US2008262001A1PendingUtilityA1
Agonists of a2a adenosine receptors for treating recurrent tumor growth in the liver following resection
Assignee: ADENOSINE THERAPEUTICS LLCPriority: Apr 23, 2007Filed: Apr 14, 2008Published: Oct 23, 2008
Est. expiryApr 23, 2027(~0.8 yrs left)· nominal 20-yr term from priority
C07H 19/16A61P 35/00A61P 35/04A61K 31/52
51
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Claims
Abstract
The present invention relates to a method for treating recurrent tumor metastases following liver resection that includes administration of an effective amount of an agonist of A 2A adenosine receptors (ARs).
Claims
exact text as granted — not AI-modified1 . A method for treating recurrent tumor metastases following liver resection, comprising:
administering to a patient in need thereof a therapeutically effective amount of an A 2A adenosine receptor agonist.
2 . The method of claim 1 , wherein the agonist is administered prior to liver resection.
3 . The method of claim 1 , wherein the agonist is administered during liver resection.
4 . The method of claim 1 , wherein the agonist is administered post liver resection.
5 . The method of claim 1 , wherein the agonist is administered prior to and post liver resection.
6 . The method of claim 1 , wherein the agonist comprises: a substituted 6-amino-9-(tetrahydrofuran-2′-yl)purine, or a pharmaceutically acceptable salt thereof.
7 . The method of claim 1 wherein the agonist comprises: a 6-amino-9-(3′,4′-dihydroxy-tetrahydrofuran-2′-yl)purine substituted at the 3- and 5′-positions, or a pharmaceutically acceptable salt thereof.
8 . The method of claim 1 , wherein the agonist comprises: a 5-[6-amino-2-(3-piperidin-4-yl-prop-1-ynyl)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid cyclopropylamide, substituted on the piperidine nitrogen, or a pharmaceutically acceptable salt thereof.
9 . The method of claim 1 wherein the agonist comprises: a 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid ester or a pharmaceutically acceptable salt thereof.
10 . The method of claim 1 , wherein the agonist comprises: a 5-[6-amino-2-(3-piperidin-4-yl-prop-1-ynyl)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide, substituted on the piperidine nitrogen, or a pharmaceutically acceptable salt thereof.
11 . The method of claim 1 , wherein the agonist comprises: a 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid ester or a pharmaceutically acceptable salt thereof.
12 . The method of claim 1 , wherein the A 2A adenosine receptor agonist is a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein
Z a is C≡C, O, NH, or NHN═CR 3a ;
Z is CR 3 R 4 R 5 or NR 4 R 5 ;
each R 1 is independently hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryl(C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, —OPO 3 R a , R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O)—, R a S(═O) 2 —, or —N═NR b ;
each R 2 is independently hydrogen, halo, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryl(C 1 -C 8 )alkylene-, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene-;
alternatively, R 1 and R 2 and the atom to which they are attached is C═O, C═S or C═NR d ,
R 4 and R 5 are independently H or (C 1 -C 8 )alkyl;
alternatively, R 4 and R 5 together with the atom to which they are attached form a saturated, partially unsaturated, or aromatic ring that is mono-, bi- or polycyclic and has 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms optionally having 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine (—NR b —) in the ring;
wherein R 4 and R 5 are independently substituted with 0-3 R 6 groups or any ring comprising R 4 and R 5 is substituted with from 0 to 6 R 6 groups;
each R 6 is independently hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocycle, heterocycle (C 1 -C 8 )alkylene-, aryl, aryl (C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, —OPO 3 R a , R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O)—, —NNR b , or two R 6 groups and the atom to which they are attached is C═O, C═S; or two R 6 groups together with the atom or atoms to which they are attached can form a carbocyclic or heterocyclic ring comprising from 1-6 carbon atoms and 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine (—NR b —) in the ring;
R 3 is hydrogen, halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryl(C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R b , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, —OPO 3 R a , R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O)—, R a S(═O) 2 —, —NNR b ; or if the ring formed from CR 4 R 5 is aryl or heteroaryl or partially unsaturated then R 3 can be absent;
R 3a is hydrogen, (C 1 -C 8 )alkyl, or aryl;
each R 7 is independently hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene-;
X is —CH 2 OR a , —CO 2 R a , —CH 2 OC(O)R a , —C(O)NR b R c , —CH 2 SR a , —C(S)OR a , —CH 2 OC(S)R a , —C(S)NR b R c , or —CH 2 N(R b )(R c );
alternatively, X is an aromatic ring of the formula:
each Z 1 is non-peroxide oxy (—O—), S(O) 0-2 , —C(R 8 )—, or amine (—NR 8 —), provided that at least one Z 1 is non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine (—NR 8 —);
each R 8 is independently hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkylene, (C 3 -C 8 )cycloalkenyl, (C 3 -C 8 )cycloalkenyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene, wherein any of the alkyl or alkenyl groups of R 8 are optionally interrupted by —O—, —S—, or —N(R a )—;
wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, groups of R 1 , R 2 , R 3 , R 3a , R 6 , R 7 and R 8 is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of halo, —OR a , —SR a , (C 1 -C 8 )alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, heterocycle, heterocycle(C 1 -C 8 )alkylene-, aryl, aryloxy, aryl(C 1 -C 8 )alkylene-, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, —CO 2 R a , R a C(═O)O—, R a C(═O)—, —OCO 2 R a , R b R c NC(═O)O—, R a OC(═O)N(R b )—, R b R c N—, R b R c NC(═O)—, R a C(═O)N(R b )—, R b R c NC(═O)N(R b )—, R b R c NC(═S)N(R b )—, —OPO 3 R a , R a OC(═S)—, R a C(═S)—, —SSR a , R a S(═O) p —, R b R c NS(O) p —, and —N═NR b ;
wherein any (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 12 )bicycloalkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkanoyl, (C 1 -C 8 )alkylene, or heterocycle, is optionally partially unsaturated;
each R a , R b and R c is independently hydrogen, (C 1 -C 12 )alkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkoxy-(C 1 -C 12 )alkylene, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl-(C 6 -C 12 )alkylene, (C 1 -C 8 )alkylthio, amino acid, aryl, aryl(C 1 -C 8 )alkylene, heterocycle, heterocycle-(C 1 -C 8 )alkylene, heteroaryl, or heteroaryl(C 1 -C 8 )alkylene;
alternatively R b and R c , together with the nitrogen to which they are attached, form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl groups of R a , R b and R c is optionally substituted on carbon with 1 or 2 substituents selected from the group consisting of halo, —(CH 2 ) a OR e , —(CH 2 ) a SR e , (C 1 -C 8 )alkyl, (CH 2 ) a CN, (CH 2 ) a NO 2 , trifluoromethyl, trifluoromethoxy, —(CH 2 ) a CO 2 R 3 , (CH 2 ) a NR e R e , and (CH 2 ) a C(O)NR e R e ;
R d is hydrogen or (C 1 -C 6 )alkyl;
R e is independently selected from H and (C 1 -C 6 )alkyl;
a is 0, 1, or 2;
i is 1 or 2
m is 0 to 8; and
p is 0 to 2;
provided that m is at least 1 when Z is NR 4 R 5 ; or
a pharmaceutically acceptable salt thereof.
13 . The method of claim 9 , wherein the A 2A adenosine receptor agonist is a compound selected from the compounds of the following table or a stereoisomer or pharmaceutically acceptable salt thereof:
Ex. #
R c
R 7
—(R 1 ) m —Z
1.
Et
H
2.
Et
H
3.
cPr
H
4.
Et
H
5.
cPr
H
6.
Et
H
7.
cPr
H
8.
Et
H
9.
Et
H
10.
Et
H
11.
Et
H
12.
cPr
H
13.
Et
H
14.
cPr
H
15.
Et
H
16.
cPr
H
17.
cPr
H
18.
Et
H
19.
cPr
H
20.
Et
H
21.
cPr
H
22.
Et
H
23.
Et
H
24.
cPr
H
25.
Et
H
26.
Et
H
27.
Et
H
28.
Et
H
29.
Et
H
30.
Et
H
31.
cPr
H
32.
Et
H
33.
Et
H
34.
cPr
H
35.
cPr
H
36.
Et
H
37.
cPr
H
38.
Et
H
39.
cPr
H
40.
Et
H
41.
cPr
H
42.
Et
H
*signifies the point of attachment.
14 . The method of claim 1 , wherein the A 2A adenosine receptor agonist is a compound of formula II or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
R 1 and R 2 independently are selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkylene, aryl, aryl(C 1 -C 8 )alkylene, heteroaryl, heteroaryl(C 1 -C 8 )alkylene-, diaryl(C 1 -C 8 )alkylene, and diheteroaryl(C 1 -C 8 )alkylene, wherein the aryl and heteroaryl rings are optionally substituted with 1-4 groups independently selected from fluoro, chloro, iodo, bromo, methyl, trifluoromethyl, and methoxy;
each R independently is selected from the group consisting of H, C 1 -C 4 alkyl, cyclopropyl, cyclobutyl, and (CH 2 ) a cyclopropyl;
X is CH or N, provided that when X is CH then Z cannot be substituted with halogen, C 1 -C 6 alkyl, hydroxyl, amino, or mono- or di-(C 1 -C 6 -alkyl)amino;
Y is selected from the group consisting of O, NR 1 , —(OCH 2 CH 2 O) m CH 2 —, and —(NR 1 CH 2 CH 2 O) m CH 2 —, provided that when Y is O or NR 1 , then at least one substituent is present on Z;
Z is selected from the group consisting of 5-membered heteroaryl, 6-membered aryl, 6-membered heteroaryl, carbocyclic biaryl, and heterocyclic biaryl, wherein the point of attachment of Y to Z is a carbon atom on Z, wherein Z is substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, (C 1 -C 4 )alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 R 3 , —NHOH, —NR 3 NR 3 R 3 , nitro, —(CH 2 ) a CN, (CH 2 ) a CO 2 R 3 , —(CH 2 ) a CONR 3 R 3 , trifluoromethyl, and trifluoromethoxy;
alternatively, Y and Z together form an indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety wherein the point of attachment is via the ring nitrogen and wherein said indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety, which is substituted with 0-4 groups independently selected from the group consisting of F, Cl, Br, I, C 1 -C 4 alkyl, —(CH 2 ) a OR 3 , —(CH 2 ) a NR 3 NR 3 R 3 , —NHOH, —NR 3 NR 3 R 3 , NO 2 , —(CH 2 ) a CN, —(CH 2 ) a CO 2 R 3 , —(CH 2 ) a CONR 3 R 3 , CF 3 , and OCF 3 ;
R 3 is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, cycloalkyl, aryl, and heteroaryl;
R 4 is selected from the group consisting of CH 2 OR, C(O)NRR, and CO 2 R;
R 5 is selected from the group consisting of CH 2 CH 2 , CH═CH, and C≡C;
a is selected from 0, 1, and 2;
m is selected from 1, 2, and 3;
n is selected from 0, 1, and 2;
each p independently is selected from 0, 1, and 2; and,
q is selected from 0, 1, and 2.
15 . The method of claim 11 , wherein the A 2A adenosine receptor agonist is a compound selected from the compounds of the following table or a stereoisomer or pharmaceutically acceptable salt thereof:
i
ii
iii
R 4 =A: CH 2 OH; B: C(O)NEthyl; C: C(O)NCyclopropyl;
Compounds are of formula (i), unless indicated.
Ex. #
R 4
Z′
1
C
2
C
3
C
4
A
5
C
6
A
7
A
8
C
9
C
10
C
11
A
12
A
13
A
14
C
15
B
16
B
17
C
18
C
19
B
20
C
21
C
22
C
23
C
24
B
25
B
26
B
27
A
28
A
29
A
30
A
31
B
32
B
33
B
34
B
35
A
36
A
37(iii)
B
38(iii)
C
39(iii)
C
40(iii)
C
41(iii)
C
42
C
43(ii)
C
44(ii)
A
45(ii)
A
46(ii)
A
47(ii)
C
48(ii)
C
49
B
50
B
51
C
52
C
53
A
54
A
55
A
56
C
57
C
16 . The method of claim 1 , wherein the A 2A adenosine receptor agonist is a compound of formula (Ib)-(Id) or a pharmaceutically acceptable salt thereof:
17 . The method of claim 1 , wherein the A 2A adenosine receptor agonist is selected from:
or a pharmaceutically acceptable salt thereof.
18 . The method of claim 1 , wherein the A 2A adenosine receptor agonist is a compound of the following formula or a pharmaceutically acceptable salt thereof:
19 . The method of claim 1 , wherein the A 2A adenosine receptor agonist is a compound of the following formula or a pharmaceutically acceptable salt thereof:Cited by (0)
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