MXPA98002490A - Method for making acid (s (r *, r *)) - 3-methyl-2- (3-oxo-3h-benzo (d) isotiazol-2-il) pentanoic and acid (s- (r *, r * )), l-2- (2- (2- (1-carboxy-2-methylbutylcarbamoil) fenildisulfonil] benzoyl-amino-3-methyl pentane - Google Patents
Method for making acid (s (r *, r *)) - 3-methyl-2- (3-oxo-3h-benzo (d) isotiazol-2-il) pentanoic and acid (s- (r *, r * )), l-2- (2- (2- (1-carboxy-2-methylbutylcarbamoil) fenildisulfonil] benzoyl-amino-3-methyl pentaneInfo
- Publication number
- MXPA98002490A MXPA98002490A MXPA/A/1998/002490A MX9802490A MXPA98002490A MX PA98002490 A MXPA98002490 A MX PA98002490A MX 9802490 A MX9802490 A MX 9802490A MX PA98002490 A MXPA98002490 A MX PA98002490A
- Authority
- MX
- Mexico
- Prior art keywords
- acid
- benzoyl
- carboxy
- amino
- methyl
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims abstract description 52
- -1 benzoyl-amino-3-methyl pentane Chemical compound 0.000 title claims abstract description 40
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical group C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 title claims description 7
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000002194 synthesizing Effects 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- DSFZYLCRXIWFFW-UHFFFAOYSA-N 2-[(2-carbonochloridoylphenyl)disulfanyl]benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1SSC1=CC=CC=C1C(Cl)=O DSFZYLCRXIWFFW-UHFFFAOYSA-N 0.000 claims description 11
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 230000002140 halogenating Effects 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- LBEMXJWGHIEXRA-UHFFFAOYSA-N 2-[(2-carboxyphenyl)disulfanyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1SSC1=CC=CC=C1C(O)=O LBEMXJWGHIEXRA-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 229960000310 ISOLEUCINE Drugs 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- WHGLQYBALPTZNJ-UHFFFAOYSA-N furan;oxolane Chemical compound C1CCOC1.C=1C=COC=1 WHGLQYBALPTZNJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 210000004027 cells Anatomy 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000011701 zinc Substances 0.000 description 16
- 238000004166 bioassay Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 13
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 12
- 229910052725 zinc Inorganic materials 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 10
- 241000700605 Viruses Species 0.000 description 9
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- 230000000694 effects Effects 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drugs Drugs 0.000 description 7
- 238000001125 extrusion Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
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- 210000003739 Neck Anatomy 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
- PTFCDOFLOPIGGS-UHFFFAOYSA-N zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 3
- 210000004366 CD4-Positive T-Lymphocytes Anatomy 0.000 description 2
- 101700067048 CDC13 Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 108020000999 Viral RNA Proteins 0.000 description 2
- 210000002845 Virion Anatomy 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 235000012970 cakes Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
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- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
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- 239000012044 organic layer Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001850 reproductive Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 230000017613 viral reproduction Effects 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- 206010060945 Bacterial infection Diseases 0.000 description 1
- 102100000129 CHURC1 Human genes 0.000 description 1
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- 206010057248 Cell death Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- HKRNYOZJJMFDBV-UHFFFAOYSA-N N-(6-methoxyquinolin-8-yl)-4-methylbenzenesulfonamide Chemical compound C=12N=CC=CC2=CC(OC)=CC=1NS(=O)(=O)C1=CC=C(C)C=C1 HKRNYOZJJMFDBV-UHFFFAOYSA-N 0.000 description 1
- 102000004873 Nucleocapsid Proteins Human genes 0.000 description 1
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N Phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N Phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N Phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000007759 RPMI Media 1640 Substances 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 206010047461 Viral infection Diseases 0.000 description 1
- 208000001756 Virus Disease Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 230000000711 cancerogenic Effects 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000000473 carbonimidoyl group Chemical group [H]\N=C(/*)* 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- RZYKRZDOAMZFGP-UHFFFAOYSA-N heptanenitrile Chemical compound [CH2]CCCCCC#N RZYKRZDOAMZFGP-UHFFFAOYSA-N 0.000 description 1
- AILKHAQXUAOOFU-UHFFFAOYSA-N hexanenitrile Chemical compound CCCCCC#N AILKHAQXUAOOFU-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-O hydron;2H-tetrazole Chemical class C1=NN=[NH+]N1 KJUGUADJHNHALS-UHFFFAOYSA-O 0.000 description 1
- 230000002458 infectious Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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Abstract
The present health presents a synthesis of acid (S- (R *, R *)) - 3-methyl-2- (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid and (S (R *, R *)), 1-2- (2- (1-carboxy-2-methylbutylcarbamoyl) phenyldisul fonyl) benzoyl-amino) -3-methylpentanoic acid
Description
METHOD FOR MAKING ACID (S - (R% R *)) - 3 - METTL - 2 - (3 - OXO - 3H - BENZO (D) ISOTIAZOL - 2 - TL) PENTANOIC AND ACID (S - (R% R *) ), L - 2 - (2 - (2 - (1 - CARBOXY - 2 - METD BUTD CARBAMOIL) FENILDISULFONYL) BENZOYL - AMI O) - 3 - METTLPENTANÓICO).
FIELD OF THE INVENTION The present invention provides a synthesis of (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid and acid (S - (R *, R *)), L-2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic).
BACKGROUND OF THE INVENTION The acid compound (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic is useful as an antiviral agent and It can be used to treat patients infected with the HIV virus. The acid compound (S - (R *, R *)), L - 2 - (2 - (2 - (l - carboxy - 2 - methylbutylcarbamoyl) phenyldisulfonyl) benzoyl - amino) - 3 - methylpentanoic) is an intermediate in the synthesis of the acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid and can be used to treat bacterial and viral infections, even patients infected with the HIV virus. See, for example, U.S. Patent No. 5,463,122, which is incorporated herein by reference. Thus, it would be useful to have a simple, high production method to synthesize acid (S - (R *, R *)) - 3 - methyl - 2 - (3 - oxo - 3H - benzo (d) isothiazol - 2 - yl) pentanoic acid (S - (R *, R *)), L - 2 - (2 - (2 - (l - carboxy - 2 - methylbutylcarbamoyl) phenyldisulfonyl) benzoyl - amino) - 3 - methylpentanoic acid).
SUMMARY OF THE INVENTION The present invention provides a method for making (S - (R *, R *)) - 3 -methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid which comprises the reaction of 2,2'-dithiosalicylic acid with a halogenating agent to make 2,2'-dithiobisbenzoyl halide; the reaction of halide 2,2'-dithiobisbenzoyl with L-isoleucine in tetrahydroruran or tetrahydroturan and a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy - 2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid); and the reaction of (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) with an agent halogen oxidant to make acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3 H -benzo (d) isothiazol-2-yl) pentanoic acid.
In a preferred example, the halogenating agent is thionyl chloride.
In another preferred example, the halide 2,2'-dithiobisbenzoyl is 2,2'-dithiobisbenzoyl chloride.
In another favorite, the base is sodium bicarbonate.
In another preferred example, the halogen oxidizing agent is chlorine, bromine or iodine.
In a most preferred example, the halogen oxidizing agent is bromine.
The present invention also provides a method for making acid (S - (R *,
R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic which comprises the reaction of 2,2'-dithiosalicylic acid with thionyl chloride to make chloride 2,2 '-dithiobisbenzoyl; the reaction of 2,2'-dithiobisbenzoyl chloride with at least two equivalents of L-isoleucine in tetrahydrofuran or tetrahydrofuran and sodium bicarbonate to make acid
(S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic); and the reaction of the acid (S - (R *, R *)), L - 2 - (2 - (2 - (l -carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) with bromine and acetic acid to make acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3 H -benzo (d) isothiazol-2-yl) pentanoic acid.
Also provided is a method for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic) comprising the reaction of 2,2'-dithiosalicylic acid with halogenating agent to make 2,2'-dithiobisbenzoyl halide; and the reaction of halide 2,2'-dithiobisbenzoyl with L -isoleucine in tetrahydrofuran or tetrahydrofiirand a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1 - carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic).
In another preferred example of the method, the halogenating agent is thionyl chloride.
In another preferred example of the method, the halide 2,2'-dithiobisbenzoyl is 2,2'-dithiobisbenzoyl chloride.
In another preferred example, the base is sodium bicarbonate.
Also provided is a method for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic) comprising the reaction of 2,2'-dithiosalicylic acid with thionyl chloride to make 2,2'-dithiobisbenzoyl chloride; and the reaction of 2,2'-dithiobisbenzoyl chloride with L-isoleucine in tetrahydrofuran or tetrahydrofuran and a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1 - carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic).
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for making acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid and (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) in accordance with Scheme I following.
SCHEME I
so2c?
THF or THF / NaHCO,
Br. Acetic Acid 'I
In the first step of the synthesis, 2,2'-dithiosalicylic acid, which can be purchased at
Aldrich, Mil aukee, Wisconsinn, is converted to its corresponding acid halide, halide 2.2 '
- dithiobisbenzoyl, by the reaction of 2,2'-dithiosalicylic acid with a halogenating agent. Those skilled in the art are familiar with the conversion of an acid to an acid halide. Examples of suitable halogenating agents include, but are not limited to, thionyl chloride, phosgene, phosphorus trichloride, phosphorus pentachloride, and phosphorus tribromide.
In a preferred example, the halogenating agent is thionyl chloride, and the acid halide is an acid chloride. The term "halogen" includes chlorine, bromine, fluorine and iodine.
In general, the reaction is carried out under an inert atmosphere in an aprotic solvent. Examples of aprotic solvents include, but are not limited to, toluene, heptane, hexane and acetonitrile. In a preferred specimen, the solvent is toluene. The 2,2'-dithiobisbenzoyl halide can be used in the next step as obtained, ie, in crude form, or can be purified by methods well known to those skilled in the art.
In the second step of the synthesis, the halide 2,2'-dithiobisbenzoyl is reacted with L -isoleucine in tetrahydrofuran or a mixture of tetrahydrofuran and a base to form acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic). The use of tetrahydrofuran (THF) or a solution of THF and a base provides higher yields and higher purity and is less toxic and carcinogenic than other solvents used in the formation of amides from chlorides and a-amino-acids. Moreover, the use of THF as a solvent is not obvious, since L-isoleucine has only limited solubility in THF, and THF is generally broken down with hydrogen chloride, which is generated in the reaction. Moreover, the present synthesis does not require any protection / deprotection step for the a-amino acid and is less prone to racemization, resulting in products having superior optical activity. The acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) can be used in step the following as obtained a can be further purified by methods well known to those skilled in the art. Examples of suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate. Preferably, the base is sodium bicarbonate.
In the third step of the synthesis, acid is reacted (S - (R *, R *)), L-2 - (2 - (2 - (l -carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic) with a halogen oxidizing agent to make acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid. In this step, the disulfide bond of the acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid ) is oxidized and the cyclic intermediate sulfenyl bromide to form acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid. Suitable halogen oxidizing agents include, but are not limited to, bromine, chlorine and iodine. In a preferred specimen, the halogen oxidizing agent is bromine.
In general, in this step of the synthesis, an acid slurry (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino ) - 3-methylpentanoic acid) in acetic acid is stirred with the addition of a halogen oxidizing agent. After stirring, the formed precipitate is filtered. The product is precipitated directly from the reaction of the mixture in a high state of purity.
Next, the precipitate, which is (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid, is purified by the extraction with an ether, preferably methyl t-butyl ether and water. The ether extracts are combined and concentrated to produce an oil. The oil is dissolved in an ether and then heptane is added. The resulting precipitate is filtered, washed and dried to yield (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid. .
The following examples are intended to illustrate specific specimens of the present invention and are not intended to limit the description, including the claims, in any way.
EXAMPLE 1 Chloride 2.2'-dithiobisbenzoyl A 2,2'-dithylsalicylic acid (120 g) is charged to a round bottom flask with three 2-L necks coupled to a mechanical stirrer, a thermometer and a reflux condenser with a nitrogen inlet. , toluene (600 ml), dimethylformamide (1 ml) and thionyl chloride (128 g). Stirring, the mixture is heated at 75 ° C for 21 hours under nitrogen to give a light yellow solution. The solution is heated to 80 ° C and filtered through diatomaceous earth in a Buchner funnel. The filtered cake is washed with toluene (100 ml) and the combined filtrates are transferred to a round bottom flask with three 2 L necks coupled with a mechanical stirrer, a thermometer and a distillation head. The hot solution is concentrated to a total volume of 300 ml under vacuum (5 mm Hg) and at a total group temperature of 65 ° C. Fresh toluene (500 ml) is added to the mixture which is reheated to 80 ° C. The hot solution is concentrated to a total volume of 300 ml under vacuum (5 mm Hg) and an extra charge of fresh toluene (500 ml) is made. The mixture is reheated to 80 ° C and the solution is concentrated to a final volume of 400 ml under vacuum (5 mm
Hg) and at a final group temperature of 65 ° C to give a thick yellow slurry. The slurry is cooled to 10 ° C, stirred for two hours and filtered on a Buchner filter. The filtered cake is washed with cold toluene (100 ml) and dried in a vacuum oven at 40 ° C to -45 ° C to give 120 g (89.3%) of the title compound as pale yellow crystals; melting point 156.2 - 157.9 ° C. 1 H NMRS (d, CDC13, 200 MHz): 8.41 - 8.37 (m, 2H, aromatic H), 7.78 - 7.74 (m, 2H, aromatic H), 7.60 - 7.51 (m, 2H, aromatic H), 7.43 - 7.34 (m, 2H, aromatic H).
EXAMPLE 2 Acid (S - (R * .R *). L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoin phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic) To a round bottom flask of Three necks of 1 1 coupled with a mechanical stirrer, a thermometer and a reflux condenser with a nitrogen inlet are charged with 2,2'-dithiobisbenzoyl chloride (75.0 g), L-isoleucine (62.8 g), sodium bicarbonate (55.3 g) g) and THF (750 ml) Stirring, the slurry is heated at 54 ° C to 58 ° C under nitrogen for 20 minutes and then at 60 ° C to 65 ° C for 8 hours.The reaction mixture is cooled to room temperature and slowly poured into a 3-neck round bottom flask fitted with a mechanical stirrer containing a rapidly stirred mixture of concentrated hydrochloric acid (60 g), water (550 ml), and methyl / - ether butyl (800 ml) The 1 1 flask is rinsed successively with THF (150 ml), methyl t-butyl ether (150 ml) and water (150 ml), and the juagues are added to the 3 1 bottle. The biphasic mixture is stirred at room temperature for 30 minutes and then allowed to stand. The lower aqueous layer is separated, and the upper organic layer is washed with three portions of water (2 x 375 ml, 180 ml). To the rapidly stirred organic layer hexane (1060 ml) is added to give a thick white slurry which is stirred at room temperature for 2 hours. The solids are filtered on a Buchner filter, washed with hexane (150 ml) and dried in a vacuum oven at 65 ° C to give 105.9 (91.0%) of the crude title compound.
A crude bottom flask with three 2 1 necks coupled with a mechanical stirrer, a distillation head and a thermometer is charged to the crude title compound (95.2 g) and THF (1620 ml). The pale yellow solution is heated under reflux and THF (1140 ml) is distilled out of the flask. The THF solution in the flask is cooled to room temperature and to this, with rapid stirring, hexane (760 ml) is added to give a thick white slurry which is stirred at room temperature for 2 hours. The solids are filtered on a Buchner filter, washed with hexane (375 ml) and dried in a vacuum oven at 67 ° C to give 93.8 g (98.5%) of the title compound as a white solid; HPLC 99.1% (by area); melting point 207-210 ° C; 1 H NMRS (d, DMSO, 200 MHz): 12.8 - 12.4 (br s, 2H, CO2H), 8.72 (d, J = 8.3 Hz, 2H, NH), 7.68 - 7.64 (m, 4H, aromatic H), 7.50 - 7.41 (m, 2H, aromatic H), 7.35 - 7.27 (m, 2H, aromatic H), 4.39 - 4.32 (m, 2H, NCH), 1.95 (m, 2H, CH3CH), 1.53 (m, 2H, CH2 ), 1.31 (m, 2H, CH2), 0.97 (d, J = 6.9 Hz, 6H, C & CH), 0.89 (m, 6H, CHsCHz).
EXAMPLE 3 Acid f S - (R * .R * V> - 3 - methyl - 2 - (3 - oxo - 3H - benzofd sothiazol - 2 - yl) pentanoic To a 500 ml three - necked round bottom flask with a mechanical stirrer, a thermometer and an addition funnel with a nitrogen inlet are charged with acid (S - (R *, R *)), L - 2 - (2 - (2 - (1 - carboxy - 2 - methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) (25 g) and acetic acid (163 ml). To the stirred slurry under nitrogen a solution of bromine (7.9 g) in acetic acid (12 ml) is added dropwise over 15 minutes. The orange slurry is stirred at room temperature for 4 hours under nitrogen, filtered on a Buchner funnel, and washed with heptane (2 x 500 ml) to give 31.7 g of the wet title compound with crude solvent.
The crude title compound (31.7 g), methyl t-butyl ether (69 ml) and water (66 ml) are charged to a 500 ml separatory funnel. After extraction the lower aqueous layer is separated and extracted with methyl t-butyl ether (19 ml). The methyl t-butyl ether layers are combined, washed with water (50 ml) and concentrated in an oil using a rotary evaporator under vacuum (25 mm Hg) and at a final group temperature of 50 ° C. The oil is kept under vacuum at 50 ° C for 1 hour, dissolved in methyl t-butyl ether (80 ml) and filtered on a Buchner filter. The filtrates are transferred to a 250 ml three-necked round bottom flask coupled with a mechanical stirrer, a thermometer and an addition funnel with a nitrogen inlet. To the stirred and hot methyl t-butyl ether solution (45 ° C) is added heptane (40 ml). The cloudy solution is maintained at 45 ° C for 1 hour and an additional charge of heptane 819 ml) is made. The slurry is cooled to room temperature, then cooled to 10 ° C and stirred for 1 hour. The solids are cooled in a Buchner funnel, washed with heptane (40 ml) and dried in a vacuum oven at 45 ° C for 16 hours to give 19.3 g (77.5%) of the title compound as white crystals; melting point 122-123 ° C; 1 H NMRS (d, CDC13, 200 MHz): 8.81 (br s, 1H, CO2H), 8.07 (d, J = 7.8 Hz, 1H, aromatic H), 7.67-7.54 (m, 2H, aromatic H), 7.44 - 7.36 (m, 1H, aromatic H), 5.28 (d, J
= 9.4 Hz), 1H, CHN), 2.28-2.23 (m, 1H, CHCH3), 1.42 - 1.38 (m, 1H, CH2), 1.29 - 1.20
(m, 1H, CH2), 1.11 (d, J = 6.8 Hz, 3H, CHCH,), 0.91 (t, J = 7.3 Hz, 3H, CHjCHj).
EXAMPLE 4 Activity Antiviral acid (S - (R *. R * Vl-3-methyl-2 - (3-oxo-3H-benzo (d-isothiazol-2-yl) pentanoic acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic (Example 3) causes the extrusion of zinc from the HIV-1 mucleocapsid protein (NCp7) The NC protein is highly conserved among all retroviruses (South T., Blake P., et al., Biochemistry, 1990; 29: 7786) and is essential for viral infectivity (Aldovani A. and Young R., J. Virology, 1990; 64: 1920 and Gorelick R., Nigida S "et al., J. Virology, 1990; 64: 3207). Zinc is normally maintained in NC proteins by 1 or 2 zinc fingers. In the case of VLH - 1. Two zinc fingers are present (Summers M., South T., et al., Biochemistry, 1990; 29: 329) and are specifically involved with the PSI site of the viral RNA that controls the packaging of viral RNA. Interference from this packaging causes the formation of non-infectious virions (Dannull J., Surovoy A., et al., EMBO, 1994; 13: 1525). It has previously been shown that compounds that cause zinc extrusion have potent anti-VLH activity in multiple cell lines and against retroviruses (Rice W., Schaeffer C, et al., Nature, 1993; 361: 473).
A fluorescence-based assay has been developed to monitor the expulsion of zinc from purified NCp7 VLH. The fluorophore, N - (6-methoxy-8-quinolyl) -p-toluenesulfonamide (TSQ), has an increased fluorescent signal after the binding of the zinc ion in solution. The NCp7 protein containing 2 zinc fingers and two Zinc ions is incubated with a drug that causes the extrusion of Zinc ions. The released zinc is then sequestered with the TSQ and the increased fluorescence is monitored in relation to the control. The assay was carried out as follows: 10 μm of compound was added to 2.8 μm of NCp7 and 47 μM of TSQ buffer of pH 7.4 at 26 ° C for 90 minutes. The fluorescence (excitation 355 nm emission 400 nm) was monitored against time. The controls were NCp7 under test conditions without drug, and apo NCp7 (not Zn) with drug. The percentage of zinc extrusion was calculated based on the fluorescence of all the theoretical extruded zinc (5.6 μm) x 100.
The test systems used to establish the cellular antiviral activity of acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid are well recognized in the art and used routinely for that purpose. For example, the assay used to evaluate the activity of the compound against VLH virus is that employed by the National Cancer Institute of the United States as described by Weislow O.S., et al., J. Nati. Cancer Ins, 1989; 81: 577-586, incorporated herein by reference.
The procedure is designed to detect agents that act at any stage of the virus's reproductive cycle. The trial basically involves the death of T4 lymphocytes by VLH. Small amounts of VLH are added to the cells and at least two cycles composed of the reproduction of the virus are necessary to obtain the required cell death. Agents that interact with the virions, cells or genetic products of the virus to interfere with viral activities will protect the cells from cytolysis. The system is automated in several features to accommodate large numbers of candidate agents, and is generally designed to detect anti-HIV activity. However, compounds that degenerate or metabolize rapidly under culture conditions can not show activity on this screen.
Another test system used to evaluate the compounds of the invention is called the H9 VLH assay. The H9 VLH cell assay measures the required concentration of inhibitor to suppress the reproduction of the HIV-1 virus. In this system, viral growth occurs through multiple laps of the life cycle. Any suppression of reproductive kinetics results in a geometric decrease in virus production. As a result, this assay is a sensitive means of measuring the ability of a compound to inhibit viral reproduction of HIV-1.
A cell line T H9 is infected in a group with VLH virus at a multiple of infection MOI) of 0.01. After two hours of absorption, the cells are washed, resuspended in RPMI-1640 (a readily available medium well known to those skilled in the art / 10% fetal calf serum, and planted at 5 x 10-3 cells / Well of a 96-well platform A duplicated platform of uninfected H9 cells is prepared for the cytotoxicity assay The drugs are serially diluted 1/3/16 in dimethylsulfoxide (DMSO), transferred to medium in a concentration of 8x, and then add to the cultures in triplicate.The final DMSO concentration of 0.002 (0.2%).
Viral production is measured by assay at room temperature and cytotoxicity is measured by XTT assay 7 days after infection. The XTT assay is well known to those skilled in the art. See, for example, J. Nati. Cancer Inst, 1989; 81: 577-586. The test at room temperature is carried out as a modification of Borroto-Esoda and Boone, J. Virol., 1991; 65: 1952-1959 and quantified using a Molecular Phospho-annealer Dynamics with Imagequant computer programs. The XTT assay is carried out as a modification of Roehm, et al., J. Immuno. Methods., 1991; 142: 257-265 and quantified using a Devices Thermomax molecular platform reader with Softmax computer programs.
The data is transferred electronically to a Microsoft Excel spreadsheet. The values of the test room temperature equivalent to 50% and 90% inhibition of virus production are calculated from the untreated controls. The concentrations of the inhibitor required to produce these values (IC50 and IC90) are interpolated from data points outside of these activities at room temperature. The XTT assay values equivalent to 50% cytotoxicity are calculated from the untreated controls. The inhibitor concentrations required to produce this value are interpolated from data points outside these XTT values.
Yet another test system used to determine antiviral activity is called a CEM cell assay.
T4 lymphocytes / CEM cell line) are exposed to HTV in a virus cell ratio of approximately 0.05, and are placed on platform along uninfected control cells in 96-well microfilter platforms.
The candidate agent is dissolved in dimethyl sulfoxide (unless noted otherwise), then diluted 1: 200 in cell culture medium. Other dilutions (half -log) are prepared before adding to an equal volume of medium containing either infected or uninfected cells.
The cultures are incubated at 37 ° C in a 5% carbon dioxide atmosphere for 6 or 7 days. Tetrazolium salt, XTT, is added to all wells and the cultures are incubated to allow development of color pormazan in viable cells, J. National Cancer Institute, 1989; 81: 577-586. Individual wells are analyzed spectrophotometrically to quantify the production of fomazan, and in addition they are observed microscopically for the confirmation of protective activity by means of detection of viable cells.
Cells infected with virus and tested with drugs are compared with uninfected cells treated with drugs (untreated untreated and untreated infected cells, wells containing drugs without cells, etc.) on the same platform. The data is reviewed in comparison to other tests done at the same time and a determination is made about the activity.
Table 1 below presents the results of the compound in the extrusion test
of zinc described above. The compound was evaluated for its ability to cause
extrusion of zinc from the nucleocapsid protein NCp7 (expressed as% relative to
to control).
TABLE 1. Extrusion of Zn from the Zn fingers of the Protein
Nucleocápsida Vffl - 1 NCp7.
Compound of Example% Extrusion of Zn in relation to control
3 30
Table 2 below presents data for the compound of Example 3 when
evaluated in the H9 and CEM cellular assays.
TABLE 2. CEM Cellular Assay of Anti-HIV Activity
Compound EC5o (μm) to TC50 μm) b Example 3 14 > 100
a Effective concentration that protects cells from viral cytopathic effects.
b Toxic concentration that inhibits cell growth 50% in relation to
control.
Claims (12)
- CLAIMS: 1. A method for making acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3 H -benzo (d) isothiazol-2-yl) pentanoic, the method comprising: to. Reaction of 2,2'-dithiosalicylic acid with a halogenating agent to make 2,2'-dithiobisbenzoyl halide; b. Reaction of halide 2,2'-dithiobisbenzoyl with L-isoleucine in tetrahydrofuran or tetrahydrofuran and a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1 - carboxy - 2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic); and c. React the acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) with halogen oxidizing agent to make acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3 H -benzo (d) isothiazol-2-yl) pentanoic acid.
- 2. The method of Claim 1 wherein the halogenating agent is thionyl chloride.
- 3. The method of Claim 1 wherein the 2,2'-dithiobisbenzoyl halide is 2,2'-dithiobisbenzoyl chloride.
- 4. The method of Claim 1 wherein the base is sodium bicarbonate.
- 5. The method of Claim 1 wherein the halogen oxidizing agent is chlorine, bromine or iodine.
- 6. The method of Claim 5 wherein the halogen oxidizing agent is bromine.
- 7. A method for making acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) -pentanoic acid, the method comprises: a. React 2,2'-dithiosalicylic acid with thionyl chloride to make 2,2'-dithiobisbenzoyl chloride; b. Reaction of 2,2'-dithiobisbenzoyl chloride with at least two equivalents of L-isoleucine in tetrahydrofuran or tetrahydrofiirand a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic); and c. React the acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic acid) with bromine and acetic acid to make acid (S - (R *, R *)) - 3-methyl-2 - (3-oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid.
- 8. A method for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic), the method comprises: a. Reaction of 2,2'-dithiosalicylic acid with a halogenating agent to make 2,2'-dithiobisbenzoyl halide; and b. Reaction of 2,2'-dithiobisbenzoyl halide with L-isoleucine in tetrahydrofuran or tetrahydrofuran and a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1 - carboxy - 2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic).
- The method of Claim 8 wherein the halogenating agent is thionyl chloride.
- 10. The method of Claim 8 wherein the 2,2'-dithiobisbenzoyl halide is 2,2'-dithiobisbenzoyl chloride.
- 11. The method of Claim 8 wherein the base is sodium bicarbonate.
- 12. A method for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic), the method comprises: a. Reaction of 2,2'-dithiosalicylic acid with thionyl chloride to make 2,2'-dithiobisbenzoyl halide; and b. Reaction of 2,2'-dithiobisbenzoyl chloride with L-isoleucine in tetrahydrofuran or tetrahydrofuran and a base for making acid (S - (R *, R *)), L - 2 - (2 - (2 - (1 - carboxy - 2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic). EXTRACT OF THE INVENTION The present application presents an acid synthesis (S - (R *, R *)) - 3 - methyl - 2 - (3 - oxo-3H-benzo (d) isothiazol-2-yl) pentanoic acid and (S - (R *, R *)), 1 - 2 - (2 - (2 - (1-carboxy-2-methylbutylcarbamoyl) phenyldisulfonyl) benzoyl-amino) -3-methylpentanoic).
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