

d) —CO 2 -(tert-butylcyclohexyl)

e) —CO 2 -tetrahydrofuran-2-yl,

f) —CO 2 -tetrahydropyran-4-yl,

g) —CO 2 —CH 2 -cyclopropyl,

h) —C(O)NH-(tert-butylphenyl),

i) —C(O)-piperidin-2-yl,

j) —C(O)—NH-(trifluoromethoxyphenyl),

k) —C(O)—NH-(1,1-diphenylmethyl),

l) —C(O)-isopropyl,

m) —C(O)-phenyl,

n) —C(O)-(fluorophenyl),

o) —C(O)-(chlorophenyl),

p) —C(O)-(cyanophenyl),

q) —C(O)-pyridin-2-yl,

r) —C(O)-pyrimidin-4-yl,

s) —C(O)-furan-2-yl,

t) —C(O)-cyclobutyl,

u) —C(O)-cyclopentyl,

v) —C(O)-cyclohexyl,

w) —C(O)-thiophene-2-yl,

x) —C(O)-benzyl,

y) —C(O)-(fluorobenzyl),

z) —C(O)-(chlorobenzyl),

aa) —C(O)-(cyanobenzyl),

bb) —C(O)-(2,5-dimethyl-oxazol-4-yl),

cc) —CH 2 -oxazol-2-yl,

dd) —CH 2 -(1-methylimdiazol-2-yl),

ee) —CH 2 -pyridin-2-yl,

ff) —CH 2 -furan-2-yl,

gg) —CH 2 -thiazol-2-yl,

hh) —CH 2 —C≡C-pyrimidin-2-yl,

ii) —CH 2 —C≡C-phenyl,

jj) —CH 2 -thiophene-2-yl,

kk) —(R)-1-(phenyl)-propyl, and

ll) —(S)-1-(phenyl)-propyl;

R is —(CH 2 ) p -G 1 -L 1 -G 2 ;

wherein

p is 1;

L 1 is a direct bond or —O—;

G 1 is 1,4-phenylene; and

G 2 is 2,3-dimethyl-pyridine-4-yl; and

R q is hydrogen.

Assignments (12)

RELEASE OF SECURITY INTEREST Recorded Jan 27, 2021

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ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2015

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CHANGE OF NAME Recorded Jun 25, 2015

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SECURITY INTEREST Recorded Feb 26, 2015

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ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 26, 2013

From: TRANSTECH PHARMA, INC.

To: TRANSTECH PHARMA, LLC

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SECURITY AGREEMENT Recorded Aug 9, 2013

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ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 11, 2013

From: MJALLI, ADNAN M.M.; BEHME, CHRISTOPHER; CHRISTEN, DANIEL P.; GOHIMUKKULA, DEVI REDDY; POLISETTI, DHARMA RAO; QUADA, JAMES; FREEMAN, JENNIFER L.R.; SANTHOSH, KALPATHY; BONDLELA, MURALIDHAR; GUZEL, MUSTAFA; YARRAGUNTA, RAVINDRA REDDY; ANDREWS, ROBERT CARL; DAVIS, STEPHEN THOMAS; YOKUM, THOMAS SCOTT

To: TRANSTECH PHARMA, INC.

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