CN1336934A - Bis-amino acid sulfonamides containing N-terminally a substituted benzyl group as HIV protease inhibitors - Google Patents
Bis-amino acid sulfonamides containing N-terminally a substituted benzyl group as HIV protease inhibitors Download PDFInfo
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- CN1336934A CN1336934A CN00802755A CN00802755A CN1336934A CN 1336934 A CN1336934 A CN 1336934A CN 00802755 A CN00802755 A CN 00802755A CN 00802755 A CN00802755 A CN 00802755A CN 1336934 A CN1336934 A CN 1336934A
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- Prior art keywords
- compound
- hiv
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- solution
- aminophenyl
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- 239000004030 hiv protease inhibitor Substances 0.000 title claims abstract description 11
- 229940124530 sulfonamide Drugs 0.000 title abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 68
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- 229940079593 drug Drugs 0.000 claims description 10
- 229940122440 HIV protease inhibitor Drugs 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 8
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims description 8
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 8
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
This invention relates generally to bis-amino acid sulfonamides containing substituted benzyl amines of formula (I) or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as HIV protease inhibitors, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.
Description
Invention field
The present invention relates generally to as the method that contains the bis-amino acid sulfonamides class material of alpha substituted benzylamine, the pharmaceutical composition that contains described material and diagnostic kit, the described material treatment of use virus infection of hiv protease inhibitor or with described material and be used as analytical standard or analytical reagent.
Background of invention
It is known that two kinds of different retrovirus are arranged is that 1-type (HIV-1) or 2 types (HIV-2) human immunodeficiency virus are that acquired immune deficiency syndrome (AIDS) (acquired immune deficiency syndrome (AIDS) (AIDS)) is relevant with immunosuppressant disease on nosetiology.The seropositive individuality of HIV is originally also asymptomatic, but generally develops into AIDS related complex, develops into acquired immune deficiency syndrome (AIDS) then.The infected shows serious immunosuppression, thereby makes its health weak, finally makes it be subjected to fatal opportunistic infection easily.
Acquired immune deficiency syndrome (AIDS) is the net result of HIV-1 or the complicated life cycle of HIV-2 virus self.When the virosome life cycle began, virosome self protects expansion property case surface glycoprotein by this virus and the combination of lymphocyte CD 4 glycoprotein adheres to host people T-4 lymphocytic immunity cell.In case after adhering to, the glycoprotein shell of this virosome comes off, and infiltrates in the film of host cell, sloughs its RNA.This virosome enzyme (reversed transcriptive enzyme) participates in becoming from rna transcription the process of single stranded DNA.The viral RNA degraded produces another DNA chain.This double-stranded DNA is incorporated in people's cytogene then, and these genes are used for virus replication.
At this moment, RNA polymerase is transcribed into viral RNA to the DNA that integrates.This viral RNA is translated into precursor gal-pol and merges in the polyprotein.This polyprotein is obtained sophisticated viral protein by the hiv protease cracking then.Therefore, hiv protease participates in regulating a series of scission reactions, causes the maturation of virion, becomes the virus that can have complete infection ability.
Because virus infection also kills immune T cell, make the typical human immunity system response of killing the intrusive viruses body form burden.In addition, be used to prepare that new virus body particulate enzyme--viral reverse transcriptase is nonspecific, and it can cause transcription error, cause the glycoprotein of viral protectiveness case surface to continue to change.Lack specificity and reduced immune effectiveness, because production of antibodies is specific, it can only resist a certain glycoprotein, and can not resist other glycoprotein, thereby is used to resist the antibody number reduction of virus.This virus continues to duplicate, and immunity system continues to weaken simultaneously.At last, the free spaces of a large amount of controls of this HIV surpass the immunity system of health, thereby when not administration antiviral agent or immunomodulator or the two during not administration, cause various opportunistic infections, thereby may cause death.
In viral life cycle, exist three key points to be accredited as the possible target spot of antiviral at least, they are: (1) virosome begins to adhere to T-4 lymphocyte or scavenger cell; (2) viral RNA be transcribed into viral DNA (reversed transcriptive enzyme, RT) and (3) hiv protease to the proteic processing of gag-pol.
These reverse transcrigt virus genome coded a kind of proteolytic enzyme, this proteolytic enzyme participate in for example proteolysis of pol and gag gene product of one or more polyprotein precursors.Referring to Wellink, Arch.Virol.981 (1988).Retroviral Protease the most normally is processed into nucleoprotein to the gag precursor, also the pol precursor is processed into reversed transcriptive enzyme and retroviral Protease simultaneously.
For the virosome that assembling is infected, retroviral Protease is necessary to the correct processing of precursor polyprotein.According to the show: the vitro mutagenesis that produces the proteolytic enzyme defective virus causes producing the infective non-ripe kernel form of shortage.Referring to Crawford etc., J.Virol.53899 (1985); Katoh etc., virusology (Virology) 145 280 (1985).Therefore, retroviral Protease suppresses to provide the attractive target spot of an antiviral therapy.Referring to Mitsuya, nature (Nature) 325 775 (1987).
Prove as commercially available proteinase inhibitor and clinical trial at present, after deliberation various compound as potential hiv protease inhibitor.A core, hydroxyethylamino sulfanilamide (SN) have caused that intensive notes.For example, PCT application WO94/05639, WO94/04492, WO95/06030 and WO96/28464 disclose following formula sulfamido and preparation method thereof:
Although there are some The compounds of this invention to fall within the general openly scope of above-mentioned publication, these compounds are not disclosed, point out or be required protection especially.
Even at present some successful proteinase inhibitor have been arranged, it is found that HIV patient may develop immunity to drugs to a kind of proteinase inhibitor.Therefore, needing the other proteinase inhibitor of exploitation infects so that further resist HIV.
Summary of the invention
Therefore, purpose of the present invention provides new proteinase inhibitor.
Another object of the present invention provides the novel method that treatment HIV infects, and comprising: at least one The compounds of this invention of treatment significant quantity or the patient that its pharmacologically acceptable salt delivers medicine to this treatment of needs.
A further object of the invention provides the novel method that treatment HIV infects, and comprising: the patient who (a) a kind of The compounds of this invention and (b) one or more combination medicines that are selected from the treatment significant quantity of hiv reverse transcriptase inhibitor and hiv protease inhibitor is delivered medicine to this treatment of needs.
A further object of the invention provides the pharmaceutical composition with protease inhibiting activity, and it comprises: at least a The compounds of this invention or its pharmacologically acceptable salt of pharmaceutically acceptable carrier and treatment significant quantity.
A further object of the invention provides a kind of method that suppresses HIV in the humoral sample, comprising: the The compounds of this invention with significant quantity is handled humoral sample.
A further object of the invention provides a kind of test kit or container, wherein contain at least a The compounds of this invention, the content of described compound is for measuring the significant quantity that potential drug suppresses to be used as in hiv protease, HIV growth or the two test and the analysis standard or reagent.
In the detailed Description Of The Invention below, these and other objects of the present invention will be more obvious, and why can reach described purpose is because the inventor has found formula (I) compound:
I (R wherein
1, R
2And R
3Be defined as follows), its steric isomer, its stereoisomer mixture or its pharmacologically acceptable salt belong to the effective protein proteins enzyme inhibitors.
Detailed Description Of The Invention
[1] therefore, in first embodiment, the invention provides new compound or its pharmacologically acceptable salt of formula I:
IR
1Be F; R
2Be F or H; And R
3Be selected from 4-aminophenyl, 3-aminophenyl, 2,3-Dihydrobenzofuranes-5-base and 1,3-benzo dioxole-5-base.
[2] in preferred embodiments, the invention provides formula II new compound:
II.[3] in a more preferred embodiment, the invention provides formula IIa new compound:
IIa.
[4] in preferred embodiment also, the invention provides R
3Formula IIa new compound for the 3-aminophenyl.
[5] in another preferred embodiment, the invention provides R
3Formula IIa new compound for the 4-aminophenyl.
[6] in another preferred embodiment, the invention provides R
3Be 2,3-Dihydrobenzofuranes-5-base or 1, the formula IIa new compound of 3-benzo dioxole-5-base.
[7] in another preferred embodiment, the invention provides new formula IIb compound:
IIb.
[8] in another preferred embodiment, the invention provides R
3Formula IIb new compound for the 3-aminophenyl.
[9] in another also preferred embodiment, the invention provides R
3Formula IIb new compound for the 4-aminophenyl.
[10] in another also preferred embodiment, the invention provides R
3Be 2,3-Dihydrobenzofuranes-5-base or 1, the formula IIb new compound of 3-benzo dioxole-5-base.
[11] in another preferred embodiment, the invention provides formula IIc new compound:
IIc.
[12] in another preferred embodiment, the invention provides R
3Formula IIc new compound for the 3-aminophenyl.
[13] in another also preferred embodiment, the invention provides R
3Formula IIc new compound for the 4-aminophenyl.
[14] in another also preferred embodiment, the invention provides R
3Be 2,3-Dihydrobenzofuranes-5-base or 1, the formula IIc new compound of 3-benzo dioxole-5-base.
[15] in another preferred embodiment, the invention provides the formula III new compound:
III.
[16] in another preferred embodiment, the invention provides formula III a new compound:
IIIa.
[17] in another preferred embodiment, the invention provides formula IV new compound:
IV.
[18] in another preferred embodiment, the invention provides formula IVa new compound:
IVa.
In another embodiment, the invention provides new pharmaceutical composition, it contains the formula I compound or pharmaceutically acceptable salt thereof of pharmaceutically acceptable carrier and treatment significant quantity.
In another embodiment, the invention provides the novel method that a kind of HIV of treatment infects, comprise formula I compound or pharmaceutically acceptable salt thereof to patient's administering therapeutic significant quantity of this treatment of need.
In another embodiment, the invention provides the novel method that treatment HIV infects, comprising: following (a) and combination medicine (b) to treat the patient that significant quantity delivers medicine to the described treatment of needs:
(a) formula I compound; With,
(b) be selected from least a compound of hiv reverse transcriptase inhibitor and hiv protease inhibitor.
In another preferred embodiment, reverse transcriptase inhibitors is selected from zidovudine (A2T), dideoxycytidine (ddC), dideoxyinosine (ddI), d4T, 3TC, U-90152, efavirenz, nevirapine, Ro18, and 893, trovirdine, MKC-442, HBY097, ACT, UC-781, UC-782, RD4-2025 and MEN10979; Proteinase inhibitor is selected from Saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, pal inavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD173606, PD177298, PD178390, PD178392, U-140690 and ABT-378.
In a more preferred embodiment, described reverse transcriptase inhibitors is selected from AZT, efavirenz and 3TC; Described proteinase inhibitor is selected from Saquinavir, ritonavir, nelfinavir and indinavir.
In a more preferred embodiment, reverse transcriptase inhibitors is AZT.
In another preferred embodiment, proteinase inhibitor is a ritonavir.
In another preferred version, component (b) is a kind of hiv reverse transcriptase inhibitor and hiv protease inhibitor.
In another embodiment preferred, component (b) is two kinds of different hiv reverse transcriptase inhibitors.
In another embodiment, the invention provides and be used for the treatment of the pharmaceutical composition that HIV infects, this pharmaceutical composition contains the treatment significant quantity:
(a) formula I compound; With,
(b) place at least a compound that is selected from hiv reverse transcriptase inhibitor and hiv protease inhibitor of one or more sterilized containers.
In another embodiment, the invention provides the novel method of the HIV that exists in the inhibition humoral sample, comprising: with the formula I compound treatment body fluid of significant quantity.
In the 9th embodiment, the invention provides new test kit or container, wherein contain formula I compound, the content of described compound is for measuring the significant quantity that potential drug suppresses to be used as in hiv protease, HIV growth or the two test and the analysis standard or reagent.
Definition
In this application, following term and expression have pointed meaning.Should be understood that: The compounds of this invention contains the carbon atom of asymmetric replacement, and it can be separated into optical activity form or racemic form.The well known optical activity form that how to prepare for example obtains by the resolution of racemic form or from the optical activity starting raw material is synthetic.Concrete unless otherwise indicated stereochemistry or isomeric forms, described compound refer to all chiralitys, diastereomer, racemize and all geometrical isomer forms.
Considering to implement the inventive method implements with multigram-scale, kilogram scale, kilogram order of magnitude scale or technical scale at least." multigram-scale " described herein is preferably such scale: wherein at least a starting raw material be 10 the gram or more, more preferably at least 50 the gram or more in addition more preferably at least 100 the gram or more." kilogram scale " described herein refers to such scale: wherein the consumption of at least a starting raw material is above 1 kilogram." technical scale " described herein refers to such scale: it does not belong to laboratory scale, and it is enough to provide the product that enough is used for clinical trial or is distributed to the human consumer.
In the compound of the present invention, in all isotropic substance forms of atom are also included within.Isotropic substance comprises that those have the same atoms ordinal number but the atom of different mass number.By for example general and unrestriced mode, the isotropic substance of hydrogen atom comprises deuterium and tritium; The carbon atom isotropic substance comprises C-13 and C-14.
" hiv reverse transcriptase inhibitor " described herein refers to the nucleosides and the non-nucleosidic inhibitors of hiv reverse transcriptase (RT).The example of nucleoside RT inhibitor includes but not limited to zidovudine (AZT), dideoxycytidine (ddC), dideoxyinosine (ddI), d4T and 3TC.The example of non-nucleoside RT inhibitor includes but not limited to U-90152 (Pharmacia and Upjohn, U90152S), efavirenz (Dupont), nevirapine (BoehringerIngelheim), Ro18,893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY097 (Hoechst), HBY1293 (Hoechst), ACT (KoreanResearch Institute), UC-781 (Rega Institute), UC-782 (Regainstitute), RD4-2025 (Tosoh Co.Ltd) and MEN10979 (MenariniFarmaceutici).
" hiv protease inhibitor " described herein refers to suppress the compound of hiv protease, its example includes but not limited to Saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex/GlaxoWellcome), nelfinavir (Agouron, AG1343), palinavir (BoehringerIngelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (GileadSciences), KNI-413 (Japanese Energry), KNI-272 (Japanese Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD173606 (ParkeDavis), PD177298 (Park Davis), PD178390 (Parke Davis), PD178392 (Parke Davis), tipranavir (Pharmacia and Upjohn U-140690) and DMP-450 (Dupont) and ABT-378.
" pharmacologically acceptable salt " described herein refers to the derivative of disclosed compound, and wherein parent compound is modified to its hydrochlorate or alkali salt.The example of pharmacologically acceptable salt includes but not limited to: the alkali residue is the inorganic acid salt or the organic acid salt of amine for example; The acid residue is the alkali salt or the organic salt of carboxylic acid for example; With similar salt.Pharmacologically acceptable salt comprises the conventional non-toxic salt or the quaternary ammonium salt of the parent compound that is prepared by for example non-toxic inorganic acid or organic acid.For example, so conventional non-toxic salt comprises: from the salt of generations such as mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid; From the organic acid salt for preparing such as acetate, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pamoic acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, sulfanilic acid, 2-globentyl, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid and isethionic acid for example.
Pharmacologically acceptable salt of the present invention can obtain from the parent compound that contains alkalescence or acidic residues is synthetic with the conventional chemical method.Normally, such salt can be prepared as follows: in water or in organic solvent, or in the two mixture, the free acid of these compounds or alkali form appropriate base or the acid-respons with chemical equivalent, this reaction is preferably for example carried out in ether, ethyl acetate, ethanol, Virahol or acetonitrile at non-water-soluble coal usually.The catalogue of acceptable acid addition salts can be referring to Lei Mingdun pharmaceutical science (Remington Pharmaceutical Sciences), and the 17th edition, Mack publishing company, Easton, PA, 1985, the 1418 pages, its disclosure is hereby incorporated by.
Term described herein " pharmaceutically acceptable " refers to those compounds, material (materials), composition and/or formulation, they reasonably are being suitable for contacting human body and animal tissues in the medical judgment scope, and do not produce excessive toxicity, stimulation, anaphylaxis or reasonable together being benefited/danger than suitable other problem or complication.
" prodrug " refers to comprise the carrier that any covalency links to each other: when such prodrug was administered to mammalian subject, described carrier can discharge the active parent drug or the compound of formula of the present invention (I) or other structural formula in vivo.The The compounds of this invention for example prodrug of formula (I) compound is prepared as follows: the functional group in the described compound is modified, and the modification mode makes modifier with routine operation or can be cracked into parent compound in vivo.Prodrug comprises such The compounds of this invention, and the hydroxyl of these compounds or amino bonded are in the group that can be cracked into free hydroxyl group or free amine group arbitrarily when this prodrug delivers medicine to Mammals respectively.The example of prodrug includes but not limited to acetate, formic acid and the benzoic acid derivative etc. of alkohol and amine functional group in the The compounds of this invention.
" stable compound " and " rock steady structure " refers to have enough stability and is separated into useful purity and can stands to be mixed with the compound of effective therapeutical agent from reaction mixture standing.Have only stable compound just to belong to the row of limit of consideration of the present invention.
" replacement " means: use the one or more hydrogen atoms that indicate on the atom in the expression of " replacement " and be selected from indicated group replacement, prerequisite is that normally tiring of specified atom is not exceeded, and this replacement causes stable compound.When substituting group was ketone group (promptly=0), then 2 hydrogen atoms were substituted.
" treatment significant quantity " refer to comprise can suppress effectively that HIV among the host infects or the treatment host in the consumption of The compounds of this invention of HIV infection symptoms or the consumption of desired Combined Preparation compound.The compound drug combination is preferably synergistic combinations.Collaborative, as Chou and Talalay, Adv.Enzyme Regul.22:27-55 (1984) is described, when the effect (referring to suppress HIV herein duplicates) of compound Combined Preparation during as the individually dosed effect sum of single agents, has just produced collaborative greater than these compounds.Usually, synergistic effect shows the most obvious when the suboptimum concentration of compound.Synergistic effect can show as combined utilization compare with single component have lower cytotoxicity, higher antiviral effect or other beneficial effect.
Some diastereomers of formula I compound may show the activity more superior than other isomer.When needs, can use chiral column by HPLC or use resolution reagent for example camphonic chloride by splitting racemic compound is separated (referring to Thomas J.Tucker etc., pharmaceutical chemistry magazine (J.Med.Chem) 1994,37,2437-2444).Can also use chiral catalyst or chiral ligand (for example referring to MarkA.Huffman etc., organic chemistry magazine (J.Org.Chem.) 1995,60,1590-1594) the direct chipal compounds of synthesis type I.
By the description to following embodiment scheme, further feature of the present invention will be more obvious, and described embodiment illustrates the present invention rather than limitation of the present invention.
Embodiment
Used in these embodiments abbreviation is defined as follows: " ℃ " for degree centigrade, " d " is bimodal, " dd " is double doublet, " eq " is equivalent, and " g " is gram, and " mg " is milligram, " mL " is milliliter, and " H " is hydrogen or hydrogen atom, and " hr " is hour, " m " is multimodal, and " M " is mole, and " min " is minute, " MHz " is megahertz, and " MS " is mass spectrum, and " nmr " or " NMR " is NMR (Nuclear Magnetic Resonance) spectrum, " t " is three peaks, and " TLC " is thin-layer chromatography.
Embodiment 1
1B is NaOH (50% aqueous solution, 44.5g) join N-[3 (S)-[N, two (phenmethyl) amino of N-]-2 (R)-hydroxy-4-phenyl butyl]-(127.6g is 251mmol) in the mixture of toluene (1L), water (500mL) and methylene dichloride (400mL) for N-isobutylamine oxalate 1A.Stir after 10 minutes, use the methylbenzene extraction reaction mixture.Merge organic layer, use the salt water washing, dry (sal epsom), removal of solvent under reduced pressure.Resistates is dissolved in THF (1L), is cooled to 0 ℃, with triethylamine (28.15g, 278mmol) and di-tert-butyl dicarbonic acid ester (55.23g, 253mmol) processing.Solution is warmed to room temperature, and stirring is spent the night.Removal of solvent under reduced pressure is dissolved in ethyl acetate (1L) to resistates, water, 5% citric acid, water, saturated sodium bicarbonate and salt water washing successively, dry (sal epsom).Removal of solvent under reduced pressure obtains carbamate IB, and it can directly be used, and need not be further purified.CIMS(NH
3)m/z：517(M+H
+，100％)。
1C palladium hydroxide/carbon (20%, 10g) join in methyl alcohol (500mL) solution of crude product 1B (about 251mmol).This suspension is placed Parr bottle (Parr bottle), pour hydrogen (55psi).After the shaken overnight, reaction mixture through diatomite filtration, removal of solvent under reduced pressure.With the solid recrystallization (ethyl acetate/hexane) that obtains, obtain the amine 1C (56.6g, productive rate 67% (2 steps)) of white solid: CIMS (NH
3) m/z:337 (M+H
+, 100%).
1D under 0 ℃, the N-hydroxybenzotriazole (38.6g, 285mmol) and EDC (35.7g, (47.5g is in DMF 179mmol) (250mL) solution 186mmol) to join N-carbonyl benzyloxy-uncle L--leucine.Stir after 1.5 hours, this solution is joined 1C, and (56.6g, 167mmol) (52.9g is in DMF 521mmol) (200mL) suspension with the 4-methylmorpholine.Reaction mixture is warmed to room temperature.After stirring is spent the night, add N, N-dimethyl-ethylenediamine (4mL) stirred this solution 1.5 hours, removal of solvent under reduced pressure.Resistates is dissolved in ethyl acetate (1L), water, 5% citric acid, water, saturated sodium bicarbonate and salt water washing successively, dry (sal epsom).Removal of solvent under reduced pressure obtains 1D (97.5g, 100%), uses this product and need not be further purified.CIMS(NH
3)m/z：584(M+H
+，100％)。
(20%, (97.5g is in methyl alcohol 167mmol) (300mL) solution 10g) to join 1D palladium hydroxide/carbon for 1E.This suspension is placed Parr bottle (parr bottle), pour hydrogen (55psi).After the shaken overnight, reaction mixture is through diatomite filtration, removal of solvent under reduced pressure.Recrystallization gained solid (ethyl acetate/hexane) obtains white solid 1E (72.8g, 97%): CIMS (NH
3) m/z:450 (M+H
+, 100%).
1F is KHCO
3(27.7g, 276mmol) and chloro-acetyl chloride (12.4g, (43.8g is 97.6mmol) in the solution of ethyl acetate (400mL) and water (270mL) 111mmol) to join amine 1E.Stir after 3 hours, add ethyl acetate (1L), gained solution is water, 5% citric acid, water, saturated sodium bicarbonate and salt water washing successively, dry (sal epsom).Removal of solvent under reduced pressure obtains white solid 1F (51.0g, 99%): CIMS (NH
3) m/z:526 (M+H
+, 100%).
(80mL, 320mmol) solution joins 1F (33.8g is in ethyl acetate 64.2mmol) (600mL) solution 1G the dioxane of 4N HCl.Stirred reaction mixture 6 hours.Removal of solvent under reduced pressure grinds the gained solid with cold diethyl ether and obtains 1G hydrochloride (28.75g, 97%): CIMS (NH
3) m/z:426 (M+H
+, 100%).
(56.7g, 411mmol) (16.9g, (32.0g is 69.2mmol) in the solution of THF (350mL) and water (450mL) 76.0mmol) to join salt 1G with the 4-nitrobenzene sulfonyl chloride salt of wormwood for 1H.Stir after 4 hours, add entry, use ethyl acetate extraction suspension.Merge organic layer, use salt solution, 5% citric acid, water, saturated sodium bicarbonate and salt water washing successively, dry (sal epsom).Removal of solvent under reduced pressure obtains white solid sulfanilamide (SN) 1H (35.8g, 85%) with gained solid recrystallization (ethyl acetate/hexane).CIMS(NH
3)m/z：611(M+H
+，100％)。
(20.0g, (16.0g's 1I in THF 26.1mmol) (200mL) solution, spends the night this reaction mixture refluxed 160mmol) to join muriate 1H the 3-flunamine.Removal of solvent under reduced pressure is dissolved in ethyl acetate with resistates, water and salt water washing successively, dry (sal epsom).Removal of solvent under reduced pressure is carried out chromatogram purification (silica gel, 4% ethanol/methylene) with resistates and is obtained white solid amine 1I (16.3g, 89%).CIMS(NH
3)m/z：700(M+H
+，100％)。
(20%, (14.6g is in methyl alcohol 20.8mmol) (500mL) solution 1.5g) to join 1I for 1 palladium hydroxide/carbon.In reaction mixture, pour hydrogen.Stir after 3 hours, mixture is through diatomite filtration, removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (13.2g, 95%).(37mL, (11.68g is in ether 17.4mmol) (300mL) and ethyl acetate (100mL) solution 37mmol) to join this free alkali the ether of 1N HCl.The mixture that obtains was stirred 15 minutes, filter and obtain white solid dihydrochloride 1 (12.5g, 96%): CIMS (NH
3) m/z:670 (M+H
+, 100%).
Embodiment 2
2A is 3, and (25.0g, (16.0g's 5-two flunamines in THF 26.1mmol) (200mL) solution, spends the night reaction mixture refluxed 174mmol) to join muriate 1H.Removal of solvent under reduced pressure is dissolved in ethyl acetate with resistates, water and salt water washing successively, dry (sal epsom).Removal of solvent under reduced pressure, resistates are carried out chromatography (silica gel, 4% methyl alcohol/chloroform) and are obtained white solid amine 2A (15.2g, 81%).CIMS(NH
3)m/z：718(M+H
+，100％)。
(20%, (15.2g in methyl alcohol 21.2mmol) (500mL) solution, charges into hydrogen to 2 palladium hydroxide/carbon in reaction mixture 1.5g) to join 2A.Stir after 4 hours, with reaction mixture through diatomite filtration, removal of solvent under reduced pressure.Resistates carries out chromatography (silica gel, 5% ethanol/methylene) and obtains white solid amine (10.3g, 71%).(32mL, 32mmol) liquid joins in the ether (300mL) and ethyl acetate (100mL) solution of this free alkali the ether of 1N HCl.The suspension that obtains was stirred 15 minutes, filter and obtain white solid dihydrochloride 2:CIMS (NH
3) m/z:688 (M+H
+, 100%).
Embodiment 3
3A is 2, and (1.2g, (300mg is in THF 0.49mmol) (4mL) solution, with this reaction mixture refluxed 4 hours 8.5mmol) to join muriate 1H for 5-two flunamines.Reaction mixture dilutes with ethyl acetate, water and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure, resistates are carried out chromatography (silica gel, 5% ethanol/methylene) and are obtained white solid amine 3A (270mg, 77%).CIMS(NH
3)m/z：718(M+H
+，100％)。
(20%, (260mg is in methyl alcohol 0.36mmol) (25mL) solution 50mg) to join 3A for 3 palladium hydroxide/carbon.In reaction mixture, charge into hydrogen.Stir after 1 hour, with mixture through diatomite filtration, removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (226mg, 91%).(0.2mL, 0.8mmol) liquid joins in the ether (30mL) and ethyl acetate (10ml) solution of this free alkali the dioxane of 4NHCl.Gained suspension was stirred 15 minutes, filter and obtain white solid dihydrochloride 3:CIMS (NH
3) m/z:688 (M+H
+, 100%).
Embodiment 4
4A is 2, and (1.2g, (300mg is in THF 0.49mmol) (4mL) solution 8.5mmol) to join muriate 1H for 6-two flunamines.With reaction mixture refluxed 4 hours.Use the ethyl acetate diluted reaction mixture then, water and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure is carried out chromatography (silica gel, 5% ethanol/methylene) with resistates and is obtained white solid amine 4A (306mg, 87%).CIMS(NH
3)m/z：718(M+H
+，100％)。
(20%, (295mg is in methyl alcohol 0.41mmol) (25mL) solution 50mg) to join 4A for 4 palladium hydroxide/carbon.In reaction mixture, charge into hydrogen.Stir after 1 hour, this mixture diatomite filtration, removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (228mg, 81%).(0.2mL, 0.8mmol) solution joins in the ether (30ml) and ethyl acetate (10mL) solution of this free alkali the dioxane of 4N HCl.Gained suspension was stirred 15 minutes, filter and obtain dihydrochloride 4, it is a white solid: CIMS (NH
3) m/z:688 (M+H
+, 100%).
Embodiment 5
(51.4g, 370mmol) (15.14g, 68.3mmol) (15.14g, (28.8g is in THF 62.1mmol) (300ml) and water (400mL) solution 68.3mmol) to join salt 1G with the 3-nitrobenzene sulfonyl chloride with the 3-nitrobenzene sulfonyl chloride salt of wormwood for 5A.Stir after 4 hours, add entry, with this suspension of ethyl acetate extraction.Merge organic layer, with salt solution, 5% citric acid, water, saturated sodium bicarbonate and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.The gained solid grinds together with ethyl acetate and hexane, obtains sulphonamide 5A, and it is white solid (32.1g, 85%).CIMS(NH
3)m/z：611(M+H
+，100％)。
(17.0g, (16.0g is in THF 26.1mmol) (200ml) solution 135mmol) to join muriate 5A the 3-flunamine for 5B.Reaction mixture refluxed is spent the night.Removal of solvent under reduced pressure is dissolved in ethyl acetate with resistates, water and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure is carried out chromatography (silica gel, 4% ethanol/methylene) with resistates, obtains white solid amine 5B (16.0g, 87%).CIMS(NH
3)m/z：700(M+H
+，100％)。
(20%, (12.0g is in methyl alcohol 17.22mmol) (400ml) solution 1.25g) to join 5B for 5 palladium hydroxide/carbon.In reaction mixture, charge into hydrogen.Stir after 3 hours, this mixture diatomite filtration, removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (11.2g, 97%).(36mL, 36mmol) solution joins in the ether (400ml) and ethyl acetate (75mL) solution of this free alkali the ether of 1N HCl.Gained suspension was stirred 15 minutes, filter and obtain dihydrochloride 5, it is a white solid: CIMS (NH
3) m/z:670 (M+H
+, 100%).
Embodiment 6
6A is 3, and (25.0g, (16.0g is in THF 26.1mmol) (200mL) solution 174mmol) to join muriate 5A for 5-two flunamines.Reaction mixture was stirred 2 hours, and backflow is spent the night.Removal of solvent under reduced pressure is dissolved in ethyl acetate with resistates, water and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure is carried out chromatography (silica gel, 3.5% ethanol/methylene) with resistates and is obtained white solid amine 6A (15.6g, 83%).CIMS(NH
3)m/z：718(M+H
+，100％)。
(20%, (14.4g is in methyl alcohol 20.0mmol) (500mL) solution 1.5g) to join 6A for 6 palladium hydroxide/carbon.In reaction mixture, charge into hydrogen.Stir after 4 hours, this mixture diatomite filtration, removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (12.5g, 91%).(31mL, 31mmol) solution joins this free alkali (9.57g is in ether 13.9mmol) (300ml) solution the ether of 1NHCl.Gained suspension was stirred 20 minutes, filter and obtain dihydrochloride 6, it is white solid (9.9g, 94%): CIMS (NH
3) m/z:688 (M+H
+, 100%).
Embodiment 7
7 3-flunamine (550mg; 4.4mmol) join N-[2R-hydroxyl-3-[[(2; 3-dihydro-2; 3-Dihydrobenzofuranes-5-yl) alkylsulfonyl] (2-methyl-propyl) amino]-1S-(phenyl methyl) propyl group]-the 2S-[(chloracetyl) amino]-3; (100mg is in THF 0.16mmol) (2mL) solution for 3-amide dimethyl butyrate 7A.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate then, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (91mg, 79%).(0.05mL, 0.20mmol) solution joins this free alkali (91mg is in ether 0.13mmol) (25ml) solution the dioxane of 4N HCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 7, and it is white solid (72mg, 65%): CIMS (NH
3) m/z:697 (M+H
+, 100%).
Embodiment 8
83, (605mg, (100mg is in THF 0.16mmol) (2mL) solution 4.2mmol) to join 7A for 5-two flunamines.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (83mg, 70%).(0.05mL, 0.20mmol) solution joins this free alkali (83mg is in ether 0.11mmol) (25ml) solution the dioxane of 4N HCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 8, and it is white solid (65mg, 75%): ultimate analysis (C
37H
49N
4O
6S
1F
2C
L1): calculated value: C, 59.15; H, 6.45; N, 7.47.Calculated value: C, 58.90; H6.51; N, 7.2l.
Embodiment 9
92, (610mg, (100mg is in THF 0.16mmol) (2mL) solution 4.3mmol) to join 7A for 5-two flunamines.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (110mg, 93%).(0.05mL, 0.20mmol) solution joins this free alkali (110mg is in ether 0.15mmol) (25ml) solution the dioxane of 4N HCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 9, and it is white solid (76mg, 66%): CIMS (NH
3) m/z:715 (M+H
+, 100%).
Embodiment 10
10 2, (600mg, (100mg is in THF 0.16mmol) (2mL) solution 4.2mmol) to join 7A for 6-two flunamines.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (103mg, 87%).(0.05mL, 0.20mmol) solution joins this free alkali (103mg is in ether 0.14mmol) (25ml) solution the dioxane of 4NHCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 10, and it is white solid (82mg, 76%): CIMS (NH
3) m/z:715 (M+H
+, 100%).
Embodiment 11
11 3-flunamine (1.1g; 8.8mmol) join N-[2R-hydroxyl-3-[[(1; 3-benzo dioxole-5-yl) alkylsulfonyl] (2-methyl-propyl) amino]-1S-(phenyl methyl) propyl group]-the 2S-[(chloracetyl) amino]-3; (750mg is in THF 1.23mmol) (2mL) solution for 3-amide dimethyl butyrate 11A.The reaction mixture stirring is spent the night.Dilute this reaction mixture with ethyl acetate then, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (532mg, 62%).(0.22mL, 0.88mmol) solution joins this free alkali (532mg is in ether 0.76mmol) (100ml) solution the dioxane of 4N HCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 11, and it is white solid (417mg, 75%): CIMS (NH
3) m/z:699 (M+H
+, 100%).
Embodiment 12
12 3, (2.42g, (2.0g is in THF 3.27mmol) (7mL) solution 16.9mmol) to join 11A for 5-two flunamines.With reaction mixture refluxed 5 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (2.26g, 97%).(0.66mL, 2.67mmol) solution joins this free alkali (1.8g is in ether 2.51mmol) (100ml) solution the dioxane of 4NHCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters to obtain white solid benzylamine salt 12 (1.65mg, 87%): CIMS (NH
3) m/z:717 (M+H
+, 100%).Ultimate analysis (C
36H
47N
4O
7S
1F
2C
L1): calculated value: C, 57.40; H, 6.17; N, 7.45.Calculated value: C, 57.25; H6.25; N, 7.24.
Embodiment 13
13 2, (1.2g, (750mg is in THF 1.23mmol) (2mL) solution 8.5mmol) to join 11A for 5-two flunamines.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (702mg, 80%).(0.3mL, 1.2mmol) solution joins this free alkali (702mg is in ether 0.98mmol) (100ml) and ethyl acetate (25mL) solution the dioxane of 4N HCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 13, and it is white solid (586mg, 79%): CIMS (NH
3) m/z:717 (M+H
+, 100%).
Embodiment 14
14 2, (1.2g, (750mg is in THF 1.23mmol) (2mL) solution 8.3mmol) to join 11A for 6-two flunamines.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (717mg, 81%).(0.3mL, 1.2mmol) solution joins this free alkali (717mg is in ether 1.00mmol) (100ml) solution the dioxane of 4N HCl.Stir after 10 minutes, removal of solvent under reduced pressure is ground the gained solid together with ether, filters and obtains hydrochloride 14, and it is white solid (663mg, 88%): CIMS (NH
3) m/z:717 (M+H
+, 100%).
Embodiment 15
15 3, (1.2g, (750mg is in THF 1.23mmol) (2mL) solution 8.3mmol) to join 11A for 4-two flunamines.With reaction mixture refluxed 3 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (760mg, 86%).(0.3mL, 1.2mmol) solution joins this free alkali (760mg is in ether 1.06mmol) (100ml) solution the dioxane of 4N HCl.Stir after 10 minutes, filter the gained solid and obtain hydrochloride 15, it is white solid (730mg, 91%): CIMS (NH
3) m/z:717 (M+H
+, 100%).
Embodiment 16
16 2, (1.2g, (750mg is in THF 1.23mmol) (2mL) solution 8.3mmol) to join 11A for 4-two flunamines.With reaction mixture refluxed 6 hours.Dilute this reaction mixture with ethyl acetate, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (693mg, 79%).(0.3mL, 1.2mmol) solution joins this free alkali (693mg is in ether 0.97mmol) (100ml) solution the dioxane of 4N HCl.Stir after 10 minutes, filter the gained solid and obtain hydrochloride 16, it is white solid (638mg, 88%): CIMS (NH
3) m/z:717 (M+H
+, 100%).
Embodiment 17
(1.0g, (500mg is in THF 0.82mmol) (2mL) solution 8.0mmol) to join 11A for 17 4-flunamines.The reaction mixture stirring is spent the night.Dilute this reaction mixture with ethyl acetate then, water (4 *) and salt water washing, dry (sal epsom).Removal of solvent under reduced pressure.Resistates is carried out chromatography (silica gel, 5% ethanol/methylene) obtain white solid amine (470mg, 82%).(0.18mL, 0.7mmol) solution joins this free alkali (400mg is in ether 0.57mmol) (30ml) solution the dioxane of 4N HCl.Stir after 15 minutes, filter the gained solid and obtain hydrochloride 17, it is white solid (413mg, 98%): CIMS (NH
3) m/z:699 (M+H
+, 100%).
Use
It is active that formula I compound has the hiv protease inhibition, therefore can be as the antiviral agent of treatment HIV infection and relative disease.Same because formula I compound has hiv protease inhibition activity, so it can suppress the HIV growth effectively.In the standard testing of viral growth and infectivity, for example use following testing method, proved that The compounds of this invention suppresses the ability of viral growth and infectivity.
Formula I compound of the present invention can also be used for suppressing the external HIV of containing sample or the external HIV that may contact the sample of HIV.Therefore, compound of the present invention can be used for suppressing to contain or suspecting containing the HIV that maybe may contact the humoral sample of HIV.
Compound provided by the invention is used as n-compound or reference compound in can also or analyzing in test, and described test and analysis are used for for example determining that in the drug research program reagent inhibition virus clone duplicates and/or the ability of hiv protease.Therefore, The compounds of this invention can be used as the contrast or the reference compound of these analyses and be used as quality control standard.During as such standard or reference compound, the form that provides of The compounds of this invention can be commercial reagent box-like formula or vessel form.
Because The compounds of this invention shows hiv protease is had specificity, so The compounds of this invention can also be used as diagnostic reagent at the diagnositc analysis that is used for the hiv protease detection.Therefore, in analyzing (analysis as described herein), The compounds of this invention shows the existence of hiv protease and HIV virus to the inhibition of protease activity.
In the symbol described herein, " μ g " refers to microgram, and " mg " refers to milligram, and " g " refers to gram, and " μ L " refers to that microlitre, " L " refer to rise, and " nM " refers to nmole, and " μ M " refers to the micromole, and " mM " refers to mmole, and " M " refers to mole, and " nM " refers to nmole." Sigma " represents St.Louis, the Sigma-Aldrich company of MO.
HIV RNA analyzing DNA plasmid and external rna transcription:
According to Erickson-Viitanen etc.Acquired immune deficiency syndrome (AIDS) research and human retrovirus (AIDS Research and Human Retroviruses) 1989,5,577 disclosed methods, preparation contains the BH10 gag that clones into PTZ 19R and the pDAB72 plasmid of pol sequence (bp113-1816).With Bam HI linearizing together, application contains the Riboprobe Gemini II of the system test kit (Promega) of t7 rna polymerase at external generation rna transcription then this plasmid.Handle phenol-chloroform extraction and ethanol sedimentation purifying synthetic RNA by using the RNA enzyme (Promega) that does not contain the DNA enzyme.RNA transcriptase is dissolved in water, stores down at-70 ℃.Measure the concentration of RNA from A260.Probe:
Application is by Cocuzza, Tet.Lett.1989,30, vitamin H-phosphoramidite the reagent of record in 6287, by vitamin H being added to 5 ' end of oligonucleotide, at applying biological system (Applied Biosystems, Foster City, CA) in the dna synthesizer behind the capturing probe of synthesizing biotinylatedization, this biotinylated capturing probe is carried out purifying by HPLC.This gag biotinylation capturing probe (5-vitamin H-CTAGCTCCCTGCTTGCCCATACTA 3 ') adds among the Nucleotide 889-912 of HXB2; This pol biotinylation capturing probe (5 '-vitamin H-CCCTATCATTTTTGGTTTCCAT3 ') add among the Nucleotide 2374-2395 of HXB2; (San Diego CA) prepares the oligonucleotide of combined alkali Phosphoric acid esterase with the probe of making reports by Syngene.This pol report probe (5 '-CTGTCTTACTTTGATAAAACCTC3 ') add among the Nucleotide 2403-2425 of HXB2.This gal report probe (5 ' CCCAGTATTTGTCTACAGCCTTCT3 ') adds among the Nucleotide 950-973 of HXB2.All Nucleotide positions are present in the GenBank gene order database, by genetic computer group sequence analysis software bag (Gnentics ComputerGroup Sequence AnalysisSoftware Package) (Devereau Nucleic Acids Research 1984,12,387) obtain.Described report probe is prepared as: 0.5 μ M stock solution (in 2 * SSC (0.3M sodium-chlor, 0.03M Trisodium Citrate), 0.05M Tris pH8.8,1mg/mL BSA).Described vitamin H capturing probe is prepared as: the aqueous solution of 100 μ M stock solutions.The culture dish of streptavidin bag quilt:
From Du Pont biotechnology system (Boston, MA) the middle culture dish that obtains streptavidin bag quilt.Cell and viral stock solution:
Cultivate MT-2 and MT-4 cell in RPMI 1640, wherein said RPMI 1640 is supplemented with 5% (for the MT-2 cell) or 10% (for the MT-4 cell) foetal calf serum (FCS), 2mM L-glutaminate and 50 μ g/mL gentamicins, all from Gibco.In same medium, HIV-1RF is bred in the MT-4 cell.After about 10 days, prepare viral stock solution through the acute infection of MT-4 cell, it is stored with sample aliquot under-70 ℃.Measure (below will describe) by MT-2 cell surface plaque, the infectious titer of HIV-1 (RF) stock solution is 1-3 * 10
7PFU (plaque forming unit)/mL.The every equal portions virus stock solution that is used to infect only thaws once.
In order to estimate antiviral effect, infecting the cell that the day before yesterday, subculture will infect.Infecting the same day, for large quantities of infection, cell with 5 * 10
5Cell/mL concentration is suspended among the RPMI 1640 that contains 5%FCS again, for the infection in the microtiter plate, cell with 2 * 10
6The virus of cell/ml is suspended in Dulbecco ' the s modification Eagle substratum that contains 5%FCS again.Add virus, continue to cultivate 3 days down at 37 ℃.HIV RNA public affairs are analysed:
Purified RNA is with 5M GED and capturing probe mixing cellular lysate or in 3M or 5M GED, and the ultimate density that makes guanidinium isothiocyanate is 3M, and the ultimate density of vitamin H oligonucleotide is 30nM.At 37 ℃, hybridization is 16-20 hour in the 96 hole tissue culture wares (Nunc or Costar) of the U type bottom of sealing.Three times of RNA hybridization reaction solution dilutions, making the guanidinium isothiocyanate ultimate density is 1M with deionized water, etc. duplicate samples (150 μ L) transfer in the microtiter plate of streptavidin bag quilt.In room temperature, the capturing probe-RNA that makes capturing probe and hybridize to the immobilization streptavidin washed ware damping fluid (phosphate-buffered salt (PBS), 0.05% polysorbas20) with DuPont ELISA then and washs this titer plate 6 times in conjunction with 2 hours.Add the 120 μ l hybridization cocktail that contains 4 * SSC, 0.66%Triton * 100,6.66% deionized formamide, 1mg/mL BSA and 5nM report probe, streptavidin bag after washing is made the report probe hybridize to capturing probe immobilization mixture and hybridization target RNA for the second time by in the hole., once more this titer plate is washed 6 times after 1 hour 37 ℃ of hybridization.Add the 0.2mM 4-methyl umbelliferyl phosphoric acid ester (MUBP of 100 μ L in damping fluid δ (2.5M diethanolamine pH8.9 (JBL Scientific), 10mM magnesium chloride, 5mM zinc acetate dihydrate and 5mMN-hydroxyethyl-quadrol-nitrilotriacetic), JBLScientific), detect fixedly choline phosphatase activity.This titer plate 37 ℃ of cultivations, is applied to the fluorescence that microtiter plate photofluorometer (Dynateck) that 365nM excites is measured the 450nM place.In the MT-2 of infected by HIV-1 cell, estimate compound based on microtiter plate:
Compound dissolution to be evaluated in DMSO, is diluted to 2 times of maximum concentrations to be measured in substratum, and makes the DMSO peak concentration reach 2%.Directly bottom the U type, in the droplet plate (Nunc), make compound in substratum, carry out 3 times of serial dilutions then.Behind the diluted chemical compound, add MT-2 cell (50 μ l) to 5 * 10
5/ ml (1 * 10
5/ hole) final concentration.At 37 ℃, in CO2gas incubator, cell and compound were cultivated 30 minutes.For estimating anti-virus ability, the viral stock solution of HIV-1 (RF) (50 μ L) of suitably dilution is joined in the culture hole of the test compounds that contains cell and dilution.The final volume in each hole is 200 μ L.It is not infected to keep 8 holes in each titer plate, promptly adds 50 μ L substratum and replaces virus, does not add any antiviral compound simultaneously in 8 infected holes.For assessing compound toxicity, do not having to cultivate parallel titer plate under the condition of virus infection.
In the moist chamber in CO2gas incubator, after 3 days, from the titer plate that HIV infects, take out all substances, only leave 25 μ L substratum/holes 37 ℃ of cultivations.The 5M GED that 37 μ L is contained the biotinylation capturing probe joins in this fixed cell, makes each hole residue certain culture base, so that the ultimate density of GED is 3M, the ultimate density of capturing probe is 30nM.In the same droplet hole that is used for virus culture, the sealing of droplet plate, HIV RNA is hybridized with droplet plate sealer, cultivation 16-20 hour in 37 ℃ of incubators then.Then distilled water is joined in each hole,, this diluted mixture thing of 150 μ L is transferred in the droplet plate of streptavidin bag quilt 3 times of hybridization reaction solution dilutions.As mentioned above HIV RNA is carried out quantitative assay.By known quantity pDNA 72 external rna transcription products are joined in the hole of containing the non-infected cells lysate, make typical curve, in order to be determined at the viral RNA amount for preparing between period of infection, this curve is applied to each droplet plate.
For to being used for the used virus inoculation liquid stdn of assessing compound antiviral activity, select those to cause dideoxycytidine (ddC) IC
90Value (reducing the required compound concentration of 90%HIV rna level) is the virus dilution liquid of 0.2 μ g/mL.When carrying out this method, use several HIV-1 (RF) storing solution, the IC of other antiviral compound (comprising the compound stronger or more weak) than dideoxycytidine
90Value can be reproduced.Virus concentration is equivalent to ~ and 3 * 10
5PFU (at the MT-2 cell through the plaque assay determination)/analyze hole, the 75% maximum viral RNA content that can reach when generally producing approximately with any virus inoculation.Analyze for HIV RNA,, analyze net signal from RNA and reduce per-cent, determine IC with respect to the net signal (the cells infected sample signal deducts the non-infected cells sample signal) that produces by the untreated cell that infects on same culture plate (average 8 holes) surface
90Value.Judge the validity that each infects and RNA analyzes according to three standards.Should be: virus infection can cause being equal to or greater than the RNA analytical signal that is produced by 2ng pDNA 72 external rna transcriptions; The IC of the dideoxycytidine of each assay determination (ddC)
90Scope should be 0.1-0.3 μ g/ml; Stablizing content by the dull and stereotyped viral RNA of effective proteinase inhibitor generation should be less than reach content 10% when not suppressing to infect.If find the IC of compound
90Less than 1 μ M, think that then it is effective.
For viral measure of merit, after beginning joined 2X enriched compound solution in one round, application Perkin Elmer/Cetus Propette carried out the operation in all droplet plates.Dosage and formulation
As the treatment of virus infection, can in mammalian body, contact the any-mode administration antiviral compound of the present invention that its site of action is a virus protease by making activeconstituents.No matter as the treatment reagent of single treatment reagent or combined utilization, these compounds can be by any conventional administering mode administration of medicine.They can be individually dosed, but preferably with pharmaceutical carrier administration together, and the selection of wherein said pharmaceutical carrier is based on that selected route of administration and standard drug routine carry out.
Obviously, dosage also can change, and it is decided by known facts, for example: the pharmacokinetic properties of concrete medicine; Mode of administration and route of administration; Medication person's age, healthy state and body weight; The character of illness and severity; The kind of concurrent treatment; Therapeutic frequency; The required desired result that reaches.Dosage every day of activeconstituents can be expected about 1000mg/kg body weight for about 0.001-, and preferred dose is the about 30mg/kg of about 0.1-.
The combination dosage form that is fit to administration contains the about 100mg of the 1mg-that has an appointment activeconstituents/unit.In these pharmaceutical compositions, the content of activeconstituents is generally about 0.5-95% of composition total weight.Described activeconstituents can solid dosage for example capsule, tablet and pulvis or at liquid dosage form for example elixir, syrup and suspensoid form oral administration.It can also pass through parenterai administration with the sterile liquid dosage form.
Gelatine capsule contains activeconstituents and powder carrier for example lactose, starch, derivatived cellulose, Magnesium Stearate and stearic acid etc.Thinner carries out compressing tablet like can also application class.Tablet and capsule all can be prepared into slow release product, thereby medicine can continue in during a few hours to discharge.The tablet of compacting can carry out sweet tablet or film dressing sheltering any undesirable taste, and the protection tablet avoids environmental influence, makes its selectivity disintegration in gi tract thereby perhaps tablet is carried out enteric coating.The liquid oral formulation can contain tinting material and correctives so that increase patient's acceptability.
In a word, for example propylene glycol or polyoxyethylene glycol belong to the carrier that is suitable as the parenteral admin preparation for water, suitable oil, salt solution, water-soluble dextrose (glucose) and associated sugars solution and dibasic alcohol.The solution of parenteral admin preferably contains water-soluble salt, the suitable stabilizers of activeconstituents, if desired, can also contain buffer substance.For example sodium bisulfite, S-WAT or xitix be separately or unite and can be used as suitable stabilizers for antioxidant.Can also use citric acid and salt thereof and EDTA sodium.In addition, the parenteral admin preparation can also contain sanitas for example benzalkonium chloride, methyl p-hydroxybenzoate or propyl ester and chlorobutanol.Suitable pharmaceutical carrier is recorded in the canonical reference textbook of this area--in the Lei Mingdun pharmaceutical science (the same).
The useful pharmaceutical dosage form of administration The compounds of this invention is exemplified below: capsule
Many units capsule can be prepared as follows: fill 100mg powder activity composition, 150mg lactose, 50mg Mierocrystalline cellulose and 6mg Magnesium Stearate in the hard gelatin capsule of two joint fits of each standard.Soft gelatin capsule
Prepare the mixture of activeconstituents in digestible oil such as soybean oil, Oleum Gossypii semen or sweet oil, by displacement pump this mixture is injected into and is prepared into the soft gelatin capsule that contains the 100mg activeconstituents in the gelatin.Should wash and drying this capsule then.Tablet
Many tablets can prepare according to ordinary method, and formulation contains 100mg activeconstituents, 0.2mg colloid silica, 5mg Magnesium Stearate, 275mg Microcrystalline Cellulose, 11mg starch and 98.8mg lactose like this.The dressing that carries out that can also be suitable absorbs to improve mouthfeel or to postpone.Suspensoid
Be prepared into oral aqueous suspension, contain activeconstituents, 200mg Xylo-Mucine, 5mg Sodium Benzoate, 1.0g Sorbitol Solution USP (U.S.P.) and the 0.025mg Vanillin of 25mg fine grinding in every 5mL dosage.Injection
Parenteral admin composition by drug administration by injection can be prepared as follows: in the polyoxyethylene glycol and water of 10% volume ratio, stir the activeconstituents of 1.5% weight ratio, use routine techniques to this solution disinfection.Composition (a) and associating (b)
Each therapeutic agent component of the present invention can independently be present in any formulation, for example above-mentioned formulation, and they can also pass through aforesaid various administrations.In the following description, composition (b) is construed as foregoing one or more therapeutical agents of representative.Therefore, if do to handle equally composition (a) with (b), perhaps use independently, each therapeutical agent of composition (b) also can be done same the processing or independent utility.
Composition of the present invention (a) and (b) can prepare (that is they are united in the formulations such as being present in same capsule, tablet, pulvis or liquid) together as combined prod by single dosage unit form.When composition (a) and (b) in single dose unit, not preparing together, composition (a) can with composition (b) administration or with the random order administration at one time; At first administration of composition for example of the present invention (a), and then administration composition (b), perhaps they can be according to opposite order administration.If composition (b) contains more than one therapeutical agent, for example contain a kind of RT inhibitor and a kind of proteinase inhibitor, the administration or with the random order administration together of these therapeutical agents.When not at one time during administration, preferably composition (a) and delivery time (b) were less than about 1 hour.Preferably, and (b) with oral way administration composition (a).Representative such as term described herein " oral therapeutics ", " oral inhibitor " or " oral administration of compound " can oral administration compound.Though, preferably according to identical approach (for example all being oral) or formulation administration composition (a) and composition (b), still if desired, they can be by different approaches (promptly, for example a kind of composition can be oral in the joint product, and another kind of composition can intravenous administration) or the different dosage form administration.
This area the medical technician understand easily, the dosage of combination therapy of the present invention can change, its depend on pharmacokinetic properties, its administering mode and route of administration, the medication person's of for example concrete therapeutical agent of multiple factor the character of age, healthy state and body weight, illness and severity, combined treatment kind, therapeutic frequency and expect the result of treatment that reaches, these factors are as mentioned above.
This area medical technician determines composition of the present invention (a) and suitable dose (b) easily according to content disclosed by the invention.In principle, general about 100 milligrams-Yue 1.5 grams of dosage every day of each composition.If composition (b) is represented more than one compound, then dosage every day of each therapeutical agent of composition (b) is generally about 100 milligrams-Yue 1.5 grams.In principle, when composition (a) and composition (b) Combined Preparation because the synergistic effect of drug combination, with they as the individually dosed treatment of single therapy agent HIV infection compare, the dosage of each component can reduce about 70-80%.
Drug combination product of the present invention can be prepared into such formulation: though activeconstituents is combined in single dose unit, should as much as possible reduce the physics contact of activeconstituents.In order to reduce contact, for example, when product oral, one of them activeconstituents can carry out enteric coating.By one of them activeconstituents is carried out enteric coating, not only might reduce the contact between the activeconstituents of combination as far as possible, and might control one of them these activeconstituentss release in gi tract, thereby wherein one of these activeconstituentss are not under one's belt but discharge in enteron aisle.In another oral embodiment of needs, the invention provides a kind of joint product, wherein a kind of activeconstituents can be made this activeconstituents reach the slowly-releasing purpose in whole gi tract by the slow-release material dressing like this, and can reduce the contact between the activeconstituents of combination.And this slowly-releasing composition can carry out enteric coating again, and this composition only discharges in enteron aisle like this.Also has another mode, in the product of combination, a kind of composition is surrounded by slowly-releasing and/or enteric release polymers, and another composition also is aggregated thing for example low-viscosity hydroxypropylmethylc,llulose or other this area suitable material dressing, so that further separate these activeconstituentss.These polymer coatings form an additional barrier to avoid the interaction with other composition.In each preparation, when prevent by dressing or some other materials composition (a) and (b) between contact the time, also can prevent the contact between each reagent of composition (b).
Wherein a kind of activeconstituents can be a tablet form by the combined prod formulation of the present invention of enteric coating, and enteric coating composition and other activeconstituents mix like this, are pressed into tablet then; Perhaps also can be pressed into a lamella to enteric coating, other activeconstituents is pressed into another lamella.Randomly, two-layer in order further to separate this, can there be one or more placebo layers, placebo layer is in the middle of the activeconstituents layer like this.In addition; formulation of the present invention can be a capsule form; one of them activeconstituents is pressed into microplate, particle, particulate or piller; then it is carried out enteric coating, then the microplate of these enteric coatings, particle, particulate or piller are placed capsule or put into capsule together with other active ingredient particle.
Combined prod of the present invention no matter with single formulation administration still with formulation separately but administration or administration simultaneously at one time in the same manner, these modes and to reduce the alternate manner that contacts between the combined prod composition of the present invention all be conspicuous for the those skilled in the art that read the disclosure of invention.
Scope of the present invention also comprises the medicinal reagent box that is used for the treatment of the HIV infection, this medicinal reagent box contains the composition of the treatment significant quantity that is present in one or more sterile chambers, and wherein said composition contains component (a) compound and one or more components (b) compound.Can carry out asepticize to described container according to conventional asepticize technology well known to those skilled in the art.Component (a) and component (b) may reside in the same sterile chamber, or exist in the container separately.As required, described sterile chamber can comprise the container that independently separates or comprise one or more many parts containers.Component (a) and component (b) can separate, and perhaps are mixed into single dose form or unit according to physical method as mentioned above.If desired, such test kit can also contain one or more different conventional medicine test kit integral parts, for example one or more pharmaceutically acceptable carrier, in addition be used to mix reach bottle of branch etc., this is apparent to those skilled in the art.This test kit can also comprise the specification sheets of attachment version or label form, and dosage, the administration policy of component and/or the method for mixing these compositions wherein are described.
Obviously, according to above-mentioned instruction, also may make many modifications and change to the present invention.Therefore be appreciated that within the scope of the appended claims, can also implement the present invention by other method except that method described herein.
Claims (24)
1. formula I compound or pharmaceutically acceptable salt thereof,
I is R wherein
1Be F; R
2Be F or H; And R
3Be selected from the 4-aminophenyl, 3-aminophenyl, 2,3-Dihydrobenzofuranes-5-base and 1,3-benzo dioxole-5-base.
2. the compound of claim 1, wherein said compound is a formula II compound:
II.
3. the compound of claim 2, wherein said compound is a formula IIa compound:
IIa.
4. the compound of claim 3, wherein R
3Be the 3-aminophenyl.
5. the compound of claim 3, wherein R
3Be the 4-aminophenyl.
6. the compound of claim 3, wherein R
3Be 2,3-Dihydrobenzofuranes-5-base or 1,3-benzo dioxole-5-base.
7. the compound of claim 2, wherein said compound is a formula IIb compound:
IIb.
8. the compound of claim 7, wherein R
3Be the 3-aminophenyl.
9. the compound of claim 7, wherein R
3Be the 4-aminophenyl.
10. the compound of claim 7, wherein R
3Be 2,3-Dihydrobenzofuranes-5-base or 1,3-benzo dioxole-5-base.
11. the compound of claim 2, wherein said compound are the IIc compound:
IIc.
12. the compound of claim 11, wherein R
3Be the 3-aminophenyl.
13. the compound of claim 11, wherein R
3Be the 4-aminophenyl.
14. the compound of claim 11, wherein R
3Be 2,3-Dihydrobenzofuranes-5-base or 1,3-benzo dioxole-5-base.
15. the compound of claim 1, wherein said compound are the formula III compound:
III.
16. the compound of claim 15, wherein said compound are formula III a compound:
IIIa.
17. the compound of claim 1, wherein said compound are formula IV compound:
IV.
18. the compound of claim 17, wherein said compound are formula IVa compound:
IVa.
19. a pharmaceutical composition comprises: any described compound of claim 1-19 of pharmaceutically acceptable carrier and treatment significant quantity.
20. treat the method that HIV infects, comprising for one kind: to any described compound or pharmaceutically acceptable salt thereof of claim 1-19 of host's drug treatment significant quantity of this treatment of needs.
21. treat the method that HIV infects, comprising for one kind: to host's Combined Preparation treatment significant quantity of this treatment of needs:
(a) any described compound of claim 1-19 or its steric isomer, its stereoisomer mixture or its pharmacologically acceptable salt; With,
(b) at least a compound that is selected from hiv reverse transcriptase inhibitor and hiv protease inhibitor.
22. the method for claim 21, wherein reverse transcriptase inhibitors is selected from zidovudine, dideoxycytidine, dideoxyinosine, d4T, 3TC, U-90152, efavirenz, nevirapine, Ro18, and 893, trovirdine, MKC-442, HBY097, ACT, UC-781, UC-782, RD4-2025 and MEN10979; Proteinase inhibitor is selected from Saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD173606, PD177298, PD178390, PD178392, U-140690 and ABT-378.
23. the method for claim 22, wherein reverse transcriptase inhibitors is selected from AZT, efavirenz and 3TC, and proteinase inhibitor is selected from Saquinavir, ritonavir, nelfinavir and indinavir.
24. the method for claim 21, wherein compound (b) is a ritonavir.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11574699P | 1999-01-13 | 1999-01-13 | |
| US60/115,746 | 1999-01-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1336934A true CN1336934A (en) | 2002-02-20 |
Family
ID=22363180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00802755A Pending CN1336934A (en) | 1999-01-13 | 2000-01-13 | Bis-amino acid sulfonamides containing N-terminally a substituted benzyl group as HIV protease inhibitors |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1140983A1 (en) |
| JP (1) | JP2002536298A (en) |
| KR (1) | KR20010101478A (en) |
| CN (1) | CN1336934A (en) |
| AU (1) | AU2725700A (en) |
| BR (1) | BR0007854A (en) |
| CA (1) | CA2353088A1 (en) |
| CZ (1) | CZ20012435A3 (en) |
| HU (1) | HUP0105235A3 (en) |
| IL (1) | IL143763A0 (en) |
| NO (1) | NO20013338L (en) |
| PL (1) | PL349774A1 (en) |
| SK (1) | SK9522001A3 (en) |
| TR (1) | TR200102033T2 (en) |
| WO (1) | WO2000042060A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1188766A1 (en) * | 1995-03-10 | 2002-03-20 | G.D. Searle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US7339078B2 (en) | 1995-03-10 | 2008-03-04 | G.D. Searle Llc | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6861539B1 (en) | 1995-03-10 | 2005-03-01 | G. D. Searle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US20020022742A1 (en) * | 2000-07-19 | 2002-02-21 | Harris Gregory D. | Salt forms of an HIV protease inhibitor |
| US6617310B2 (en) | 2000-07-19 | 2003-09-09 | Bristol-Myers Squibb Pharma Company | Phosphate esters of bis-amino acid sulfonamides containing substituted benzyl amines |
| US20020022659A1 (en) * | 2000-07-19 | 2002-02-21 | Harris Gregory D. | Crystalline and salt forms of an HIV protease inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994004492A1 (en) * | 1992-08-25 | 1994-03-03 | G.D. Searle & Co. | Hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| AU7669794A (en) * | 1993-08-24 | 1995-03-21 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
| US6150556A (en) * | 1995-03-10 | 2000-11-21 | G. D. Dearle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
-
2000
- 2000-01-13 TR TR2001/02033T patent/TR200102033T2/en unknown
- 2000-01-13 IL IL14376300A patent/IL143763A0/en unknown
- 2000-01-13 BR BR0007854-9A patent/BR0007854A/en not_active IP Right Cessation
- 2000-01-13 PL PL00349774A patent/PL349774A1/en not_active Application Discontinuation
- 2000-01-13 WO PCT/US2000/000820 patent/WO2000042060A1/en not_active Application Discontinuation
- 2000-01-13 HU HU0105235A patent/HUP0105235A3/en unknown
- 2000-01-13 CZ CZ20012435A patent/CZ20012435A3/en unknown
- 2000-01-13 CA CA002353088A patent/CA2353088A1/en not_active Abandoned
- 2000-01-13 SK SK952-2001A patent/SK9522001A3/en unknown
- 2000-01-13 AU AU27257/00A patent/AU2725700A/en not_active Abandoned
- 2000-01-13 JP JP2000593627A patent/JP2002536298A/en active Pending
- 2000-01-13 KR KR1020017008803A patent/KR20010101478A/en not_active Application Discontinuation
- 2000-01-13 CN CN00802755A patent/CN1336934A/en active Pending
- 2000-01-13 EP EP00905604A patent/EP1140983A1/en not_active Withdrawn
-
2001
- 2001-07-05 NO NO20013338A patent/NO20013338L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO20013338L (en) | 2001-09-13 |
| BR0007854A (en) | 2002-01-15 |
| KR20010101478A (en) | 2001-11-14 |
| HUP0105235A3 (en) | 2002-08-28 |
| CA2353088A1 (en) | 2000-07-20 |
| NO20013338D0 (en) | 2001-07-05 |
| CZ20012435A3 (en) | 2002-02-13 |
| TR200102033T2 (en) | 2001-12-21 |
| HUP0105235A2 (en) | 2002-04-29 |
| IL143763A0 (en) | 2002-04-21 |
| EP1140983A1 (en) | 2001-10-10 |
| JP2002536298A (en) | 2002-10-29 |
| WO2000042060A1 (en) | 2000-07-20 |
| AU2725700A (en) | 2000-08-01 |
| SK9522001A3 (en) | 2002-03-05 |
| PL349774A1 (en) | 2002-09-09 |
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