USH1345H - Method for preventing or treating hepatitis D - Google Patents
Method for preventing or treating hepatitis D Download PDFInfo
- Publication number
- USH1345H USH1345H US07/968,079 US96807992A USH1345H US H1345 H USH1345 H US H1345H US 96807992 A US96807992 A US 96807992A US H1345 H USH1345 H US H1345H
- Authority
- US
- United States
- Prior art keywords
- carbons
- alkyl
- alkenyl
- halogen
- alkynyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 208000005331 Hepatitis D Diseases 0.000 title claims abstract description 10
- 239000003558 transferase inhibitor Substances 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 110
- 125000003342 alkenyl group Chemical group 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- 150000002500 ions Chemical class 0.000 claims description 30
- 229910052751 metal Inorganic materials 0.000 claims description 30
- 239000002184 metal Substances 0.000 claims description 30
- -1 nitro, amino Chemical group 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 14
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrugs Drugs 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 8
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 8
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
- 125000005110 aryl thio group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 6
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 6
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 6
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 6
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 6
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 6
- 241000894007 species Species 0.000 claims description 4
- 229940112871 Bisphosphonate drugs affecting bone structure and mineralization Drugs 0.000 claims 2
- 150000004663 bisphosphonates Chemical group 0.000 claims 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 2
- 102000004169 proteins and genes Human genes 0.000 abstract description 10
- 108090000623 proteins and genes Proteins 0.000 abstract description 10
- 230000000903 blocking Effects 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 101700032244 LHDAG Proteins 0.000 description 14
- 241000724709 Hepatitis delta virus Species 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 10
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 8
- 235000018417 cysteine Nutrition 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229930000007 farnesylpyrophosphate Natural products 0.000 description 8
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 108090000992 Transferases Proteins 0.000 description 6
- 102000004357 Transferases Human genes 0.000 description 6
- 206010047461 Viral infection Diseases 0.000 description 6
- 208000001756 Virus Disease Diseases 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000017613 viral reproduction Effects 0.000 description 6
- 229940107161 Cholesterol Drugs 0.000 description 4
- 108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 description 4
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 4
- XJLXINKUBYWONI-NNYOXOHSSA-N Nicotinamide adenine dinucleotide phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 4
- YYGNTYWPHWGJRM-RUSDCZJESA-N Squalene Natural products C(=C\CC/C(=C\CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)/C)(\CC/C=C(\C)/C)/C YYGNTYWPHWGJRM-RUSDCZJESA-N 0.000 description 4
- 125000004946 alkenylalkyl group Chemical group 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000037348 biosynthesis Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 235000011180 diphosphates Nutrition 0.000 description 4
- 125000003709 fluoroalkyl group Chemical group 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 2
- 125000006040 2-hexenyl group Chemical group 0.000 description 2
- 125000006024 2-pentenyl group Chemical group 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 101710025073 ACR2.1 Proteins 0.000 description 2
- 101710025041 ACR2.2 Proteins 0.000 description 2
- 101700041492 CYS3 Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 241001533413 Deltavirus Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N Mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 2
- 102000019337 Prenyltransferase Human genes 0.000 description 2
- 108050006837 Prenyltransferase Proteins 0.000 description 2
- 229940031439 Squalene Drugs 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- ICTGSQARZKHWET-UHFFFAOYSA-N [(E)-prop-1-enyl]benzene Chemical group C=C[CH]C1=CC=CC=C1 ICTGSQARZKHWET-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000038129 antigens Human genes 0.000 description 2
- 108091007172 antigens Proteins 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000001851 biosynthetic Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 235000017471 coenzyme Q10 Nutrition 0.000 description 2
- 210000004748 cultured cells Anatomy 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 150000002031 dolichols Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000003228 microsomal Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000546 pharmaceutic aid Substances 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229940096701 plain lipid modifying drugs HMG CoA reductase inhibitors Drugs 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 230000001737 promoting Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000002829 reduced Effects 0.000 description 2
- 238000006456 reductive dimerization reaction Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000004059 squalene synthase inhibitor Substances 0.000 description 2
- 101700042500 str6 Proteins 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- 150000003669 ubiquinones Chemical class 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 230000003612 virological Effects 0.000 description 2
Abstract
A method is provided for blocking or preventing the prenylation of CXXX box containing proteins thereby preventing and/or treating hepatitis D which includes the step of administering a therapeutically effective amount of a protein-prenyl transferase inhibitor.
Description
The present invention relates to a method for treating and/or preventing hepatitis delta virus (also referred to as hepatitis D) by blocking the prenylation of CXXX box containing proteins by administering a therapeutic amount of a protein-prenyl transferase inhibitor.
J. Glenn et al, "Identification of a Prenylation Site in Delta Virus Large Antigen", Science, Vol. 256, 29 May 1992, pp. 1331-1333, discloses that during replication, hepatitis delta virus (HDV) switches from production of small to large delta antigen which is prenylated and packaged into virus particles.
The last four amino acids of large delta antigen are Cys-Arg-Pro-Gln-COOH. This COOH-terminal configuration is termed a CXXX box, where C is cysteine and X is any amino acid.
The CXXX box has been implicated as a substrate for prenyltransferases that add to the cysteine 15 (farnesyl) or 20 (geranylgeranyl) carbon moieties derived from mevalonic acid. (J. A. Glomset et al, Trends Biochem. Sci. 15, 139 (1990); W. A. Maltese, FASEB J. 4, 3319 (1990); S. L. Moores et al, J. Biol. Chem. 266, 14603 (1991)).
Glenn et al determined that large delta antigen undergoes prenylation in cultured cells and thus is a substrate for prenylation which is required for productive viral infection. In fact, Glenn et al found that mutation of Cys211 (the only cysteine in large delta antigen) in the CXXX box of the large delta antigen abolished both prenylation and viral particle formation. In conclusion, Glenn et al suggest "prenylation as a new target for anti-HDV therapy." As strategies designed to interfere with the prenylation stage of the HDV life cycle, Glenn et al suggest "drugs that inhibit enzymes along the prenylation pathway, and CXXX box analogs." (See page 1332).
Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds," Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway.
Squalene synthetase inhibitors which block the action of squalene synthetase (after the formation of farnesyl pyrophosphate) are disclosed in U.S. Pat. Nos. 4,871,721 and 5,025,003, U.S. application Ser. No. 501,204, filed Mar. 29, 1990, and U.S. application Ser. No. 699,429, filed May 13, 1991.
In accordance with the present invention, it has been found that post-translational modification of CXXX box containing proteins may be inhibited by administering a protein-prenyl transferase inhibitor which inhibits the transfer of the prenyl group (such as farnesyl, geranyl or geranylgeranyl) to the cysteine of the CXXX box by the protein-prenyl transferase enzyme. The protein-prenyl transferase inhibitor will block the protein-prenyl transferase enzyme from catalyzing the transfer of the prenyl group (for example, farnesyl, geranyl or geranylgeranyl) from the prenyl pyrophosphate to the cys residue of the CXXX box. Prenylation being prevented, productive HDV viral infection (hepatitis delta virus) is inhibited.
Thus, the present invention resides in a method for blocking or preventing the prenylation of CXXX box containing proteins such as large delta antigen, and thereby inhibit disease promoting effects of the CXXX box containing protein or more specifically prevent and/or treat hepatitis D viral infection, by administering to a patient in need of treatment a therapeutic amount of a protein-prenyl transferase inhibitor.
The protein-prenyl transferase inhibitors, unlike HMG CoA reductase inhibitors, will interfere with prenylation of the large delta antigen and inhibit their transforming activity, yet may or may not interfere with the synthesis of FPP, a precursor in the synthesis of ubiquinones, dolichols and Haem A.
The activity of the protein-prenyl transferase inhibitors in blocking the protein-prenyl (e.g. farnesyl, geranyl or geranylgeranyl) transferase from catalyzing the transfer of the prenyl group (e.g. farnesyl, geranyl or geranylgeranyl) from the prenyl pyrophosphate to the cys residue of the CXXX box may be assayed by a procedure similar to that described in U.S. application Ser. No. 520,570 filed May 8, 1990, by Barbacid et al, the disclosure of which is incorporated herein by reference.
Protein-prenyl transferase inhibitors suitable for use herein include compounds disclosed in U.S. application Serial No. 699,429 filed May 13, 1991, by Biller et al. These protein-prenyl transferase inhibitors have the following structure ##STR1## wherein
R1, R2, R3 and R4 are the same or different and are H, alkyl, a metal ion or a prodrug ester;
R5 is H, halogen or lower alkyl;
Z a lipophilic group containing at least 6 carbons and can be substituted alkenyl wherein the alkenyl group contains from 7 to 25 carbon atoms in the chain and from 1 to 4 double bonds; substituted alkynyl containing 1 to 4 triple bonds; mixed alkenyl-alkynyl containing 1 to 3 double bonds and 1 to 3 triple bonds and wherein alkenyl and/or alkynyl may be substituted or unsubstituted; or a substituted phenylalkyl group of the structure ##STR2## wherein (CH2)p contains from 1 to 15 carbons, preferably 2 to 12 carbons, in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and/or may include 0, 1, 2 or 3 substituents; and R6, R7 and R8 are the same or different and are H, alkyl containing 1 to 40 carbons, preferably from 3 to 15 carbons, alkoxy containing 1 to 40 carbons, preferably from 3 to 15 carbons, alkenyl containing 2 to 40 carbons, preferably from 3 to 15 carbons, alkenyloxy containing 2 to 40 carbons, preferably from 3 to 15 carbons, alkynyl containing 2 to 40 carbons, preferably from 3 to 15 carbons, alkynyloxy containing 2 to 40 carbons, preferably from 3 to 15 carbons, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, arylcarbonylamino or alkylcarbonylamino, at least one of R6, R7 and R8 being alkenyl, alkenyloxy, alkynyl or alkynyloxy; and wherein the total number of carbons in the substituted phenylalkyl group exceeds 10 carbons.
The terms "substituted alkenyl" and "substituted alkynyl" as employed herein with respect to Z refers to alkenyl or alkynyl substituted with 1 to 4 groups which may be alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryl and/or cycloalkyl.
The (CH2)p group may contain one or more alkyl, alkoxy, alkenyl, alkynyl, hydroxy and/or halogen substituents.
Preferred embodiments of formula I protein-prenyl transferase inhibitors have the structure ##STR3## wherein R1, R2, R3, R4 and R5 are as defined above and Za is substituted alkenyl which includes from 1 to 4 double bonds and is substituted with from 1 to 4 alkyl groups.
In addition, other protein-prenyl transferase inhibitors suitable for use herein and disclosed in application Ser. No. 699,429 have the structure ##STR4## wherein Zb is ##STR5## wherein R1, R2, R3, R4, R5, R6, R7 and (CH2)p are as defined hereinbefore, except that R6 and R7 may be any one of the groups included under the definition R6 and R7, set out hereinbefore, without limitation; R8', R9 and R10 are the same or different and are as defined hereinbefore with respect to R6 and R7, without limitation.
Preferred are compounds of formula III wherein the R8', R9 phenyl is para to the R6 R7 -phenylene. These compounds have been found to inhibit cholesterol biosynthesis when administered orally.
In another embodiment of the present invention, compounds which are protein-prenyl transferase inhibitors (disclosed in Ser. No. 699,429) may be employed which have the structure ##STR6## wherein R1, R2, R3, R4 and R5 are as defined hereinbefore and Zc is alkyl wherein the alkyl group contains from 9 to 14 carbons in the normal chain and is substituted with 1, 2, 3 or 4 alkyl groups.
Still another embodiment of compounds which are protein-prenyl transferase inhibitors (disclosed in Ser. No. 699,429) have the structure ##STR7## wherein Zd is ##STR8## wherein R1, R2, R3, R4 and R5 are as defined hereinbefore and (CH2)q contains at least 2 carbons in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, preferably 3 to 7 carbons in the normal chain, and may include one or more alkyl, alkenyl, alkynyl, alkoxy, hydroxy and/or halogen substituents; and R15 is alkyl containing from 2 to 20 carbons, and preferably is in the para position, and the total number of carbons in Zd exceeds 10.
Other protein-prenyl transferase inhibitors suitable for use herein are compounds disclosed in U.S. application Ser. No. 501,204 filed Mar. 29, 1990, by Biller et al and have the following structure ##STR9## wherein m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; Y1 and Y2 are H or halogen, preferably H or F; R2, R3 and R4 are independently H, metal ion. C1 to C8 alkyl or C3 to C12 alkenyl; X is O, NH, ##STR10## or S (wherein R15 is H or C1 to C5 alkyl); R1 is R5 --Q1 --Q2 -13 Q3 --wherein Q1, and Q2 and Q3 are independently: ##STR11## or a bond, with the stipulation that if Q1 is a bond, then Q2 and Q3 must be bonds, and if Q2 is a bond, then Q3 is a bond; R6 is H, lower alkyl, halo or haloalkyl (e.g. CH2 F, CF3); R7 is H, halogen, lower alkyl or alkylthio; R8 is H, halogen, trimethylsilyl or lower alkyl; R9 is H, or lower alkyl; R5 is ##STR12## R16 --C.tbd.C--CH2 --(wherein R16 is lower alkyl or H), ##STR13## or CH3 (CH2)p --where p is 2 to 7; R10 and R11 are independently hydrogen, lower alkyl such as methyl or ethyl, halogen, lower alkenyl or haloalkyl R10 or and R11 can be taken together to form (CH2)s', where s is 2 to 7; R12 is hydrogen, lower alkyl, halogen or lower alkenyl; R13 and R14 are independently lower alkyl such as methyl or ethyl; with the provisos that if all of Q1, Q2 and Q3 are bonds, then R10 and R11 cannot both be H, and R5 cannot be CH3 (CH2)p --, with p≦4; if m is o, X is other than S; and if m is o and X is O, then n is 1, 2, 3 or 4, including all stereoisomers thereof.
The term "lower alkenyl" or "alkenyl" as used above by itself or as part of another group refers to straight or branched chain radicals of 2 to 12 carbons, preferably 3 to 6 carbons in the normal chain, which include one double bond in the normal chain, and which may include an aryl or alkyl substituent, such as vinyl, 2-propenyl, 2-butenyl, 3-phenyl-2-propenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl, 2-undecenyl, 2-dodecenyl and the like.
Preferred are those compounds of formula VI which have the following formula: VII ##STR14## wherein R5 is ##STR15## Q3 is a bond; Q2 is ##STR16## --CH2 --C.tbd.C--CH2 --: or --CH2 --CH═CH--CH2 --; Q1 is ##STR17## n is 0 or 1; m is 1 or 2; X is O and Y1 and Y2 are each H or F, in the form of the salts or acid.
In addition, preferred are those compounds of formula VI which have the following structure VIA-A ##STR18## wherein Q is or a bond; n is 1 or 2; X is O, Y1 and Y2 are each H or each F; R2, R3 and R4 are alkyl, H or metal ions; or X is NH and n is 0.
In addition, protein-prenyl transferase inhibitors which may be employed herein include compounds disclosed in U.S. Pat. No. 5,025,003 to Biller and have the following structure ##STR19## wherein R2 is a metal ion, lower alkyl or H;
R3 is a metal ion or lower alkyl;
R is R1 --(CH2)n --, R1 --(CH2)m O--or R1 --(CH2)m OCH2 --, wherein n is 1 to 4, m is 0 to 3; and R1 is R5 --Q1 --Q2 --Q3 --wherein Q1, Q2 and Q3 are independently: ##STR20## or a bond, with the stipulation that if Q1 is a bond, then Q2 and Q3 must be bonds, and if Q2 is a bond, then Q3 is a bond; R6 is H, lower alkyl, fluoro or fluoroalkyl (e.g., CH2 F, CF3); R7 is H, fluoro, lower alkyl or alkylthio; R8 is H, fluoro, trimethylsilyl or lower alkyl; R9 is H, or lower alkyl; R5 is ##STR21## (wherein R16 is lower alkyl or H), or CH3 (CH2)p --where p is 2 to 7; R10 and R11 are independently hydrogen, lower alkyl such as methyl or ethyl, fluoro, lower alkenyl or fluoroalkyl or R10 and R11 can be taken together to form (CH2)s, where s is 2 7; R12 is hydrogen, lower alkyl, fluoro or lower alkenyl; R13 and R14 are independently lower alkyl such as methyl or ethyl; with the proviso that if all of Q1, Q2 and Q3 are bonds, then R10 and R11 cannot both be H, and R5 cannot be CH3 (CH2)p, with p<4, including all stereoisomers thereof.
The term "lower alkenyl" or "alkenyl" as used herein is defined hereinbefore.
Preferred are those compounds of formula VIII wherein R1 is ##STR22## n is 1, 2 or 3, m is 1 or 2, R2 is H or a metal ion, and R3 is lower alkyl, a metal ion or H.
Other protein-prenyl transferase inhibitors suitable for use herein include compounds disclosed in U.S. Pat. No. 4,871,721 to Biller and have the following structure: ##STR23## wherein
Q is ##STR24##
Z is --(CH2)hd n--or --(CH2)p --CH═CH--(CH2)m, wherein n is 1 to 5; p is 0, 1 or 2; m is 0, 1 or 2;
R, R1 and R1a may be the same or different and are H, lower alkyl or a metal ion; and
R2 and R3 may be the same or different and are H or halogen.
Preferred are those compounds of formula IX which have the following structure ##STR25## wherein
Q is ##STR26## Z is --CH2 CH2 --or --CH═CH--; R2 and R3 are each H or each F; R, R1 and R1a are OH or metal ions.
Other protein-prenyl transferase inhibitors suitable for use herein (disclosed in U.S. application Ser. No. 950,555, filed Sep. 25, 1992) has the structure ##STR27## wherein
R2, R3 and R4, are independently H, alkyl, a metal ion or a prodrug ester; and
R1 is a lipOphilic group containing at least 6 carbons, and including pharmaceutically acceptable salts thereof.
R1 is alkyl, alkenyl, alkynyl or aryl.
More specifically R1 is alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 4 double bonds; alkynyl containing 1 to 4 triple bonds; mixed alkenyl-alkynyl containing 1 to 3 double bonds and 1 to 3 triple bonds, and where in the above groups alkyl, alkenyl and/or alkynyl may be substituted or unsubstituted; or a group of the structure ##STR28## wherein (CH2)p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and/or may include 0, 1, 2 or 3 substituents; and R6, R7 and R8 are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy containing 2 to 40 carbons, aryl, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkyl-sulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, arylcarbonylamino or alkylcarbonylamino.
The disclosures of the above U.S. patents and U.S. patent applications are incorporated herein by reference. The preferred compounds in these patents and patent applications are the preferred compounds for use in the method of the invention.
In carrying out the method of the invention, a pharmaceutical composition will be employed containing at least one protein-prenyl transferase inhibitor in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations. The dose for adults is preferably between 200 and 2,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.
A typical capsule for oral administration contains protein-prenyl transferase inhibitor (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
A typical injectable preparation is produced by aseptically placing 250 mg of sterile protein-prenyl transferase inhibitor into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
Claims (7)
1. A method for treating and/or preventing hepatitis D, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a protein-prenyl transferase inhibitor.
2. The method as defined in claim 1, wherein the protein-prenyl transferase inhibitor has the structure ##STR29## wherein R1, R2, R3 and R4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester;
R5 is H, halogen or lower alkyl;
Z is substituted alkenyl wherein the alkenyl group contains at least 7 carbon atoms in the chain and from 1 to 4 double bonds; substituted alkynyl containing 1 to 4 triple bonds; mixed alkenyl-alkynyl containing 1 to 3 double bonds and 1 to 3 triple bonds, and wherein alkenyl and/or alkynyl may be substituted or unsubstituted; or a substituted phenylalkyl group of the structure ##STR30## wherein (CH2)p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain and/or may include 0, 1, 2 or 3 substituents which are alkyl, alkenyl, alkoxy, alkynyl, hydroxy and/or halogen; and R6, R7 and R8 are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy, aryloxy, hydroxy, halogen, nitro, amino, thiol, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyl, arylcarbonylamino alkylcarbonylamino, at least one of R6, R7 and R8 being alkenyl, alkenyloxy, alkynyl or alkynyloxy, and wherein the total number of carbons in ##STR31## exceeds 10 carbons.
3. The method as defined in claim 1, wherein the protein-prenyl transferase inhibitor is a bisphosphonate.
4. The method as defined in claim 3, wherein the protein-prenyl transferase inhibitor has the structure ##STR32## wherein R1, R2, R3 and R4 are the same or different and are H, alkyl, a metal ion or a prodrug ester; R5 is H, halogen or alkyl, and Za is substituted alkenyl which includes 1 to 4 double bonds and is substituted with from 1 to 4 lower alkyl groups.
5. The method as defined claim 3, wherein the protein-prenyl transferase inhibitor has the structure ##STR33## wherein Zb is ##STR34## R1, R2, R3 and R4 are the same or different and are H, alkyl, a metal ion or a prodrug ester;
R5 is H, halogen or alkyl;
p is 1 to 15;
(CH2)p may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and/or may include 0, 1, 2 or 3 substituents which are alkyl, alkoxy, alkenyl, alkynyl, hydroxy and/or halogen and
R6, R7, R8', R9 and R10 are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, hydroxy, alkynyl containing 2 to 40 carbons, alkynyloxy containing 2 to 40 carbons, aryloxy, halogen, nitro, amino, thio, alkylthio, arylthio, arylsulfinyl, alkylsulfinyl, arylsulfonyl, alkylsulfonyl, carboxy, alkycarbonyloxy, arylcarbonyloxy, alkoxycarbonyl, aminocarbonyl, arylcarbonylamino or alkylcarbonylamino.
6. The method as defined in claim 3, wherein the protein-prenyl transferase inhibitor has the structure ##STR35## wherein Zc is substituted alkyl containing from 9 to 14 carbons in the normal chain and is substituted with 1 to 4 lower alkyl groups;
R1, R2, R3 and R4 are the same or different and are H, alkyl, a metal ion or a prodrug ester; and
R5 is H, halogen or alkyl.
7. The method as defined in claim 3, wherein the protein-prenyl transferase inhibitor has the structure ##STR36## wherein Zd is ##STR37## q is 2 to 15, (CH2)q may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain and may optionally include one or more alkyl, alkenyl, alkynyl, hydroxy, alkoxy and/or halogen substituents;
R1, R2, R3 and R4 are the same or different and are H, alkyl, a metal ion or a prodrug ester; and
R5 is H, halogen or lower alkyl; and R15 is alkyl containing from 2 to 20 carbons;
the total number of carbons in Zd exceeds 10.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| USH1345H true USH1345H (en) | 1994-08-02 |
Family
ID=
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5503973A (en) * | 1992-05-29 | 1996-04-02 | The Regents Of The University Of California | Method for inhibition of viral morphogenesis |
| WO1997031641A1 (en) * | 1996-02-29 | 1997-09-04 | Duke University | Method of treating hepatitis delta virus infection |
| US6159939A (en) * | 1995-06-23 | 2000-12-12 | Glenn; Jeffrey | Method for inhibition of viral morphogenesis |
| US20030158149A1 (en) * | 2000-03-29 | 2003-08-21 | Casey John L. | Method of treating hepatitis delta virus infection |
| US20030181355A1 (en) * | 1992-05-29 | 2003-09-25 | Glenn Jeffrey S. | Method for inhibition of viral infection |
| US6627610B1 (en) | 1992-05-29 | 2003-09-30 | Jeffrey Glenn | Method for inhibition of viral morphogenesis |
Non-Patent Citations (1)
| Title |
|---|
| Glenn, Jeffrey S. et al, "Identification of a Prenylation Site in Delta Virus Large Antigen", Science, vol. 256, pp. 1331-1333, May 29, 1992. |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5503973A (en) * | 1992-05-29 | 1996-04-02 | The Regents Of The University Of California | Method for inhibition of viral morphogenesis |
| EP0672192A4 (en) * | 1992-05-29 | 1996-04-17 | Jeffrey S Glenn | Method for inhibition of viral morphogenesis. |
| US20030181355A1 (en) * | 1992-05-29 | 2003-09-25 | Glenn Jeffrey S. | Method for inhibition of viral infection |
| US6627610B1 (en) | 1992-05-29 | 2003-09-30 | Jeffrey Glenn | Method for inhibition of viral morphogenesis |
| US20060040259A1 (en) * | 1992-05-29 | 2006-02-23 | Glenn Jeffrey S | Method for inhibition of viral infection |
| US20080214471A1 (en) * | 1992-05-29 | 2008-09-04 | Jeffrey S. Glenn, M.D. | Method for inhibition of viral infection |
| US6159939A (en) * | 1995-06-23 | 2000-12-12 | Glenn; Jeffrey | Method for inhibition of viral morphogenesis |
| WO1997031641A1 (en) * | 1996-02-29 | 1997-09-04 | Duke University | Method of treating hepatitis delta virus infection |
| US20030158149A1 (en) * | 2000-03-29 | 2003-08-21 | Casey John L. | Method of treating hepatitis delta virus infection |
| US7511027B2 (en) * | 2000-03-29 | 2009-03-31 | Georgetown University | Method of treating hepatitis delta virus infection |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| J Roelofs et al. | Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages | |
| US5447922A (en) | α-phosphonosulfinic squalene synthetase inhibitors | |
| CN1217666C (en) | Interleukin-6 production inhibitors | |
| Rowe et al. | The mechanism of dietary alterations in rat hepatic xanthine oxidase levels | |
| JP3657516B2 (en) | Use of organophosphorus compounds for the treatment and prevention of infectious diseases | |
| Mönkkö et al. | The effects of liposome-encapsulated and free clodronate on the growth of macrophage-like cells in vitro: the role of calcium and iron | |
| AU651579B2 (en) | Method for preventing, stabilizing or causing regression of atherosclerosis employing a combination of a cholesterol lowering drug and an ace inhibitor | |
| US6087349A (en) | Method for blocking neoplastic transformation of cells induced by ras oncogenes | |
| HUT67667A (en) | Pharmaceutical composition causes inhibition of phosphatidylinositol-3-kinase containing wortmannin and analogs thereof and process for its production | |
| JP2859318B2 (en) | Pharmaceutical for bone disease containing inositol triphosphate | |
| US5057507A (en) | Method of alleviating bone damage with inositoltriphosphate | |
| EP0609440B1 (en) | Phosphorus-substituted isoprenoid derivative | |
| USH1345H (en) | Method for preventing or treating hepatitis D | |
| US6057306A (en) | Method of treating the navicular disease in horses | |
| HU219589B (en) | Process for producing medicaments containing uracyl reductase enzyme inhibitors and medicaments comprising the same compounds | |
| WO2005117864A1 (en) | Combination product comprising anastrozole and a dual prenyl transferase inhibitor | |
| US5846957A (en) | Use of an ester of inositoltrisphosphate for the preparing of medicaments | |
| JPH05507061A (en) | 1-azetidyl and 1-hexamethyleneimine alkyl or arylbisphosphonic acids and their use as medicines | |
| AU780788B2 (en) | Imidazole derivatives as phosphodiesterase VII inhibitors | |
| US4439451A (en) | Treatment of the blood-brain barrier with flurbiprofen | |
| JPH05201869A (en) | Treatment and preventive agent for ras related cancer | |
| US5846977A (en) | Nerve growth factor production accelerators and compositions for preventing or treating neuronal degeneration | |
| AU748608B2 (en) | MTP inhibitors and fat soluble vitamin therapeutic combinations to lower serum lipid levels | |
| US5332728A (en) | Method for treating a fungal infection | |
| US4022907A (en) | Pharmaceutical compositions containing 1,3-dithiacycloalkylidene malonates |