US2004167102A1PendingUtilityA1
Isoprenoid analog compounds and methods of making and use thereof
Est. expiryApr 3, 2021(expired)· nominal 20-yr term from priority
A61K 49/0021C07F 9/113C07F 9/3839C07F 9/4015C07F 9/098
57
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Claims
Abstract
The invention provides compounds of formula I: wherein X, R 1 , R 2 , and n have any of the values defined in the specification, and their pharmaceutically acceptable salts. The compounds are useful, for example, for blocking prenylation transferase enzymes, for probing or diagnosing protein prenylation processes, and for treating cancer in a mammal. The invention also provides pharmaceutical compositions, processes for preparing compounds of formula I, and intermediates useful for the synthesis of compounds of formula I.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula I:
wherein:
X is independently O or S;
R 1 is a detectable group;
R 2 is independently
OH,
(C 1 -C 10 )alkanoyloxy,
—O—P(═O)(—OR a ) 2 ,
—O—P(═O)(—OR a )—O—P(═O)(—OR a ) 2 ,
—CH 2 —O—P(═O)(—OR a ) 2 ,
—CH 2 —O—P(═O)(—OR a )—O—P(═O)(—OR a ) 2 ,
—CH 2 —P(═O)(—OR a ) 2 ,
—CH{—P(═O)(—OR a ) 2 } 2 ,
—CH 2 —P(═O)(—OR a )—O—P(═O)(—OR a ) 2 ,
—CH═CH{—P(═O)(—OR a ) 2 }, or
—CH═C{—P(═O)(—OR a ) 2 } 2 ;
each R a is independently hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkanoyl, (C 1 -C 10 )alkanoyloxy, (C 1 -C 10 )alkoxycarbonyl, or —CH 2 —O—(C 1 -C 10 )alkanoyl;
n is independently 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 wherein the detectable group is aryl or Het, optionally substituted with one or more substituents independently selected from —COOR b , —S(O) n NR b R b , halo, cyano, nitro, aryl, heterocycle, (C 1 -C 10 )alkoxy, (C 2 -C 6 )alkenyl, —C(═O)NR b R b , —OC(═O)NR b R b , —NR b R b , or —S(O) n R b , where each R b is independently hydrogen, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkanoyl.
3 . The compound of claim 2 wherein aryl or Het is phenyl, indenyl, naphthyl, anthracenyl, or anthranil, which aryl or Het is optionally substituted with one or more substituents independently selected from —COOR b , —S(O) n NR b R b , halo, cyano, nitro, aryl, heterocycle, (C 2 -C 6 )alkenyl, —C(═O)NR b R b , —OC(═O)NR b R b , —NR b R b , or —S(O) n R b , where each R b is independently hydrogen, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkanoyl.
4 . The compound of claim 1 wherein R 1 is substituted phenyl.
5 . The compound of claim 1 wherein R 1 is phenyl substituted with —COOR b .
6 . The compound of claim 1 wherein R 1 is 2-methoxycarboxy phenyl.
7 . The compound of claim 1 wherein R 1 is substituted naphthyl.
8 . The compound of claim 1 wherein R 1 is naphthyl substituted with a —S(O) n NR b R b .
9 . The compound of claim 1 wherein R 1 is naphthyl substituted at the 5-position with a —S(O) n NR b R b substituent.
10 . The compound of claim 1 wherein R 1 is 5-N,N′—dimethylaminosulfonyl naphthy-1-yl.
11 . The compound of claim 1 wherein R 2 is OH.
12 . The compound of claim 1 wherein R 2 is (C 1 -C 10 )alkanoyloxy.
13 . The compound of claim 1 wherein R 2 is —O—P(═O)(—OR a ) 2 .
14 . The compound of claim 1 wherein R 2 is —O—P(═O)(—OR a )—O—P(═O)(—OR a ) 2 .
15 . The compound of claim 1 wherein R 2 is —CH 2 —O—P(═O)(—OR a ) 2 .
16 . The compound of claim 1 wherein R 2 is —CH 2 —O—P(═O)(—OR a )—O—P(═O)(—OR a ) 2 .
17 . The compound of claim 1 wherein R 2 is —CH 2 —P(═O)(—OR a ) 2 .
18 . The compound of claim 1 wherein R 2 is —CH{—P(═O)(—OR a ) 2 } 2 .
19 . The compound of claim 1 wherein R 2 is —CH 2 —P(═O)(—OR a )—O—P(═O)(—OR a ) 2 .
20 . The compound of claim 1 wherein R 2 is —CH═CH{—P(═O)(—OR a ) 2 }.
21 . The compound of claim 1 wherein R 2 is —CH═C {—P(═O)(—OR a ) 2 } 2 .
22 . The compound of claim 1 wherein R a is hydrogen.
23 . The compound of claim 1 wherein R a is —C(═O)—CH 3 .
24 . The compound of claim 1 wherein R a is —CH 3 .
25 . The compound of claim 1 wherein R a is —CH 2 —O—(C 1 -C 6 )alkanoyl.
26 . The compound of claim 2 wherein R b is hydrogen.
27 . The compound of claim 2 wherein R b is —CH 3 .
28 . The compound of claim 1 wherein n is 1.
29 . The compound of claim 1 wherein n is 2.
30 . The compound of claim 1 wherein n is 3.
31 . The compound of claim 1 wherein X is —O—.
32 . The compound of claim 1 wherein X is —S—.
33 . A pharmaceutical composition comprising a compound as described in claim 1 and a pharmaceutically acceptable diluent or carrier.
34 . A method of treating cancer, comprising administering to a mammal afflicted with cancer, an amount of a compound as described in claim 1 effective to treat said cancer.
35 . A method of inhibiting a prenylation transferase enzyme or synthase enzyme comprising contacting the enzyme with an effective amount of a compound as described in claim 1 .
36 . A method of accessing the metabolic status of an enzyme comprising:
contacting the enzyme with an effective amount of a mixture of a farnesol analog compound and a geraniol or geranylgeraniol analog compound as described in claim 1; and measuring the relative ratio of farnesylation to geranylgeranylation of the famesol and the geraniol or geranylgeraniol analog compounds accomplished by the enzyme.
37 . A compound as described in claim 1 for use in medical therapy or diagnosis.
38 . The compound of claim 37 wherein the therapy or diagnosis is treating cancer.
39 . The use of a compound as described in claim 1 for the manufacture of a medicament useful for the treatment of cancer.
40 . The use of a compound as described in claim 1 for the manufacture of a medicament useful for inhibiting prenylation transferase enzymes in a mammal.
41 . A protein conjugate comprising a protein linked to a fluorescent fragment of a compound of claim 1.Cited by (0)
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