CN1179948C - HIV protease inhibitors - Google Patents
HIV protease inhibitors Download PDFInfo
- Publication number
- CN1179948C CN1179948C CNB988045389A CN98804538A CN1179948C CN 1179948 C CN1179948 C CN 1179948C CN B988045389 A CNB988045389 A CN B988045389A CN 98804538 A CN98804538 A CN 98804538A CN 1179948 C CN1179948 C CN 1179948C
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- group
- acid
- hiv
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
HIV protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds, as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingredients, are suitable for treating patients or hosts infected with the HIV virus, which is known to cause AIDS.
Description
The present invention relates to can be used as a series of new compounds of hiv protease inhibitor, and relate to the purposes of this compounds as antiviral agent.
Acquired immunodeficiency syndrome (AIDS) is a kind of disease or illness of new knowledge comparatively speaking.AIDS causes human immune system's the destruction gradually and the progressive failure of nervus centralis and peripheral nervous system.Since as far back as 1980 begin understanding since, AIDS is rapid spread, now the local relatively part the city has reached the popular degree.Deep research has had been found that replys agent, and viral III (HTLV-III) is recorded in people γ-close lymph sex reversal, is called human immunodeficiency virus or HIV now more at large.
HIV is a member that is known as retroviral virus type.The reverse transcription virus gene group is made up of the RNA that is converted into DNA by reverse transcription.This retrovirus DNA incorporates the karyomit(e) of main body cell then securely into, and utilizes the reproduction process of main body cell, produces new retroviral particle, promotes the infection of other cells.As if HIV has special avidity to people T-4 lymphocyte, and this cell is played the part of vital role in the human immune system.The HIV of these white cells has infected emptying white corpuscle group.At last, immunity system becomes to various opportunistic diseases such as interstitial plasma cell pneumonia, and Kaposi ' s sarcoma and lymphoid cancer are inoperative and invalid.
Although the formation of HIV virus and to act on really the cutter reason unclear, the identification of virus has caused some progress aspect this disease of control.For example, it is effective for the reverse transcription of the reverse transcription virus gene group that suppresses HIV virus that medicine azido-thymus pyrimidine (AZT) has been found, and the patient who suffers from AIDS is provided to a certain degree control, cures although be not.Continue to seek and to cure or the medicine that fatal HIV virus is had the control of improvement degree is provided at least.
It is feature that retrovirus duplicates general back-translation process with polyprotein.This process is finished by the hiv protease of encoding viral.This has produced sophisticated polypeptide, participates in the formation and the function of infective virus subsequently.If this molecular process is suppressed, then the ordinary production of HIV is terminated.Therefore, the hiv protease inhibitor can be used as the anti HIV-1 virus agent.
Hiv protease is from one of translation product of HIV structural protein pol gene.This retroviral Protease discharges these new activatory structural protein and enzymes at other structural polypeptides of dispersive locus specificity ground cracking, makes virus particle that replication be arranged.Therefore, suppress hiv protease by compounds effective and can prevent provirus to combine, and suppress the proteolysis process of virus in its later stage at the early stage and T-lymphocyte that infects of HIV-1 life cycle.In addition, proteinase inhibitor may have easier acquisition, retains longer in virus and than the more hypotoxic advantage of present getable medicine, may be because its specificity to retroviral Protease causes.
According to the present invention, provide and can suppress and/or block the active compounds of hiv protease, this compound stops the propagation of HIV virus, and the pharmaceutical composition that contains these compounds and this compound purposes as the hiv protease inhibitor is provided.
The present invention relates to fall into compound and its pharmaceutical salts in following formula (9) scope, prodrug, and solvate, they suppress by 1 type (HIV-1) or 2 types (HIV-2) human immunodeficiency viruses (HIV) encoded protein enzyme.These compounds can be used for treating HIV to be infected, and treatment acquired immunodeficiency syndrome (AIDS).This compound, its pharmaceutical salts and pharmaceutical composition of the present invention can use separately, perhaps with other antiviral agents, immunomodulator, microbiotic or vaccine combination.The compounds of this invention also can be used as prodrug.Disclosed the method for treatment AIDS, method that treatment HIV infects and the method that suppresses hiv protease.
Compound of the present invention is an acceptable prodrugs on the compound of formula (9) or its pharmacology, salt or its solvate:
Wherein:
R and R ' are independently selected from H, replace or unsubstituted alkyl-OR
1Group is by (C
1-C
6) alkyl group or (C
1-C
6) cycloalkyl that replaces of alkyl-OH group, by (C
1-C
6) alkyl group or (C
1-C
6) heterocyclic group that replaces of alkyl-OH group, alkyl-NR
2R
3Group, or (Y) R of alkyl-S (X)
4Group,
Wherein:
R
1Be H, replace or unsubstituted alkyl, or acyl group;
R
2And R
3Be selected from H independently of one another, replace or unsubstituted alkyl cycloalkyl, heterocycle, and aryl, acyl group and alkylsulfonyl;
R
4Be H, replace or unsubstituted alkyl cycloalkyl, heterocycle, or aryl;
X and Y be selected from independently of one another=O or do not exist.
Preferably, in formula 9 compounds, R is H.More preferably, R is H, and R ' is selected from following cycloalkyl:
Preferably, in formula 9 compounds, when at least one R and R ' are alkyl-OR
1The time, R
1Be H.Particularly working as at least one R and R ' is alkyl-OR
1The time, alkyl-OR
1Be selected from-C (CH
3)
2CH
2OH ,-CH (CH
3) CH
2OH ,-CH
2CH
2OH ,-C (CH
3) (CH
2OH)
2,-C (CH
3)
2-O-CH
2-O-CH
3,-C (CH
3)
2CH
2-O-CH
2-O-CH
3And-C (CH
3)
2CH
2-O-acyl group, or acceptable prodrugs on its pharmacology, salt or its solvate.
Preferably, when at least one R and R ' by (C
1-C
6) alkyl group or (C
1-C
6) alkyl-OH group replace cycloalkyl the time, cycloalkyl is selected from:
Preferably, when at least one R and R ' by (C
1-C
6) alkyl group or (C
1-C
6) alkyl-OH group replace heterocyclic group the time, heterocyclic radical is selected from:
Preferred formula (9) compound is [3S-[2[(2S*, 3S*), 3 α, 4a β, 8a β]]-N-(1,1-dimethyl-2-hydroxyethyl) decahydro-2-[2-hydroxyl-3-[(3-hydroxy-2-methyl benzoyl) amino]-4-(thiophenyl) butyl]-3-isoquinoline 99.9 methane amide
With its pharmaceutical salts and its prodrug.Preferred prodrug can be used acyl group, and more preferably amino acid acyl is replaced the hydrogen of an alcohol radical and obtained.
The present invention further provides and comprise significant quantity formula (9) compound or pharmaceutically acceptable salt thereof, with pharmaceutical carrier, as thinner or vehicle bonded pharmaceutical preparation.
The present invention further provides the method for treatment AIDS, comprise main body or patient are used the The compounds of this invention of significant quantity as primate.
The present invention further provides and suppress the method that HIV duplicates, comprise the cell that HIV is infected, be subject to cell or main body or patient that HIV infects, use the The compounds of this invention of significant quantity as primate.
Detailed Description Of The Invention
The invention provides the new compound in the formula that falls into as mentioned above (9) scope, can be used for treating HIV and infect and/or AIDS.
The applicant is by references to U.S. patent 5484926, U.S. Patent application 08/708411 and 08/708607, with Japanese patent application No. JP 95-248183 and JP 95-248184 combination, need to prove, the preferred version that is used for each application, term, variable, the definition of symbol or the like only is applicable to that this application is open accordingly.
Particularly, because above-mentioned each unicity application incorporated by reference is separately to prepare, original application may be used same term in some cases, and symbol or variable mean that some things are different.For example, variable " X " is used to each application, but that each application has is own unique, the substituting group of being represented by this variable or the definition of part.Those skilled in the art be it is evident that, in by each application incorporated by reference, term, symbol and variable only only limit to disclosing of this application, and can be by term, symbol and the variable replacing of other suitable expression specified substituent and part.Certainly, those skilled in the art should be realized that, any cover term, symbol and variable can be used to prevailingly or more specifically the expression disclosed in this application theme, comprise the term that generally can be used in the above-mentioned unicity application of being quoted open and following open, symbol, variable or the like.
Formula (9) compound can be a prodrug, and it can be used for improving the pharmacological properties of compound, as pharmacokinetic property, for example, improves bioavailability and solvability.The preparation of prodrug can be undertaken by the known standard method of those skilled in the art.Preferred prodrug can be CH (CH by working as R and R '
3)
2CH
2The acylations or the alkylation of the raw alcohol of OH obtain.
All temperature of explaining in this article all be degree centigrade (℃).The linear module of this paper that is useful on all is a weight unit, and having only liquid is volume unit.
The term " alkyl " that is used for this paper refers to the straight or branched group, preferably, has 1 to 8, more preferably has 1 to 6, most preferably has 1 to 4 carbon atom.Term " C
1-C
6Alkyl " expression has the straight or branched alkyl of 1 to 6 carbon atom.C
1-C
6The example of alkyl comprises methyl, ethyl, and n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, neo-pentyl, hexyl, isohexyl, or the like.Term " C
1-C
6Alkyl " be included in the term " C in its range of definition
1-C
4Alkyl ".
Term " cycloalkyl " expression is saturated or fractional saturation, one-or many-carbocyclic ring, preferably have 5-14 ring carbon atom.The example of cycloalkyl comprises having 3-7, the monocycle of preferred 3-6 carbon atom, and as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or the like.An example of cycloalkyl is C
5-C
7Cycloalkyl, it is the stable hydrocarbon ring structure that contains 5 to 7 carbon atoms.
Term " alkoxyl group " expression-O-alkyl.An example of alkoxyl group is C
1-C
6What alkoxyl group, expression had 1 to 6 carbon atom is connected the straight or branched alkyl with Sauerstoffatom.C
1-C
6The example of alkoxyl group comprises methoxyl group, oxyethyl group, and propoxy-, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy, hexyloxy, or the like.C
1-C
6Alkoxyl group is included in the C within its scope
1-C
4Alkoxyl group.
The term " aryl " that is used for this paper refers to carbocyclic ring or heterocycle, fragrance, 5-14 person's monocycle or many rings.The example of aryl comprises phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrryl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazan base ， isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidyl, triazinyl, benzo [b] thienyl, naphtho-[2,3-b] thianthrenyl, isobenzofuran-base, chromenyl, xanthenyl, fen xanthenyl, the indolizine base, pseudoindoyl, indyl, indenyl, purine radicals, isoquinolyl, quinolyl, 2, the 3-phthalazinyl, naphthyridine base, quinoxalinyl, quinazolyl, benzothiazolyl, benzimidazolyl-, tetrahydric quinoline group, the cinnolines base, pteridine radicals, carbazyl, β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl is with phenoxazinyl.
Term " aryloxy " expression-O-aryl.
Term " hydrolysable group " is to form ester when being connected with oxygen, and it is hydrolyzed to the group of hydroxyl in can body.Comprised acyl group functional group by the example of the hydrolysable group of non-imposed replacement, sulfonate functional groups and phosphate functional group.For example, this class hydrolysable group comprises sealing or untight amino-acid residue, hemisuccinic acid residue and nicotinic acid residue.
Term " halogen " expression chlorine, fluorine, bromine or iodine.Term " halogen atom " expression chlorine, fluorine, bromine or iodine atom.
Term " carbocyclic ring " expression 5-14 person's monocycle fragrance or saturated or fractional saturation or many rings, as 5-to 7-member monocycle or 7-to 10-member dicyclo, wherein all ring memberses all are carbon atoms.
Term " heterocycle " expression 5-14 person's monocycle fragrance or saturated or fractional saturation or many rings, as 5-to 7-member monocycle or 7-to 10-member dicyclo, have 1 to 3 and be selected from nitrogen, the heteroatoms of oxygen and sulphur, wherein any nitrogen and sulfur heteroatom can be oxidized non-imposedly, and any nitrogen heteroatom can be quaternized non-imposedly.Heterocycle can connect on any suitable heteroatoms or carbon atom.This class heterocyclic example comprises the Decahydroisoquinolinpreparation base, octahydro-thiophene [3,2-c] pyridyl, piperidyl, piperazinyl, azepines base, pyrryl, pyrrolidyl, pyrazolyl, pyrazolidyl, imidazolyl, isobenzofuran-base, the furazan base, imidazolinyl, imidazolidyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl ， oxazolyl oxazolidinyl ， isoxazolyl, thianthrenyl, triazinyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, quinuclidinyl, isothiazole alkyl, indyl, quinolyl, chromenyl, xanthenyl, isoquinolyl, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl benzoxazolyl, furyl, tetrahydrofuran base, THP trtrahydropyranyl, thienyl, benzothienyl, benzo [b] thienyl, naphtho-[2,3-b] thienyl, thio-morpholinyl, thio-morpholinyl sulfoxide, thio-morpholinyl sulfone oxadiazole base, triazolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, fen xanthenyl, indolizine base, pseudoindoyl, indenyl, purine radicals, isoquinolyl, quinolyl, 2, the 3-phthalazinyl, the naphthyridine base, quinoxalinyl, quinazolyl, tetrahydric quinoline group, the cinnolines base, pteridine radicals, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl is with phenoxazinyl.
Term " thioether " comprises the S-aryl, as thiophenyl and naphthalene sulfenyl; The S-heterocycle, wherein heterocycle is saturated or fractional saturation; S-(C
5-C
7)-cycloalkyl; With the S-alkyl, as C
1-C
6Alkylthio.In thioether ,-aryl ,-heterocycle ,-cycloalkyl and-alkyl can non-imposedly be substituted.An example of thioether is " C
1-C
6Alkylthio ", the straight or branched alkyl chain that expression is connected with sulphur atom with 1 to 6 carbon atom.C
1-C
6The example of alkylthio comprises methylthio group, ethylmercapto group, and the rosickyite base, the iprotiazem base, butylthio, secondary butylthio, uncle's butylthio, penta sulfenyl, own sulfenyl, or the like.
Term " sulfydryl " expression-SH.
Term " amino " expression-NL
1L
2, L wherein
1And L
2Preferably be independently selected from oxygen, carbocyclic ring, heterocycle, alkyl, alkylsulfonyl and hydrogen; Or NC (O) L
3, L wherein
3Be preferably alkyl, alkoxyl group, hydrogen or-NL
1L
2Aryl, alkyl and alkoxyl group can be substituted non-imposedly.An amino example is C
1-C
4Alkylamino, expression and the amino straight or branched alkyl chain that is connected with 1 to 4 carbon atom.C
1-C
4The example of alkylamino comprises methylamino, ethylamino, and propyl group amino, sec.-propyl amino, butyl amino, sec-butyl amino, or the like.Other amino examples are two (C
1-C
4) alkylamino, two straight or branched alkyl chains that respectively have 1 to 4 carbon atom that expression is connected with common amino.Two (C
1-C
4) example of alkylamino comprises dimethylamino, ethylmethylamino, methyl-propyl amino, ethyl sec.-propyl amino, butyl methyl amino, the sec-butyl ethylamino, or the like.An amino example is C
1-C
4Alkyl sulfonyl-amino, it has the straight or branched alkyl chain with 1 to 4 carbon atom that is connected with the Herbicidal sulphonylamino base section.C
1-C
4The example of alkyl sulfonyl-amino comprises methyl sulphonyl amino, ethylsulfonyl amino, and sulfonyl propyl base amino, the sec.-propyl sulfuryl amino, the butyl sulfuryl amino, the sec-butyl sulfuryl amino, tertiary butyl sulfuryl amino, or the like.
Term " acyl group " expression L
6C (O) L
4, L wherein
6Be singly-bound ,-O or-N, and L wherein
4Preferably alkyl, amino, hydroxyl, alkoxyl group or hydrogen.Alkyl and alkoxyl group can be substituted non-imposedly.An example of acyl group is C
1-C
4Carbalkoxy, it is the straight or branched alkyl chain with 1 to 4 carbon atom that is connected with carbonyl moiety.C
1-C
4The example of carbalkoxy comprises methoxycarbonyl, ethoxycarbonyl, and the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, or the like.Another example of acyl group is L wherein
6Be singly-bound, and L
4Be alkoxyl group, hydrogen, or the carboxyl of hydroxyl.Another example of acyl group is N-(C
1-C
4) alkyl-carbamoyl (L
6Be singly-bound and L
4Be amino), it is the straight or branched alkyl chain with 1 to 4 carbon atom that is connected with the nitrogen-atoms of carbamyl base section.N-(C
1-C
4) example of alkyl-carbamoyl comprises N-methylamino formyl radical, N-ethylamino formyl radical, N-propyl group formamyl, N-sec.-propyl formamyl, N-butyl formamyl and N-tertiary butyl formamyl, or the like.Another example of acyl group is N, N-two (C
1-C
4) alkyl-carbamoyl, it has two and is connected with the nitrogen-atoms of carbamyl base section, respectively has the straight or branched alkyl chain of 1 to 4 carbon atom.N, N-two (C
1-C
4) example of alkyl-carbamoyl comprises N, N-formyl-dimethylamino, N, N-ethylmethylamino formyl radical, N; N-methyl-propyl formamyl, N, N-ethyl sec.-propyl formamyl, N; N-butyl methyl formamyl, N, N-sec-butyl ethylamino formyl radical, or the like.
Term " sulfinyl " expression-SO-L
5, L wherein
5Preferably alkyl, amino, aryl, cycloalkyl or heterocycle.This alkyl, aryl, cycloalkyl and heterocycle can be substituted non-imposedly.
Term " alkylsulfonyl " expression-SO
2-L
5, L wherein
5Preferably alkyl, aryl, cycloalkyl, heterocycle or amino.This alkyl, aryl, cycloalkyl and heterocycle can be substituted non-imposedly.The example of alkylsulfonyl is C
1-C
4Alkyl sulphonyl, it is the straight or branched alkyl chain with 1 to 4 carbon atom that partly is connected with alkylsulfonyl.C
1-C
4The example of alkyl sulphonyl comprises methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl, butyl alkylsulfonyl, sec-butyl alkylsulfonyl, tertiary butyl alkylsulfonyl or the like.
As mentioned above, many groups are by non-imposed replacement.In fact, unless stated otherwise, used group by the term definition that defines among the application can be replacement or unsubstituted.For example,, be understood to include and replace and unsubstituted alkyl, unless get rid of a kind of, or another kind of especially by positive statement when term " alkyl " when being used.The substituent example of alkyl and aryl comprises sulfydryl, thioether, nitro (NO
2), amino, aryloxy, halogen, hydroxyl, alkoxyl group, and acyl group, and aryl, cycloalkyl and saturated and heterocycle fractional saturation.Listed above the substituent example of heterocycle and cycloalkyl comprises to alkyl and aryl, and aryl and alkyl.
The example of the aryl that replaces comprises that by one or more substituting groups preferred one to three is independently selected from halogen, hydroxyl, morpholino (C
1-C
4) carbalkoxy, pyridyl (C
1-C
4) carbalkoxy, halo (C
1-C
4) alkyl, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, carboxyl, C
1-C
4Carbalkoxy, formamyl, N-(C
1-C
4) alkyl-carbamoyl, amino, C
1-C
4Alkylamino, two (C
1-C
4) alkylamino or formula-(CH
2)
a-R
7The phenyl or naphthyl ring that replaces of the substituting group of group, wherein a is 1,2,3 or 4; And R
7Be hydroxyl, C
1-C
4Alkoxyl group, carboxyl, C
1-C
4Carbalkoxy, amino, formamyl, C
1-C
4Alkylamino, two (C
1-C
4) alkylamino.
The alkyl of another replacement is halo (C
1-C
4) alkyl, its expression has 1～3 halogen atom connected, has the straight or branched alkyl chain of 1 to 4 carbon atom.Halo (C
1-C
4) example of alkyl comprises chloromethyl, 2-bromotrifluoromethane, 1-chloro isopropyl, 3-fluoropropyl, 2,3-two brombutyls, 3-chlorine isobutyl-, the iodo tertiary butyl, trifluoromethyl or the like.
The alkyl of another replacement is hydroxyl (C
1-C
4) alkyl, the straight or branched alkyl chain that expression is connected with hydroxyl with 1 to 4 carbon atom.Hydroxyl (C
1-C
4) example of alkyl comprises methylol, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyl sec.-propyl, 4-hydroxybutyl or the like.
Another replacement alkyl be C
1-C
4Alkylthio (C
1-C
4) alkyl, expression has connected C
1-C
4The straight or branched C of alkylthio
1-C
4Alkyl.C
1-C
4Alkylthio (C
1-C
4) example of alkyl comprises methylthiomethyl, ethylmercapto group methyl, rosickyite base propyl group, secondary butylthio methyl or the like.
The example of the alkyl of another replacement is heterocycle (C
1-C
4) alkyl, the straight or branched alkyl chain that expression is connected with heterocycle with 1 to 4 carbon atom.Heterocycle (C
1-C
4) example of alkyl comprises the pyrryl methyl, quinolyl methyl, 1-indyl ethyl, 2-furyl ethyl, 3-thiophene-2-base propyl group, 1-imidazolyl sec.-propyl, 4-thiazolyl butyl or the like.
The alkyl of another replacement is aryl (C
1-C
4) alkyl, the alkyl chain that expression is connected with aryl with 1 to 4 carbon atom.Aryl (C
1-C
4) example of alkyl comprises phenmethyl, 2-phenylethyl, 3-naphthyl propyl group, 1-naphthyl sec.-propyl, 4-phenyl butyl or the like.
Heterocycle can, for example, be independently selected from halogen, halo (C by 1,2 or 3
1-C
4) alkyl, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, carboxyl, C
1-C
4Carbalkoxy, formamyl, N-(C
1-C
4) alkyl-carbamoyl, amino, C
1-C
4Alkylamino, two (C
1-C
4) alkylamino or formula-(CH
2)
a-R
7The substituting group of group replace, wherein a is 1,2,3 or 4; And R
7Be hydroxyl, C
1-C
4Alkoxyl group, carboxyl, C
1-C
4Carbalkoxy, amino, formamyl, C
1-C
4Alkylamino or two (C
1-C
4) alkylamino.
The heterocyclic example that replaces comprises 3-N-tert-butylformamide Decahydroisoquinolinpreparation base, 6-N-tert-butylformamide octahydro thieno-[3,2-c] pyridyl, the 3-methylimidazolyl, 3-Methoxy Pyridine base, 4-chloroquinoline base, 4-aminothiazole base, 8-toluquinoline base, 6-chloro-quinoxaline base, the 3-ethylpyridine base, 6-methoxyl group benzo imidazolyl, 4-hydroxyl furyl, 4-methylisoquinolinium base, 6,8-dibromo quinolyl, 2-methyl isophthalic acid, 2,3,4-tetrahydro isoquinolyl, N-toluquinoline-2-base, 2-tertbutyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-7-base or the like.
The example of the heterocyclic system of being represented by A or B comprises (1) 5-person's monocyclic groups such as thienyl, pyrryl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazan base ， isoxazolyl, thiazolyl or the like; (2) 6-person's monocycle such as pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl or the like; (3) many ring heterocyclic radicals, as the Decahydroisoquinolinpreparation base, octahydro thieno-[3,2-c] pyridyl, benzo [b] thienyl, naphtho-[2,3-b] thianthrenyl, isobenzofuran-base, chromenyl, the homologue of the complete saturated or fractional saturation of xanthenyl and its.
Cycloalkyl can be independently selected from halogen by 1,2 or 3, halo (C non-imposedly
1-C
4) alkyl, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, carboxyl, C
1-C
4Carbalkoxy, formamyl, N-(C
1-C
4) alkyl-carbamoyl, amino, C
1-C
4Alkylamino, two (C
1-C
4) alkylamino or have formula-(CH
2)
a-R
7The group of structure replaces, and wherein a is 1,2, and 3 or 4; And R
7Be hydroxyl, C
1-C
4Alkoxyl group, carboxyl, C
1-C
4Carbalkoxy, amino, formamyl, C
1-C
4Alkylamino or two (C
1-C
4) alkylamino.The example of the cycloalkyl that replaces comprises the 3-methylcyclopentyl, 4-oxyethyl group cyclohexyl, 5-carboxyl suberyl, 6-chlorine cyclohexyl or the like.
The example of the hydrolysable group that replaces comprises N-benzyl glycyl, the valyl and N-methylnicotinic acid base of N-Cbz-L-.
Compound of the present invention has at least 5 asymmetric centers that marked by asterisk in following formula (9):
Result as these asymmetric centers, The compounds of this invention can exist by any possible stereoisomer form, and can use by stereoisomer mixture, and this mixture can be optically active or racemic, or pure stereoisomers, i.e. at least 95% pure independent use basically.All asymmetrical forms, single steric isomer and its mixture, all within the scope of the invention.
Single steric isomer can pass through said process, by resolving racemic mixtures, or by separating diastereomer, from its precursor preparation separately.Fractionation can be in the presence of resolving agent, by chromatography or by repeating crystallization or being undertaken by certain combination of the known technology of these these specialties.The further details of relevant fractionation can be at Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley ﹠amp; Find among the Sons 1981.
Preferably, The compounds of this invention is pure basically, and promptly purity surpasses 50%.More preferably, compound purity at least 75%.Also more preferably, this compound purity is greater than 90%.More preferably, this compound purity at least 95%, more preferably, purity at least 97%, most preferably purity at least 99%.
As mentioned above, the present invention includes the pharmaceutical salts of the compound of formula (9) definition.The compounds of this invention has enough acidity, enough alkalescence, or two kinds of functional groups, thereby with many inorganic or organic basess and inorganic and any one reactions of organic acid, form pharmaceutical salts.
Term used herein " pharmaceutical salts " refers to the salt to the nontoxic basically following formula compound of organs of living beings.The example of pharmaceutical salts comprises by The compounds of this invention and inorganic or organic acid or the prepared salt of mineral alkali reaction.Reactant has ether or benzene generally at codissolved solvent for acid salt, for base addition salt water or alcohols is arranged.This salt normally precipitated from solution within about 1 hour to about 10 days, and can be by filtering or other ordinary methods separation.This class salt is known acid salt and base addition salt.
The acid that can be used to form acid salt is the mineral acid example hydrochloric acid, Hydrogen bromide, and hydroiodic acid HI, sulfuric acid, phosphoric acid or the like, organic acid such as tosic acid, methylsulfonic acid, oxalic acid, to bromo-benzene sulfonic acid, carbonic acid, succsinic acid, citric acid, phenylformic acid, acetate or the like.
The example of pharmaceutical salts has vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1,4-diacid salt, hexin-1,6-diacid salt, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, Citrate trianion, lactic acid salt, g-hydroxybutyric acid salt, glycollate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate or the like.
Preferred medicinal acid addition salt is the salt that forms with mineral acid example hydrochloric acid and Hydrogen bromide and the salt that forms with organic acid such as toxilic acid and methylsulfonic acid.
Base addition salt comprises from inorganic and organic bases, as ammonium or basic metal or alkaline earth metal hydroxides, carbonate, supercarbonate, or the like deutero-salt.This class alkali can be used for preparing salt of the present invention, comprises sodium hydroxide, potassium hydroxide, ammonium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, calcium hydroxide, lime carbonate or the like.Sylvite and sodium-salt form are preferred.
" acceptable prodrugs on the pharmacology " means can be under physiological condition or be converted into the compound of formula 9 compounds by solvolysis.
" medicinal solvent thing " means the biopotency of freeze mode 9 compound bioactive ingredients and the solvate of character.
The example of medicinal solvent thing includes, but not limited to formula 9 compounds and water, Virahol, ethanol, methyl alcohol, DMSO, ethyl acetate, acetate, or thanomin combination.
Should be realized that the concrete counter ion that form any salt of the present invention are not key factors, as long as this salt is acceptable on the pharmacology as a whole, and counter ion do not produce negative interaction to whole salt.
Preferred compound is a compound 21
[3S-[2[(2S*, 3S*), 3 α, 4a β, 8a β]]-N-(1,1-dimethyl-2-hydroxyethyl) decahydro-2-[2-hydroxyl-3-[(3-hydroxy-2-methyl benzoyl) amino]-4-(thiophenyl) butyl]-3-isoquinoline 99.9 methane amide.
The method of making compound 21 provides below.Compound 21 is also as metabolite [3S-(3R disclosed from be applied in United States Patent (USP) 5484926,4aR*, 8aR*, 2 ' S*, 3 ' S*)]-and 2-[2 '-hydroxyl-3 '-thiophenyl methyl-4 '-azepine-5 '-oxo-5 '-(2 "-methyl-3 ' hydroxy phenyl) amyl group] obtain in patient's blood plasma of Decahydroisoquinolinpreparation-3-N-tert-butylformamide mesylate.
Formula 9 compounds can be according to following reaction scheme I preparation.
Reaction scheme I
Diagram I. produces the general route of synthesis of 9b and derivative
Will from NSC Technologies (Chicago, IL) or Procos SpA (acid hydrolysis that perhydro isoquinoline 99.9 prolongs in step 1a obtains compound 2a for Milan, Italy) the compound 1a of Gou Maiing.Many mineral acids both can also can only use in the temperature that is higher than 50 ℃ in water in moisture/ORGANIC SOLVENT MIXTURES.The example of this class mineral acid is a 6N hydrochloric acid.The quid pro quo of compound 1a comprises corresponding ester 1b, monothioester 1c or other acid amides 1d:
Z wherein, Z
1And Z
2Be alkyl independently of each other, cycloalkyl, heterocycle, or aryl.
Compound 2a protects on amine nitrogen atom then, obtains compound 2b in step 1b.
Protecting group R
pBe defined as suitable conjugation group, in step 2, avoid the undesirable decomposition of compound 2b activatory carboxylic acid derivative.This class protecting group typically can be to constitute carbamic part, has the general structure of formula 11:
R in formula 11 " definition can be alkyl, cycloalkyl, aryl, or the heterocycle that can easily remove in the deprotection steps after step 2.R " example include, but are not limited to methyl, ethyl, propyl group; sec.-propyl, normal-butyl, isobutyl-; the tertiary butyl or senior side chain or non-branched-chain alkyl, 2,2; 2-three chloroethyls, the silica-based ethyl of 2-front three, allyl group; phenyl, the phenyl of replacement, benzyl; the benzyl of replacement, 9-fluorenyl methyl, the fragrant ring system of 9-anthryl methyl and senior many cyclophane.As the following material of giving a definition can obtain from Aldrich Chemical Co. (Sigma Aldrich Fluka):
This class protecting group can be typically by corresponding haloformate 12a or heavy carbonic ester 12b
In the presence of suitable alkali, at the organic solvent such as the halogenated solvent that are being used for the reaction of this class, the acylation reaction in ether and the hydro carbons and adding.This class alkali is mineral alkali typically, as metal hydroxides, and supercarbonate and carbonate, or organic bases such as amine, triethylamine for example, diethylamine, diethyl isopropylamine, 1,8-diazabicyclo [2.2.2] octane (DABCO) or relevant two-or trialkylamine, and amidine, for example 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) and 1,8-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN).As the following material of giving a definition can obtain from AldrichChemical Co. (Sigma Aldrich Fluka):
These reactions are typically carried out from being lower than room temperature to any temperature between about 100 ℃.
Acid amides coupling step 2 can be finished by any amount of mode how basis is activated carboxyl.Group J reaction by carboxylic acid 2b in step 2 connects, and produces activatory derivative 2c.
Step 2
Group J can be many leaving groups such as alkoxyl group, hydroxyl, halogen, pseudohalogen (comprises azido-, cyano group, isocyanato, the isothiocyanic acid base), the alkyl or aryl sulfonic group, aromatic heterocycle (connecting by heteroatoms) and N-hydroxyl heterocycle comprise any in maloyl imines or the hydroxybenzotriazole ester.Following definition is applicable to above-mentioned term:
Azido-
Cyano group
Isocyanato
The isothiocyanic acid base
The alkylsulphonic acid base
Alkyl
Aryl sulfonic acid groups
Aryl
N-hydroxyl heterocycle
N-maloyl imines
Nitrogen heterocyclic
Hydroxybenzotriazole
Carboxylic acid halides (2c, J=halogen) can be used alkyl halide agent such as thionyl chloride or thionyl bromide, phosphorus trichloride or phosphorus tribromide, phosphorus pentachloride or phosphorus pentabromide or organic halogenation agent such as oxalyl chloride or TCCA (Trichloroisocyanuric acid) preparation.Ester (2c, J=OR ") (R " as above definition) can be by number of ways, is the acyl chlorides 2c of Cl from J wherein, with required alcohol chemical combination and preparing in the presence of the aforementioned organic or inorganic alkali that is used for compound 12a or 12b acidylate.This ester can produce in the presence of required alcohol by sour promoted esterification in addition.Sulphonate (2c, J=OSO
2W
1, W wherein
1Be alkyl or aryl) typically pass through carboxylic acid 2b and alkyl or aryl SULPHURYL CHLORIDE in the presence of organic amine alkali such as triethylamine, in non-polar solvent, make being lower than 0 ℃ thermotonus.The alkyl or aryl alkylsulfonyl is as giving a definition:
Alkyl sulfonyl chloride
Alkyl
Aryl sulfonyl chloride
Aryl
The pseudohalogen derivative of 2c (J=pseudohalogen) is typically by reacting in the presence of alkali with the false halogenide of alkyl and preparing from carboxylic acid halides 2c (J=halogen).This class alkali includes, but are not limited to metal hydroxides, supercarbonate and carbonate, or organic bases such as amine, triethylamine for example, diethylamine, diethyl isopropylamine, 1,8-diazabicyclo [2.2.2] octane (DABCO) or relevant two-or trialkylamine, and amidine, for example 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (BBU) and 1,8-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN).Particularly preferred alkali is triethylamine.The assorted fragrance derivatives of 2c also from carboxylic acid halides 2c (J=halogen),, prepares in non-polar solvent in the presence of amine alkali with specific assorted aromatic compound.The N-hydroxyl Hete rocyclic derivatives of 2c can prepare from carboxylic acid halides as mentioned above, also can use alkyl carbodiimide (alkyl-N=C=N-alkyl, wherein alkyl can be identical or different) or aryl carbodiimide (aryl-N=C=N-aryl, wherein aryl can be identical or different) and amine alkali produce as condensing agent.
Being used for the uncle of couling process or secondary amine (being shown in the arrow of the step 2 of diagram I) can be according to being present in functional group in the amine and used coupling manner, in conjunction with suitable protecting group.2c can be undertaken by many approach according to the definition of J with the coupling manner of uncle or secondary amine.When using free acid (2c, J=OH) time, coupling can be the method on basis in order to carbodiimide, with any one of this class general reagent, comprise dicyclohexylcarbodiimide or relevant dialkyl group carbodiimide, EDC (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide) or relevant water-soluble reagent are with organic amine alkali, at polar organic solvent such as diox, DMF, in NMP and the acetonitrile, in the presence of N-hydroxyl heterogeneous ring compound such as N-maloyl imines or 3-hydroxybenzotriazole, carry out.In addition, haloformate as 12d, can be used for interim activated acids, provides the mixed acid anhydride of general formula 2d.
This class haloformate typically shown in top 12d, and comprise methyl-, ethyl-, sec.-propyl-, isobutyl--, normal-butyl-, phenyl-with as relevant the carbonochloridic acid alkyl and the aryl ester of giving a definition.
Alkyl chloroformate=alkyl
Chloroformic acid aryl ester=aryl
Formula 2d be in step from formula 2b to formula 3 possible intermediate.Formula 2d is an intermediate, but method production 3 described here is not isolated 2d.
These reactions are typically at multiple non-polar organic solvent, for example hydro carbons and ethers such as ether, methyl tertiary butyl ether is among Di Iso Propyl Ether ， diox and the THF, in the temperature that is lower than 0 ℃, and organic amine alkali such as triethylamine are arranged, diethylamine, diethyl isopropylamine, DABCO or relevant two-or trialkylamine, and amidine alkali for example DBU and DBN carry out under existing.
When J is alkyl or aryl sulfonic group (J=OSO in compound 2c
2R or OSO
2Ar) time, coupling can be at multiple non-polar organic solvent, for example hydro carbons and ethers such as ether, methyl tertiary butyl ether, among Di Iso Propyl Ether diox and the THF,, and organic amine alkali such as triethylamine are arranged in the temperature that is lower than 0 ℃, diethylamine, the diethyl isopropylamine, DABCO or relevant two-or trialkylamine, and amidine alkali for example DBU and DBN carry out under existing.
When J was halogen or pseudohalogen in compound 2c, coupling can be carried out in prevailing organic solvent, as THF, and ether ， diox, methyl tertiary butyl ether or other ethers; Acetone, pimelinketone, methyl iso-butyl ketone (MIBK) and other ketone; Ester such as acetate ethyl ester, methyl ester and isopropyl esters; Halogenated solvent such as methyl halide and ethane, chlorobenzene and other halogeno-benzenes; Nitrile such as acetonitrile and propionitrile; Lower alcohol such as ethanol, Virahol, the trimethyl carbinol and relevant alcohol; With polar organic solvent such as dimethyl formamide, methyl-sulphoxide, N-N-methyl-2-2-pyrrolidone N-and relevant amide containing solvent.Alkali is often used, and can be many mineral alkalis such as metal hydroxides, supercarbonate and carbonate, or organic bases such as amine, triethylamine for example, diethylamine, the diethyl isopropylamine, DABCO or relevant two-or trialkylamine, and amidine alkali any among DBU and the DBN for example.
Those skilled in the art can be implemented acid amides coupling step 2 by enough other possible J groups.
In step 3, removing protecting group can finish with any standard method that is used to remove the specific type protecting group.Simple carboxylamine alkyl-and the alkyl ester that replaces can be with alkali aqueous solution in the highest about 100 ℃ temperature, use any common inorganic metal oxyhydroxide such as sodium hydroxide, lithium hydroxide, the oxyhydroxide of potassium hydroxide or hydrated barta or other metals removes with stoichiometric at least amount.The carboxylamine protecting group that contains the benzyl that is connected with oxygen can be by removing with palladium or platinum catalyst hydrogenolysis.In addition, alkaline hydrolysis can be used any common inorganic metal oxyhydroxide such as sodium hydroxide in the highest about 100 ℃ temperature, lithium hydroxide, and the oxyhydroxide of potassium hydroxide or hydrated barta or other metals is used with stoichiometric at least amount.Many anhydrous acids also can be used to the deprotection with the carbamate of benzyl, comprise HCl, HBr and HI.Boron in non-polar solvent and the Lewis of aluminium acid are as AlCl
3, BBr
3, BCl
3Also be effective.The benzyl of some replacement that wherein selected specific replacement part can be removed under given conditions, aryl or alkyl also can be used.For example, the silica-based ethyl carbonyl of 2-front three (Teoc) is to design it to have the active protecting group of special reaction of the silica-based ethyl of 2-front three in the deprotection process.The silica-based ethyl carbonyl of 2-front three chlorine can be used for protecting amine nitrogen, and in the back with fluoride sources such as HF or fluoridize tetraalkylammonium salt and remove.
In step 4, the perhydro isoquinoline 99.9 fragment of formula 4 connects the closed epoxide intermediates (13) that produces of chloropharin functional group via alkali-inductive and connects with chloropharin (compound 5, diagram I).
Compound 5 is by kaneka Industries, and Japan produces.When carrying out compound 5 → compound 13 → compound 6, can use several closing-extraction of root.Epoxide 13 can be separated, perhaps with 4 reactions, 4 both and then 13 formation be added into, also can exist at the very start.Epoxide 13 can be used mineral alkali such as metal hydroxides, and carbonate and supercarbonate be at solvent such as alcohols methyl alcohol for example, ethanol or Virahol, and ethers such as THF are with produce in diox or both mixtures.Epoxide also can produce with alkali in the 2-phase solvent system of being made up of water and halogenated hydrocarbon solvent such as methylene dichloride.Phase-transfer catalyst such as tetraalkylammonium salt can be used to promote this process.The method of opening epoxide 13 with compound 4 is finished in alcoholic solvent or pure and mild another kind can be the mixture of solvent of ether or two utmost point non-protonic solvents such as dimethyl formamide or methyl-sulphoxide.Epoxide provides compound 6 with compound 4 open loops and is preferably in 50-60 ℃ and carried out in 2-7 hour.
In step 5, carbobenzoxy-(Cbz) can be removed and provide free amine 7.This can carry out with cosolvent such as halohydrocarbon in acetate with HBr.Also can use the halogenide such as the BBr of boron
3And BCl
3Or the halogenation boron that replaces of alkyl such as dimethyl boron bromide, carry out 0 ℃ of temperature to room temperature for example in chloroform and the methylene dichloride at halogenated hydrocarbon solvent.In addition, carbobenzoxy-(Cbz) can be by with metal hydroxides hydrated barta for example, sodium hydroxide, and the water/alcoholic solution of lithium hydroxide or potassium hydroxide is being higher than room temperature, and hydrolysis removes in several hours time.
Step 6a is that the benzoic acid derivative coupling of formula 8 provides 9a.In formula 8, Q can be a leaving group.Q can be any leaving group of discussing among the group J in the above.Wherein formula 8 compounds of Q=OH or Cl can be from EMS Dottikon, Lenzburg, and the Sugai Chemical Industries of Switzerland and Japan, Ltd buys.According to the definition of Q, coupling can be undertaken by multiple mode.When using free acid (Q=OH), coupling can be used carbodiimide, carry out based on method with this class general reagent, comprise dicyclohexylcarbodiimide or relevant dialkyl group carbodiimide, EDC (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide) or relevant water-soluble reagent are with organic amine alkali, at polar organic solvent such as diox, DMF in NMP and the acetonitrile, comprises in the presence of N-maloyl imines or the 3-hydroxybenzotriazole at N-hydroxyl heterocycle.When Q=halogen or pseudohalogen, coupling can be at prevailing solvent such as THF, ether ， diox, methyl tertiary butyl ether or other ethers; Ketone, pimelinketone, methyl iso-butyl ketone (MIBK) other ketones; Ester class such as ethyl acetate, methyl esters and isopropyl esters; Halogenated solvent such as methyl halide and ethane, chlorobenzene and other halogeno-benzenes; Nitrile such as acetonitrile and propionitrile; Lower alcohol such as ethanol, Virahol, the trimethyl carbinol and relevant alcohol, polar organic solvent such as dimethyl formamide carry out in the methyl-sulphoxide, N-N-methyl-2-2-pyrrolidone N-and relevant amide containing solvent.Alkali is often used and can is a large amount of mineral alkalis such as metal hydroxides, supercarbonate and carbonate or organic bases such as amine, for example triethylamine, diethylamine, the diethyl isopropylamine, DABCO or relevant two-or three-alkylamine, and acid amides alkali any among DBU and the DBN for example.
Removing in step 6b with mineral alkali such as metal hydroxides of acetoxyl in the water or alcoholic solution of carbonate and supercarbonate, ℃ finished in room temperature to 100.If with methane amide that perhydro isoquinoline 99.9 member ring systems is connected on the functional group of protection is arranged, be preferably in this point (during the step 6b or afterwards) and remove.The character of this step depends on the definite definition of protecting group.
The preferred method of finishing in the entire method shown in the diagram I is shown among the diagram II.
The amino acid/11 5 of Cbz-protection provides acid amides 16 with amine 22 couplings.The Cbz group removes by hydrogenation and provides amine 17.
Diagram II, acid amides 21 synthetic
Itself and chloropharin are provided adducts 18 through epoxide with method coupling on the spot.Provide acid amides 21 with the conventional deprotection of alkali and will dissociate primary amine and acyl chlorides 20 couplings.The details of this method provides among the embodiment 1A to F below.Alphabetical A to F in diagram II is corresponding to the following examples 1A to F.
The following example illustrates each side of the present invention.These embodiment are used to illustrate, and do not limit the scope of the invention.
Be used for the term fusing point, nuclear magnetic resonance spectrum, fast atom bombardment MS, infrared spectra, UV spectrum, ultimate analysis, the abbreviation of high performance liquid chromatography and thin-layer chromatography are respectively m.p., NMR, EIMS, MS (FD), MS (FAB), IR, UV analyzes HPLC, and TLC.In addition, the maximum absorption of in IR spectrum, listing be interested those, rather than viewed all maximum absorption.
For the NMR spectrum, use following abbreviation: unimodal (s), bimodal (d), double doublet (dd), triplet (t), quartet (q), multiplet (m), two multiplets (dm), wide unimodal (br.s), wide bimodal (br.d), wide triplet (br.t) and wide multiplet (br.m).J refers to the coupling constant with hertz (Hz) expression.Unless otherwise indicated, the NMR data refer to the free alkali of motif compound.
The NMR spectrum obtains on General Electric QE-300 300MHz instrument.The δ value representation of chemical shift to represent by ppm.Mass spectrum on VG ZAB-3 spectrometer at ScrippsResearch Institute, La Jolla, CA obtains.Infrared spectra is record on the MidacCorporation spectrometer.The UV spectrum obtains on Varian Cary 3E instrument.Thin-layer chromatography uses the silica-gel plate that obtains from E.Merck to carry out.Fusing point is measured on Mettler FP62 instrument, and not calibrated.
Embodiment 1
The method of synthesis type 21 acid amides
[3S-[2 (2S*, 3S*), 3 α, 4a β, 8a β]]-N-(1,1-dimethyl-2-hydroxyethyl) decahydro-2-[2-hydroxyl-3-[(3-hydroxy-2-methyl benzoyl) amino]-4-(thiophenyl) butyl]-3-isoquinoline 99.9 methane amide
A. with perhydro isoquinoline 99.9 (26.4g, 111mmol) (from NSC Technologies (Chicago, IL) or Procos SpA (Milan, Italy) buy) be suspended in water (200mL) and the concentrated hydrochloric acid (200mL).This mixture heating up refluxes and stirred 3 days, becomes solution during this period.Removal of solvent under reduced pressure provides light yellow solid.With solid pulp and filtration in 2-propyl alcohol (200mL).Reduction vaporization filtrate is oily matter.Add ethyl acetate (100mL) and water (100mL), making the pH of solution by adding 2N potassium hydroxide aqueous solution is 8.0.Dripped benzyl chloroformate (15.8mL 111mmol), remained between 7 and 8 the pH of solution by adding the 2N potassium hydroxide aqueous solution at 30 minutes.With mixture stirring at room 18 hours.Add ethyl acetate (200mL), organic layer washs with 1N hydrochloric acid (100mL) and salt solution (100mL).With organic layer drying (sal epsom), filter, and reduction vaporization is an oily matter.Product with 1: 1 40-60 petrol ether/ethyl acetate wash-out, is then used 100% eluent ethyl acetate by the silica gel column chromatography purifying.Fraction and reduction vaporization that collection contains product provide compound 15 (11.3g, 32%) colorless oil:
1H NMR(300MHz，CDCl
3)δ7.43-7.28(m，5H)，5.17(br s，2H)，4.76(m，1H)，3.79(m，1H)，3.33(m，1H)，2.19(m，1H)，1.96(m，1H)，1.88-1.15(m，10H).
B. at room temperature, with I-hydroxybenzotriazole (4.2g, 31.4mmol) and EDC (6.0g, (8.3g is in DMF 26.2mmol) (128mL) solution 31.4mmol) to add acid 15.Mixture was 80 ℃ of heating 10 minutes.Add by with the clean thing reflux of mixture several hours, then with obtain after the volatile component evaporation 1,1-dimethyl-2-three silyloxy ethylamine (5.1g, 31.4mmol, from 1,1-dimethyl-2-hydroxyethyl amine (Aldich Chemical Co.) and hexamethyldisilazane (Aldich Chemical Co.) preparation), solution was 80 ℃ of heating 17 hours.Yellow solution is poured in acetate ethanol (250mL) and the 2N hydrochloric acid (250mL).Stir after 10 minutes, add ethyl acetate (750), the mixture water (3 * 500mL) and salt solution (1 * 250mL) washs.(1 * 250mL) extracts the organic layer that merges with ethyl acetate.The organic layer drying (sodium sulfate) that merges is also provided compound 16 colorless oil (7.9g, 78%) by flash chromatography (50/50 ethyl acetate/hexane) purifying:
1H NMR (300MHz, CD
3OD) δ 7.36 (m, 5H), 5.20 (d, J=8.1Hz, 1H), 5.10 (m, 1H), 4.53 (m, 1H), 3.78 (dd, J=13.2,4.4Hz, 1H), 3.60 (m, 2H), 3.48 (d, J=10.7Hz, 1H), 2.15-1.25 (m, 12H), 1.31 (s, 3H), 1.29 (s, 3H).
C. with carboxylamine 16 (7.9g, 20.4mmol) and 5% palladium carbon (Pd/C) mixture (1.6g) in 50psi hydrogen, in absolute ethanol (110mL), hydrogenation is 18 hours under the room temperature.Mixture filtration over celite and vacuum-evaporation are provided amine 17 white crystalline solid:
1H NMR(300MHz，CD
3OD)δ3.63(q，J＝7.0Hz，2H)，3.34(m，1H)，3.27(dd，J＝11.8，3.3Hz，1H)，2.91(m，1H)，2.02-1.15(m，12H)，1.32(s，3H)，1.31(s，3H).
D. under the mechanical stirring, (2.4mL, (10.4g is 28.6mmol) in Virahol (IPA) warm (27 ℃) suspension in (104mL) 24.5mmol) to be added to chloropharin (obtaining from Kaneka Industries in Japan) with the 10.2N aqueous sodium hydroxide solution.After 1 hour, add the aqueous solution of 1N hydrochloric acid in IPA (prepare) (about 1mL) neutralize (pH=7) by will the 1mL concentrated hydrochloric acid adding among the 12mL IPA.(5.2g, 20.4mmol), this dilute suspension was 60 ℃ of heating 10 hours to add amine 17 with the form of solution in IPA (50mL).Vacuum is removed IPA.Resistates dilutes with ethyl acetate (150mL), and water (2 * 50mL), saturated sodium bicarbonate aqueous solution (1 * 50mL), and salt solution (1 * 50mL) washing.(1 * 25mL) extracts the water layer that merges with ethyl acetate.The organic layer drying (sodium sulfate) that merges also provides compound 18 white solids (8.98g, 76%) by purification by flash chromatography (75/25 ethyl acetate/hexane, ethyl acetate then):
1H NMR(300MHz，CD
3OD)δ7.33(m，10H)，5.08(AB，J
AB＝12.2Hz，ΔU
AB＝12.1Hz，2H)，3.96，(m，2H)，3.56(q，J＝7.3Hz，2H)，3.50，(m，1H)，3.20(dd，J＝13.6，9.2Hz，1H)，3.03(m，1H)，2.64(m，2H)，2.20-1.20(m，14H)，1.28(s，6H).
E. at room temperature, ((6.75g is 11.6mmol) in the suspension in IPA (34mL) 33.6mmol) to add carbamate 18 for 2.7g, 1.8mL with 50% aqueous sodium hydroxide solution.Mixture heating up was refluxed 12 hours.After being cooled to room temperature, mixture (600mL) dilute with methyl tertiary butyl ether (MTBE), and water (2 * 250mL) and salt solution (1 * 125mL) washs.(1 * 150mL) extracts the water layer that merges with MTBE.The organic layer drying (sodium sulfate) that merges, vacuum-evaporation provides the mixture of compound 19 and benzylalcohol, is the oily white solid:
1H NMR(300MHz，CD
3OD)δ7.34(m，10H)，4.63(s，2H)，3.81(m，1H)，3.58(m，3H)，3.03-2.60(m，5H)，2.17(m，1H)，2.05(m，1H)，1.87-1.05(m，12H)，1.30(s，3H)，1.28(s，3H).
F. (3.2g, 4.3mL is 31.2mmol) the ethanol (23mL) of the mixture of adding amine 19 (4.7g, 10.4mmol is from 18 Theoretical Calculation) and benzylalcohol with triethylamine under the room temperature.Add 3-acetoxyl group-2-methyl benzoyl chloride (20) (the U.S. Patent application No.08/708411 according to application on September 5th, 1996 draws the reference for this paper especially, and the method for proposition obtains) (2.4g, THF 11.5mmol) (4mL) solution.After 2 hours, (52.2mmol), mixture was by reflux 1 hour for 4.1g, 2.8mL to add 50% aqueous sodium hydroxide solution.After being cooled to room temperature, mixture is neutralized to pH=7 with 2N hydrochloric acid (26mL).This mixture dilutes with ethyl acetate (500mL), and water (1 * 250mL), saturated sodium bicarbonate aqueous solution (2 * 250mL), water (1 * 250mL), and salt solution (1 * 125mL) washing.With organic layer drying (sodium sulfate), and provide acid amides 21 white foam bodies (1173-57A, 1.39g, 23%) by flash chromatography (75/25 ethyl acetate/hexane) purifying.
1There is the 11wt% ethyl acetate in H NMR indication, and vacuum can not be removed.Analyze:
1H NMR(300MHz，CD
3OD)δ7.53(d，J＝7.3Hz，2H)，7.32(t，J＝7.0Hz，2H)，7.20(t，J＝7.3Hz，1H)，7.06(t，J＝8.1Hz，1H)，6.92(d，J＝8.1Hz，1H)，6.83(d，J＝8.1Hz，1H)，4.42(m，1H)，4.08(m，1H)，3.61(dd，J＝13.6，4.0Hz，1H)，3.45(AB，J
AB＝11.0Hz，ΔU
AB＝18.0Hz，2H)，3.29(dd，J＝13.6，10.3Hz，1H)，3.10(m，1H)，2.66(m，2H)，2.28(s，3H)，2.22(m，2H)，2.04(m，1H)，1.86-1.20(m，11H)，1.19(s，3H)，1.18(s，3H).
13C NMR(75.5MHz，CD
3OD)δ175.7，172.5，155.9，138.8，136.7，129.8，128.9，126.3，126.0，122.4，118.4，115.9，70.3，69.9，68.2，59.3，58.8，54.9，53.0，36.5，34.2，34.1，31.1，30.7，26.4，26.0，23.1，23.0，20.8，12.1.
Embodiment 2
The hiv protease of compound 21 suppresses active and the HIV (human immunodeficiency virus)-resistant activity in cell cultures
The dynamic analysis of combining closely is used to measure the K of compound 21
iThe amount of value.K
i＝5.6±0.91nM。
Method
The expression of HIV-1 proteolytic enzyme
Isolate the HIV-proteinase gene from virus strain IIIB (Ratner, L.et al., Nature, 316,227-184 (1985)).In order to increase the proteolytic enzyme (Rose of purifying, J.R.etal., J.Biol.Chem., 268,11939-11945 (1993)) stability, by replacing 33 base pairs between proteinase gene sequence of N deI and BstEII site with synthetic oligonucleoside coding Q7S sudden change, the glutamine residue of 7 (Q7) is sported Serine (S).The gene order of modified is inserted plasmid vector pGZ (Menge, K.L.etal., Biochemistry, 34:15934-15942 (1995) under the control of phage t7 promotor.The structure that is produced, pGZ/HP-19Q7S#9 is transferred to from Novagen, among the E.coli bacterial strain BL21 (DE3) that Inc. buys.
The expression of HIV-1PR: culture is at 37 ℃, 2YT substratum (the 1.6%Trypticase Pepton that in 100L fermentor tank (Biolafitte SA), contains 200 μ g/L penbritins, 1% yeast extraction liquid, 0.5% sodium-chlor, final pH 7.5) growth is 5 hours in, induces by adding 1mMIPTG (sec.-propyl-β-D-thio-galactose pyran-glucoside) then.Culture temperature between inductive phase rises to 42 ℃, increases the accumulation of Recombinant HIV-1 proteolytic enzyme as insoluble inclusion body.42 ℃ after 2 hours, by with Pellicon 0.1 μ m WPP000C5 box #10 (micropore) cross-flow filtration harvested cell, cell is stuck with paste-70 ℃ of refrigerations.
The purifying of Recombinant HIV-1 proteolytic enzyme: except as otherwise noted, all steps are all carried out at 4 ℃.Protein concentration Biorad analysis of protein measured in solution, (BioRad, Richmond is CA) as standard with bovine serum albumin.The purity of chromatographic step and HIV PR is analyzed by SDS-PAGE (SDS-PAGE).Final purity＞98% of HIV-PR.Typical ultimate yield is 120mg in each 100L culture.
Stick with paste resuspending in 300mL lysis buffer (50mMTris-Cl pH8.0,25mM NaCl, 20mM 2 mercapto ethanol) from the cell of 100L culture gained, and at 22000psi, Micro Fluid in Microfluidics Corporation fluidisation device.The granular cell lysate by clarifying at 14000rpm in centrifugal 20 minutes.HIV PR mainly finds with the inclusion body form in ball.Inclusion body washs repeatedly in the lysis buffer that contains extra 0.1%Trition-X100 and 1M urea subsequently, and after each washing, inclusion body is all by forming ball in centrifugal 20 minutes at 5000rpm.The inclusion body of purifying is dissolved in and contains 50mM Tris-Cl pH8.0, and 25mM NaCl is in the damping fluid of 20mM 2 mercapto ethanol and 8M urea.Solution is by clarifying in that 14000rpm is centrifugal, and room temperature be used for same buffer equilibrated 300mL Fast Flow Q-Sepharose post (Pharmacia, Piscataway, NJ).Under these conditions, HIV PR is not joined on the post, and pure basically enzyme is found in flowing through fraction.In order to make protein renaturation, will be from the fraction of Fast FlowQ-Sepharose post gained with containing 25mM NaH
2PO
4PH7.0,25mMNaCl, three kinds of damping fluid dialysis of 10mM DTT and 10% glycerine.After folding again, the small amount of precipitate thing is removed by centrifugal, and the enzyme prepared product that produces is concentrated, and use 0.5M NaCl, 50mM MES pH5.6, and 10mM DTT dialyses, and is freezing and-70 ℃ of storages with the little aliquots containig of～2mg/mL.Combine closely dynamic test and analysis
The protease activity of the hiv protease of purifying is used by the coloring test of the modification of Richards etal. (Richards, A.D.et al., J.Biol.Chem., 256,773-7736 (1990)) development and is measured.Synthetic peptide His-Lys-Ala-Arg-Val-Leu-Phe is (to NO
2)-Glu-Ala-Nle-Ser-NH
2(American Peptide Company) (Nle is a nor-leucine) is used as substrate.This test is at 0.5M NaCl, and 50mM MES pH5.6 among 5mM DTT and the 2%DMSO, carries out at 37 ℃.(Phe is to NO at leucine and p-nitrophenyl L-Ala
2) between the cracking of easy fracture key analyze by the spectrophotometer monitoring of the minimizing that absorbs at 305nm.The deviation ratio that original speed absorbs during 100 seconds with the beginning at enzymic catalytic reaction and measuring.Under these conditions, and with Q7S HIV-1 proteolytic enzyme, the Michaelis constant (Km) of this substrate is 59 ± 17 μ M.
In order to measure the inhibition of compound 21, use the substrate saturation concentration of 200 μ M.Between 13 and 20 inhibitor concentration, estimated, as mentioned above in each measurement of concetration speed of response.Measure the performance K that as above proposes by computer assisted non-linear least squares fit data and Morrison (Morrison, J.F., Biochem.Biophys.Acta, 185,269-286 (the 1963)) equation of combining closely
i(K
iApp).
Embodiment 3
Compound 21 in cell cultures to the antiviral activity of HIV-1
Cell and virus stock
From AIDS Research and Reference Program, it is RF and IIIB that Division ofAIDS, NIAID, and NIH obtain CEM-SS and MT-2 human T-cell system and HIV-1.
Cell protection test
Each medicament is measured by MTT reducing dyes method (Alley, M.C.etal., Cancer Res.48:589-601 (1988)) the inhibition effect that HIV duplicates.Compound is dissolved in DMSO with the concentration of 40mg/ml, dilution 1: 200 in substratum (RPMI replenishes with 10% foetal calf serum) then.From the soup stock of each dilution, 100 μ l are added the 96-orifice plate, prepare a series of half-log diluents.In the test tube that separates, MT-2 cell and CEM-SS cell infect with HIV-1IIIB or HIV-1RF with 0.01 and 0.03 infection multiplicity respectively.At 4 hours absorptions week after date, the cell that 100 μ l are infected or do not infect adds in the hole that contains the medicine plate and provides 1 * 10
4The ultimate density of cells/well.After six days (CEM-SS cell) or seven days (MT-2 cell), MTT (5mg/ml) is added test board, the amount of the formazan of generation (first a ceremonial jade-ladle, used in libation) is at the 570nm spectrophotometry.Data with the formazan that in the cell of medicine-handled, produces with in the hole of not infecting, the percentage ratio expression that the formazan that the cell of no medicine produces compares.ED
50Infecting as making, the formazan of the cell of drug treating produces percentage ratio and increases to and do not infect, 50% required drug level calculating that no drug cell produced.Cytotoxicity (TC
50) do not infecting as making, the formazan percentage ratio that produces in the cell of drug treating is reduced to and does not infect, 50% required drug level calculating that no drug cell produced.Therapeutic index (TI) is by using antiviral efficacy (ED
50) divided by cytotoxicity (TC
50) and calculate.
Table 1
Antiviral activity and the Cytotoxic evaluation of compound 21 in CEM-SS cell usefulness HIV-1RF acute infection
| Compound | ED 50(nM) | ED 95(nM) | TC 50(μM) | Therapeutic index a |
| 21 | 34.2 | 154.1 | 96.6 | 2825 |
| Zidovodine (AZT) | 52.3 | 543.1 | ＞374.5 | ＞7161 |
| Zalcitabine (ddC) | 94.70 | 142.0 | 37.69 | 398 |
A therapeutic index=cytotoxicity (TC
50)+antiviral activity (ED
50).
Table 2
Antiviral activity and the Cytotoxic evaluation of compound 21 in MT-2 cell usefulness HIV-1IIIB acute infection
| Compound | ED 50(nM) | ED 95(nM) | TC 50(μM) | Therapeutic index a |
| 21 | 85.6 | ND | 92.6 | 1082 |
| AZT | 430.7 | ND | 109.4 | 254 |
| ddC | 5924 | ND | 176.3 | 30 |
A therapeutic index=cytotoxicity (TC
50)+antiviral activity (ED
50).
As mentioned above, The compounds of this invention can be used for suppressing hiv protease, the generation of this enzyme and virus composition and gather relevant.A scheme of the present invention is the method that treatment HIV infects, and comprises main body or patient, uses formula (9) compound or pharmaceutically acceptable salt thereof of significant quantity as primate.Another program of the present invention is the method for treatment AIDS, comprises formula (9) compound or pharmaceutically acceptable salt thereof of main body or patient being used significant quantity.Another program of the present invention is the method that suppresses hiv protease, comprises cell or main body or patient that HIV is infected, as the primate that is infected by HIV, uses formula (9) compound or pharmaceutically acceptable salt thereof of significant quantity.
Term " significant quantity " means the amount of virus composition generation that can suppress the hiv protease mediation effectively and formula (9) compound or pharmaceutically acceptable salt thereof of gathering.Administered compound comprises to reach treatment or inhibiting concrete dosage certainly by concrete environment according to the present invention, for example, the compound of using, route of administration, illness of being treated and the main body of specifically being treated or patient determine.The example of per daily dose (with list or multiple doses) comprises the dosage level of about 0.01mg/kg to about 50mg/kg body weight The compounds of this invention.Preferred per daily dose is generally about 0.05mg/kg to about 40mg/kg, more preferably is that about 0.1mg/kg is to about 30mg/kg.
The compounds of this invention is administration by all means, comprise oral, approach in intramuscular and the nose.The compounds of this invention is preferably prepared before administration.Therefore, another program of the present invention is pharmaceutical composition or preparation, comprises formula (9) compound or pharmaceutically acceptable salt thereof and the pharmaceutical carrier of significant quantity, as thinner or vehicle.
Activeconstituents is preferably gross weight 0.1% to 99.9% weight of preparation." medicinal " means carrier, is that other composition with preparation holds altogether as thinner or vehicle, and nontoxic to main body or patient.
Pharmaceutical preparation can be from The compounds of this invention by the composition preparation of already known processes with known and easy acquisition.When making the present composition, activeconstituents mixes with carrier, or dilutes with carrier, or is wrapped in the carrier, and it can be a capsule, sachet, paper bag or other suitable containers form.When carrier during as thinner, it can be as carrier for active principle, the solid of vehicle or medium, semisolid or liquid substance.Therefore, composition can be a tablet, pill, pulvis, lozenge, sachet agent, cachet, pond agent, suspension agent, emulsion, solution, syrup, aerosol (be solid or in liquid medium), ointment (contains, for example, up to the active compound of 10% weight), soft hard capsule, suppository, aseptic injectable solution, pulvis of sterile packed or the like.
Following example of formulations only is an illustrative, does not limit the scope of the invention.Term " activeconstituents " expression (9) compound or pharmaceutically acceptable salt thereof.
Preparation 1
Prepare hard capsule with following ingredients:
Amount (mg/ capsule)
Activeconstituents 250
Starch (doing) 200
Magnesium Stearate 10
Total amount 460mg
Preparation 2
Prepare tablet with following ingredients:
Amount (mg/ sheet)
Activeconstituents 250
Mierocrystalline cellulose (crystallite) 400
Silicon-dioxide (fumigating) 10
Stearic acid 5
Total amount 665mg
Each composition is mixed and is pressed into the tablet of each heavy 665mg.
Preparation 3
Preparation contains the aerosol solution of following ingredients:
Composition weight
Activeconstituents 0.25
Methyl alcohol 25.75
Propelling agent 22 (chloro methylene fluoride) 74.00
Total amount 100.00
Activeconstituents is mixed with ethanol, and mixture adds in the part propelling agent 22, is cooled to-30 ℃, and is transferred in the tamping unit.The stainless steel vessel of then aequum being packed into is with remaining propelling agent dilution.On container, load onto valve then.
Preparation 4
Be prepared as follows the tablet that respectively contains the 60mg activeconstituents:
Amount (mg/ sheet)
Activeconstituents 60
Starch 45
Microcrystalline Cellulose 35
Polyvinylpyrolidone (PVP) is (in water 10 4
% solution)
Sodium starch glycolate 4.5
Magnesium Stearate 0.5
Talcum 1
Total amount 150
With activeconstituents, starch and Mierocrystalline cellulose are crossed No.45 order U.S. sieve and thorough mixing.To contain the aqueous solution of Polyvinylpyrolidone (PVP) and the powder mixes of generation, then mixture be crossed No.45 order U.S. sieve.The saccharoid that is produced is 50 ℃ of dryings and cross No.18 order U.S. sieve.In saccharoid, add the prior sodium starch glycolate of crossing No.60 order U.S. sieve then, Magnesium Stearate and talcum, after the mixing, compressing tablet provides the tablet of heavy 150mg on tabletting machine.
Preparation 5
Respectively contain the following manufacturing of capsule of 80mg activeconstituents:
Amount (mg/ capsule)
Activeconstituents 80mg
Starch 59mg
Microcrystalline Cellulose 59mg
Magnesium Stearate 2mg
Total amount 200mg
With activeconstituents, Mierocrystalline cellulose, starch and Magnesium Stearate mix, and cross No.45 order U.S. sieve, insert hard capsule with the amount of 200mg.
Preparation 6
Be prepared as follows the suppository that respectively contains the 225mg activeconstituents:
Activeconstituents 225mg
Saturated fatty acid glyceride 2000mg
Total amount 2225mg
Activeconstituents is crossed No.60 order U.S. to be sieved and is suspended in the prior saturated fatty acid glyceride with the minimum heat fusing.Then mixture is poured into the suppository mold and the cooling of 2g capacity.
Preparation 7
The suspension that every 5ml dosage contains the 50mg activeconstituents is prepared as follows:
Activeconstituents 50mg
Xylo-Mucine 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Seasonings q.v.
Tinting material q.v.
Pure water is to total amount 5ml
Activeconstituents is crossed No.45 order U.S. sieve, and mix the lubricated mashed prod of formation with Xylo-Mucine and syrup.With benzoic acid solution, seasonings and tinting material dilute with portion water, and under agitation add.The required volume of water generates that adds capacity then.
Preparation 8
Be prepared as follows iv formulation:
Activeconstituents 100mg
Isotonic saline solution 1000mL
The solution of mentioned component generally with the speed of per minute 1ml to the main body intravenous administration.
Preparation 9
Prepare tablet with following ingredients:
Amount (mg/ sheet)
Activeconstituents 292mg
Calucium Silicate powder 146mg
crospovidone 146mg
Magnesium Stearate 5mg
Total amount 589mg
Claims (31)
1. formula (9) compound or pharmaceutically acceptable salt thereof or solvate:
Wherein:
R is H, and R ' is (C
1-C
6) alkyl-OH.
2. according to the compound or pharmaceutically acceptable salt thereof or the solvate of claim 1, wherein said compound has formula 21:
3. according to the compound or pharmaceutically acceptable salt thereof or the solvate of claim 1, it is the salt with formula (9b):
Wherein R and R ' definition is as claim 1.
4. pharmaceutical composition comprises:
(a) claim 1 of significant quantity compound; With
(b) pharmaceutical carrier.
5. pharmaceutical composition comprises:
(a) claim 2 of significant quantity compound; With
(b) pharmaceutical carrier.
6. claim 1 compound or pharmaceutically acceptable salt thereof or solvate are used for suppressing the application of the medicine of hiv protease in preparation.
7. the compound or pharmaceutically acceptable salt thereof of claim 2 or solvate are used for suppressing the application of the medicine of hiv protease in preparation.
8. according to the compound of claim 1, its purity is greater than 90%.
9. according to the compound of claim 1, its purity at least 95%.
10. according to the compound of claim 1, its purity at least 97%.
11. according to the compound of claim 1, its purity at least 99%.
12. according to the compound of claim 2, its purity is greater than 90%.
13. according to the compound of claim 2, its purity at least 95%.
14. according to the compound of claim 2, its purity at least 97%.
15. according to the compound of claim 2, its purity at least 99%.
16. according to the pharmaceutical composition of claim 4, wherein compound purity is greater than 90%.
17. according to the pharmaceutical composition of claim 4, wherein compound purity at least 95%.
18. according to the pharmaceutical composition of claim 4, wherein compound purity at least 97%.
19. according to the pharmaceutical composition of claim 4, wherein compound purity at least 99%.
20. according to the pharmaceutical composition of claim 5, wherein compound purity is greater than 90%.
21. according to the pharmaceutical composition of claim 5, wherein compound purity at least 95%.
22. according to the pharmaceutical composition of claim 5, wherein compound purity at least 97%.
23. according to the pharmaceutical composition of claim 5, wherein compound purity at least 99%.
24. according to the application of claim 6, wherein compound purity is greater than 90%.
25. according to the application of claim 6, wherein compound purity at least 95%.
26. according to the application of claim 6, wherein compound purity at least 97%.
27. according to the application of claim 6, wherein compound purity at least 99%.
28. according to the application of claim 7, wherein compound purity is greater than 90%.
29. according to the application of claim 7, wherein compound purity at least 95%.
30. according to the application of claim 7, wherein compound purity at least 97%.
31. according to the application of claim 7, wherein compound purity at least 99%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81595197A | 1997-03-13 | 1997-03-13 | |
| US08/815,951 | 1997-03-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1253548A CN1253548A (en) | 2000-05-17 |
| CN1179948C true CN1179948C (en) | 2004-12-15 |
Family
ID=25219265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988045389A Expired - Fee Related CN1179948C (en) | 1997-03-13 | 1998-03-12 | HIV protease inhibitors |
Country Status (35)
| Country | Link |
|---|---|
| EP (1) | EP0970055A2 (en) |
| JP (1) | JP2001516350A (en) |
| KR (1) | KR100511089B1 (en) |
| CN (1) | CN1179948C (en) |
| AP (1) | AP1358A (en) |
| AR (1) | AR012556A1 (en) |
| AU (1) | AU743078B2 (en) |
| BG (1) | BG63540B1 (en) |
| BR (1) | BR9808867A (en) |
| CA (1) | CA2284163A1 (en) |
| CO (1) | CO4940496A1 (en) |
| CZ (1) | CZ296647B6 (en) |
| EA (1) | EA002378B1 (en) |
| EE (1) | EE04114B1 (en) |
| GE (1) | GEP20022764B (en) |
| HR (1) | HRP980112A2 (en) |
| HU (1) | HUP0001380A3 (en) |
| IL (2) | IL131870A0 (en) |
| IS (1) | IS5176A (en) |
| MX (1) | MXPA99008395A (en) |
| MY (1) | MY117535A (en) |
| NO (1) | NO315555B1 (en) |
| NZ (1) | NZ337706A (en) |
| OA (1) | OA11196A (en) |
| PA (1) | PA8448801A1 (en) |
| PE (1) | PE58799A1 (en) |
| PL (1) | PL192786B1 (en) |
| SA (1) | SA98181116B1 (en) |
| SK (1) | SK283636B6 (en) |
| SV (1) | SV1998000038A (en) |
| TR (1) | TR199902508T2 (en) |
| TW (1) | TW200517112A (en) |
| UA (1) | UA57772C2 (en) |
| WO (1) | WO1998040357A2 (en) |
| ZA (1) | ZA982047B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5484926A (en) * | 1993-10-07 | 1996-01-16 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
-
1998
- 1998-03-04 HR HR08/815,951A patent/HRP980112A2/en not_active Application Discontinuation
- 1998-03-11 ZA ZA982047A patent/ZA982047B/en unknown
- 1998-03-12 AR ARP980101104A patent/AR012556A1/en active IP Right Grant
- 1998-03-12 CZ CZ0319199A patent/CZ296647B6/en not_active IP Right Cessation
- 1998-03-12 TW TW094100045A patent/TW200517112A/en unknown
- 1998-03-12 CN CNB988045389A patent/CN1179948C/en not_active Expired - Fee Related
- 1998-03-12 MX MXPA99008395A patent/MXPA99008395A/en not_active IP Right Cessation
- 1998-03-12 MY MYPI98001071A patent/MY117535A/en unknown
- 1998-03-12 NZ NZ337706A patent/NZ337706A/en unknown
- 1998-03-12 EA EA199900823A patent/EA002378B1/en unknown
- 1998-03-12 HU HU0001380A patent/HUP0001380A3/en unknown
- 1998-03-12 AU AU64575/98A patent/AU743078B2/en not_active Ceased
- 1998-03-12 IL IL13187098A patent/IL131870A0/en active IP Right Grant
- 1998-03-12 BR BR9808867-0A patent/BR9808867A/en not_active Application Discontinuation
- 1998-03-12 EE EEP199900416A patent/EE04114B1/en not_active IP Right Cessation
- 1998-03-12 SK SK1222-99A patent/SK283636B6/en not_active IP Right Cessation
- 1998-03-12 WO PCT/US1998/004735 patent/WO1998040357A2/en active IP Right Grant
- 1998-03-12 EP EP98910300A patent/EP0970055A2/en not_active Withdrawn
- 1998-03-12 GE GEAP19984984A patent/GEP20022764B/en unknown
- 1998-03-12 CA CA002284163A patent/CA2284163A1/en not_active Abandoned
- 1998-03-12 JP JP53974598A patent/JP2001516350A/en not_active Ceased
- 1998-03-12 PE PE1998000171A patent/PE58799A1/en not_active Application Discontinuation
- 1998-03-12 TR TR1999/02508T patent/TR199902508T2/en unknown
- 1998-03-12 KR KR10-1999-7008331A patent/KR100511089B1/en not_active IP Right Cessation
- 1998-03-12 AP APAP/P/1999/001648A patent/AP1358A/en active
- 1998-03-12 PL PL335672A patent/PL192786B1/en not_active IP Right Cessation
- 1998-03-13 SV SV1998000038A patent/SV1998000038A/en not_active Application Discontinuation
- 1998-03-13 PA PA19988448801A patent/PA8448801A1/en unknown
- 1998-03-13 CO CO98014251A patent/CO4940496A1/en unknown
- 1998-04-21 SA SA98181116A patent/SA98181116B1/en unknown
- 1998-12-03 UA UA99095049A patent/UA57772C2/en unknown
-
1999
- 1999-09-10 IS IS5176A patent/IS5176A/en unknown
- 1999-09-10 NO NO19994415A patent/NO315555B1/en not_active IP Right Cessation
- 1999-09-10 IL IL131870A patent/IL131870A/en not_active IP Right Cessation
- 1999-09-13 BG BG103727A patent/BG63540B1/en unknown
- 1999-09-13 OA OA9900207A patent/OA11196A/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1204144C (en) | Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors | |
| CN1117569C (en) | Bicyclic fibrinogen antagonists | |
| CN1207056C (en) | Peptide-containing & alpha, -ketoamide cysteine and serine protease inhibitors | |
| CN1045204C (en) | 10,11-methanodibenzosuberane derivaties used as chemosensitizing agents | |
| CN1244575C (en) | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors | |
| CN1088456C (en) | Substituted oxazolidine calpain and/or cathepsin B inhibitors | |
| CN1071751C (en) | Reversible protease inhibitors | |
| US5296604A (en) | Proline derivatives and compositions for their use as inhibitors of HIV protease | |
| CN1145637C (en) | Thio-substituted peptides as inhibitors for metalloproteinases and tnfliberation | |
| CN1149223C (en) | Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors | |
| CN1422253A (en) | Carbamate caspase inhibitors and uses thereof | |
| CN1505628A (en) | Triazole compounds useful in treating diseases associated with unwanted cytokine activity | |
| CN1391560A (en) | Quinazoline derivatives | |
| CN1071930A (en) | Inhibitor as the human immunodeficiency virus protease who treats acquired immune deficiency syndrome (AIDS) | |
| CN1145587A (en) | Protease inhibitors | |
| CN1331076A (en) | Condensed pyrazole compound, composition containing it and its application | |
| CN1346360A (en) | Phosphoramidate, and mono-di, and tri-phosphate esters of (1R, cis)-4-(6-amino-9H-purin-9-YL)-2-cyclopentene-1-methanol as antiviral agents | |
| CN1063491A (en) | 1, the 4-Benzothiazepine derivatives | |
| CN1046727C (en) | HIV protease inhibitors | |
| CN1265098A (en) | Heterocyclic derivatives which inhibit factor XA | |
| CN1032785A (en) | L-Dopa derivatives or its acid salt, its production method and uses thereof | |
| CN1062729A (en) | The three ring new compounds that contain amino and nitro of useful as inhibitors of ace | |
| CN1098407A (en) | Inhibitors of HIV protease as the treatment AIDS | |
| CN1150162C (en) | Biphenylamidine derivatives | |
| CN1291193A (en) | Novel triazolo (4.5-d) pyrimidine compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20041215 Termination date: 20100312 |