IP Library › Granted Patent US 8,383,644

Granted Patent B2

US 8,383,644 · App. 12/825,631 · Granted Feb 26, 2013

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

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Quick Facts

Patent No.: US 8,383,644
App. No.: 12/825,631
Granted: Feb 26, 2013
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 (117)

1. A compound, wherein the compound is selected from the group consisting of:

(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-methyl-pyridin-4-yloxy)-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-(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. A compound, 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. A compound, wherein the compound is

(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 or a pharmaceutically acceptable salt thereof.

4. A compound, wherein the compound is

(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 or a pharmaceutically acceptable salt thereof.

5. A compound, wherein the compound is

6. A compound, 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. A compound, 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. A compound, 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 pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

10. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

11. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

12. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

13. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

14. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

15. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

16. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

17. 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-di methyl-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.

18. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

19. A compound of claim 2 , 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.

20. A compound of claim 3 , wherein the compound is

21. A compound of claim 4 , wherein the compound is

22. A compound of claim 5 , wherein the compound is

23. A compound of claim 6 , 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.

24. A compound of claim 7 , 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.

25. A compound of claim 8 , 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.

Assignments (12)

RELEASE OF SECURITY INTEREST Recorded Jan 27, 2021

From: HORIZON TECHNOLOGY FINANCE CORPORATION, AS COLLATERAL AGENT

To: VTV THERAPEUTICS LLC

Reel/Frame 055133/0214 →

SECURITY INTEREST Recorded Apr 18, 2018

From: VTV THERAPEUTICS LLC

To: HORIZON TECHNOLOGY FINANCE CORPORATION, AS COLLATERAL AGENT

Reel/Frame 045969/0774 →

CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY DATA PREVIOUSLY RECORDED AT REEL: 036254 FRAME: 0780. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Sep 24, 2015

From: M&F TTP HOLDINGS LLC, AS COLLATERAL AGENT

To: VTVX HOLDINGS I LLC

Reel/Frame 036675/0407 →

RELEASE OF SECURITY INTEREST Recorded Aug 3, 2015

From: M&F TTP HOLDINGS LLC, AS COLLATERAL AGENT

To: VTVX HOLDINGS II LLC

Reel/Frame 036254/0780 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2015

From: VTVX HOLDINGS I LLC

To: VTV THERAPEUTICS LLC

Reel/Frame 036242/0354 →

CHANGE OF NAME Recorded Jul 30, 2015

From: VTV THERAPEUTICS LLC

To: VTVX HOLDINGS I LLC

Reel/Frame 036236/0165 →

CHANGE OF NAME Recorded Jun 25, 2015

From: TRANSTECH PHARMA, LLC

To: VTV THERAPEUTICS LLC

Reel/Frame 036026/0219 →

SECURITY INTEREST Recorded Feb 26, 2015

From: TRANSTECH PHARMA, LLC

To: M&F TTP HOLDINGS LLC, AS COLLATERAL AGENT

Reel/Frame 035103/0356 →

NOTICE OF RELEASE OF SECURITY INTEREST IN PATENTS FOR REEL/FRAME 030982/0803 Recorded Apr 7, 2014

From: M&F TTP HOLDINGS LLC

To: TRANSTECH PHARMA, LLC

Reel/Frame 032621/0860 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 22, 2013

From: TRANSTECH PHARMA, INC.

To: TRANSTECH PHARMA, LLC

Reel/Frame 031654/0878 →

SECURITY AGREEMENT Recorded Aug 9, 2013

From: TRANSTECH PHARMA, INC.

To: M&F TTP HOLDINGS LLC C/O MACANDREWS & FORBES HOLDINGS INC.

Reel/Frame 030982/0803 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 25, 2010

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.

Reel/Frame 024884/0796 →