HRP980112A2 - Hiv protease inhibitors - Google Patents

Hiv protease inhibitors

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Publication number
HRP980112A2
HRP980112A2 HR08/815,951A HRP980112A HRP980112A2 HR P980112 A2 HRP980112 A2 HR P980112A2 HR P980112 A HRP980112 A HR P980112A HR P980112 A2 HRP980112 A2 HR P980112A2
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Croatia
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compound
group
alkyl
purity
substituted
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HR08/815,951A
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Croatian (hr)
Inventor
Takuo Kobayashi
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Agouron Pharma
Japan Tobacco Inc
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Publication of HRP980112A2 publication Critical patent/HRP980112A2/en

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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • 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
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    • 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

Description

Stanje tehnike i izlaganje biti izuma State of the art and presentation of the essence of the invention

Ovaj se izum odnosi na nove nizove kemijskih spojeva koji su korisni kao inhibitori proteaze HIV-a, kao i na uporabu ovih spojeva kao protuvirusnih sredstava. This invention relates to new series of chemical compounds useful as HIV protease inhibitors, as well as to the use of these compounds as antiviral agents.

Sindrom stečene imunodeficijencije (AIDS) relativno je nedavno opisana bolest, odnosno stanje. AIDS uzrokuje postupan slom imunosnog sustava organizma, kao i progresivno propadanje središnjeg i perifernog živčanog sustava. Otkako je prepoznat početkom 1980-ih godina, AIDS se brzo proširio i do danas dostigao razmjere epidemije unutar relativno ograničenog dijela stanovništva. Intenzivna istraživanja dovela su do otkrivanja uzročnika, ljudskog T-limfotropnog retrovirusa III (HTLV-III), danas bolje poznatog kao virus ljudske imunodeficijencije ili HIV. Acquired immunodeficiency syndrome (AIDS) is a relatively recently described disease or condition. AIDS causes a gradual breakdown of the body's immune system, as well as progressive deterioration of the central and peripheral nervous system. Since its recognition in the early 1980s, AIDS has spread rapidly and has reached epidemic proportions within a relatively limited segment of the population. Intensive research led to the discovery of the causative agent, the human T-lymphotropic retrovirus III (HTLV-III), better known today as the human immunodeficiency virus or HIV.

HIV je član skupine virusa poznatih kao retrovirusi. Retrovirusni genom sastoji se od RNK koja se prevodi u DNK obrnutim prepisivanjem. Ova retrovirusna DNK se potom stabilno uklopi u kromosom stanice domaćina i, koristeći postupak replikacije stanice domaćina, proizvodi nove retrovirusne čestice, šireći tako infekciju na druge stanice. HIV pokazuje poseban afinitet za ljudske T-4 limfocite koji igraju ključnu ulogu u imunosnom sustavu organizma. Inficiranje ovih leukocita HIV-om iscrpljuje ovu leukocitnu populaciju. Na kraju dolazi do nedjelatnosti imunosnog sustava i njegove neučinkovitosti u borbi protiv različitih oportunističkih bolesti kao što su, između ostalih, Pneumocystis carinii pneumonija, Kaposijev sarkom i rak limfnog sustava. HIV is a member of a group of viruses known as retroviruses. The retroviral genome consists of RNA that is translated into DNA by reverse transcription. This retroviral DNA then stably integrates into the host cell's chromosome and, using the host cell's replication process, produces new retroviral particles, thereby spreading the infection to other cells. HIV shows a special affinity for human T-4 lymphocytes, which play a key role in the body's immune system. Infection of these leukocytes with HIV depletes this leukocyte population. Eventually, the immune system becomes inactive and ineffective in fighting various opportunistic diseases such as, among others, Pneumocystis carinii pneumonia, Kaposi's sarcoma, and cancer of the lymphatic system.

Iako točan mehanizam nastajanja i djelovanja HIV-a nije rasvijetljen, otkrivanje virusa je donijelo izvjestan napredak u kontroliranju bolesti. Na primjer, nađeno je da je lijek azidotimidin (AZT) učinkovit za inhibiranje obrnutog prepisivanja retrovirusnog genoma HIV-a, čime je postao sredstvo za kontroliranje, iako ne i za izlječenje, bolesti u bolesnika zahvaćenih AIDS-om. Nastavlja se potraga za lijekovima koji bi mogli izliječiti ili barem bolje kontrolirati smrtonosni HIV. Although the exact mechanism of the formation and action of HIV has not been elucidated, the discovery of the virus has brought some progress in controlling the disease. For example, the drug azidothymidine (AZT) was found to be effective in inhibiting reverse transcription of the HIV retroviral genome, making it a means of controlling, although not curing, disease in AIDS patients. The search continues for drugs that could cure or at least better control the deadly HIV.

Replikacija retrovirusa obično predstavlja poslijetranslacijsku preinaku poliproteina. Ovu preinaku provodi proteaza HIV-a, enzim koji kodira virus. Postupkom se dobiju zreli polipeptidi koji se potom uključuju u oblikovanje i djelovanje infektivnog virusa. Ako se ova molekularna preinaka onemogući, sprečava se i normalna proizvodnja HIV-a. Stoga inhibitori proteaze HIV-a mogu djelovati kao protuvirusna sredstva protiv HIV-a. Replication of retroviruses usually involves post-translational modification of polyproteins. This modification is carried out by the HIV protease, an enzyme encoded by the virus. The process produces mature polypeptides that are then involved in the formation and action of the infectious virus. If this molecular modification is disabled, the normal production of HIV is also prevented. Therefore, HIV protease inhibitors may act as antiviral agents against HIV.

Proteaza HIV-a je jedan od proizvoda translacije pol gena za strukturne proteine HIV-a. Ova retrovirusna proteaza specifično cijepa druge strukturne polipeptide na posebnim mjestima, tako da se oslobađaju novo aktivirani strukturni proteini i enzimi, čime se održava dostatna replikacija viriona. Prema tome, inhibiranje proteaze HIV-a moćnim spojevima moglo bi spriječiti uklapanje provirusa inficiranih T-limfocita tijekom rane faze životnog ciklusa HIV-1, kao i inhibirati virusnu proteolitičku preinaku tijekom kasnije faze njegovog životnog ciklusa. Pored toga, prednosti inhibitora proteaze bile bi lakša dostupnost, dulji život u virusu i manja otrovnost od lijekova koji se danas koriste, vjerojatno radi specifičnosti za retrovirusnu proteazu. HIV protease is one of the translation products of the pol gene for HIV structural proteins. This retroviral protease specifically cleaves other structural polypeptides at specific sites, so that newly activated structural proteins and enzymes are released, thereby maintaining sufficient virion replication. Therefore, inhibiting the HIV protease with potent compounds could prevent the provirus from infecting T-lymphocytes during the early phase of the HIV-1 life cycle, as well as inhibit viral proteolytic modification during the later phase of its life cycle. In addition, the advantages of protease inhibitors would be easier availability, longer life in the virus and less toxicity than the drugs used today, probably due to the specificity for the retroviral protease.

U ovom se izumu opisuje novi niz kemijskih spojeva koji mogu inhibirati i/ili blokirati aktivnost proteaze HIV-a, što dovodi do zaustavljanja proliferacije HIV-a, zatim se opisuju farmaceutski pripravci koji sadržavaju ove spojeve, kao i uporaba spojeva kao inhibitora proteaze HIV-a. This invention describes a new series of chemical compounds that can inhibit and/or block the activity of HIV protease, which leads to stopping the proliferation of HIV, then describes pharmaceutical preparations containing these compounds, as well as the use of the compounds as HIV protease inhibitors And.

Ovaj se izum odnosi na spojeve koji potpadaju pod formulu (9) navedenu dolje, kao i njihove farmaceutski prikladne soli, prolijekove i otopine koji inhibiraju proteazu koju kodira virus humane imunodeficijencije (HIV) tip 1 (HIV-1) ili tip-2 (HIV-2). Ovi spojevi su korisni pri liječenju infekcije HIV-om ili pri liječenju sindroma stečene imunodeficijencije (AIDS-a). Spojevi, njihove farmaceutski prikladne soli i farmaceutski pripravci ovog izuma mogu se upotrebljavati samostalno ili u kombinaciji s drugim protuvirusnim sredstvima, imunomodulatorima, antibioticima ili cjepivima. Spojevi ovog izuma također se mogu koristiti kao prolijekovi. Opisani su postupci liječenja AIDS-a , postupci liječenja HIV infekcije i postupci inhibiranja proteaze HIV-a. The present invention relates to compounds of formula (9) below, as well as pharmaceutically acceptable salts, prodrugs and solutions thereof, which inhibit the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1) or type-2 (HIV -2). These compounds are useful in the treatment of HIV infection or in the treatment of acquired immunodeficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts and the pharmaceutical preparations of the present invention can be used alone or in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. The compounds of this invention may also be used as prodrugs. AIDS treatment procedures, HIV infection treatment procedures and HIV protease inhibition procedures are described.

Spojevi ovog izuma imaju formulu (9): The compounds of this invention have the formula (9):

[image] [image]

pri čemu: whereby:

R i R’ su neovisno odabrani između H, supstituirane ili nesupstituirane alkil-OR1 skupine, cikloalkilne skupine supstituirane s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, heterocikličke skupine supstituirane s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, alkil-NR2R3 skupine ili alkil-S(X)(Y)R4 skupine, R and R' are independently selected from H, a substituted or unsubstituted alkyl-OR1 group, a cycloalkyl group substituted with a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, a heterocyclic group substituted with a (C1-C6)alkyl group or (C1-C6)alkyl-OH group, alkyl-NR2R3 group or alkyl-S(X)(Y)R4 group,

pri čemu whereby

R1 je H, supstituirana ili nesupstituirana alkilna skupina, ili acilna skupina; R 1 is H, a substituted or unsubstituted alkyl group, or an acyl group;

R2 i R3 su svaki neovisno odabrani između H, supstituirane ili nesupstituirane alkil, cikloalkil, heterocikl i arilne skupine, te acilne i sulfonilne skupine; R 2 and R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, heterocycle and aryl groups, and acyl and sulfonyl groups;

R4 je H, supstituirana ili nesupstituirana alkil, cikloalkil, heterocikl ili arilna skupina; a R 4 is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocycle or aryl group; And

X i Y su svaki neovisno odabrani između =O i ničega; X and Y are each independently selected from =O and nothing;

ili njihovi farmaceutski prikladne prolijekove, soli ili otopine. or their pharmaceutically acceptable prodrugs, salts or solutions.

Preporučljivo je da u spojevima formule 9 R bude H. Još je bolje da R bude H, a R’ bude cikloalkilna skupina odabrana između: It is recommended that in the compounds of formula 9 R is H. It is even better that R is H and R' is a cycloalkyl group selected from:

[image] [image]

Preporučljivo je da, u spojevima formule 9 u kojima je barem jedan od R i R’ alkil-OR1 skupina, R1 bude H. Naročito, kada je barem jedan od R i R’ alkil-OR1 skupina, alkil-OR1 treba biti odabran između -C(CH3)2CH2OH, -CH(CH3)CH2OH, -CH2CH2OH, -C(CH3)(CH2OH)2, -C(CH3)2-O-CH2-O-CH3, -C(CH3)2CH2-O-CH2-O-CH3 i -C(CH3)2CH2-O-acil, ili njihovog farmaceutski prikladnog prolijeka, soli ili otopine. It is recommended that, in compounds of formula 9 in which at least one of R and R' is an alkyl-OR1 group, R1 is H. In particular, when at least one of R and R' is an alkyl-OR1 group, the alkyl-OR1 should be selected from -C(CH3)2CH2OH, -CH(CH3)CH2OH, -CH2CH2OH, -C(CH3)(CH2OH)2, -C(CH3)2-O-CH2-O-CH3, -C(CH3)2CH2-O -CH2-O-CH3 and -C(CH3)2CH2-O-acyl, or a pharmaceutically acceptable prodrug, salt or solution thereof.

Preporučljivo je da, kada je barem jedan od R i R’ cikloalkilna skupina supsituirana s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, cikloalkilna skupina bude odabrana između: It is recommended that, when at least one of R and R' is a cycloalkyl group substituted with a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, the cycloalkyl group is selected from:

[image] [image]

Preporučljivo je da, kada je barem jedan od R i R’ heterociklička skupina supstituirana s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, heterociklička skupina bude odabrana između: It is recommended that, when at least one of R and R' is a heterocyclic group substituted with a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, the heterocyclic group is selected from:

[image] [image]

pri čemu R3 može biti H, supstituirana ili nesupstituirana alkilna, cikloalkilna, heterociklička ili arilna skupina, ili acilna ili sulfonilna skupina. wherein R 3 can be H, a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic or aryl group, or an acyl or sulfonyl group.

Preporučeni spoj formule (9) [3S-[2(2S*,3S*),3 alfa, 4a beta, 8a beta]]-N-(1,1-dimetil-2 hidroksietil) dekahidro- 2-[2-hidroksi-3-[(3-hidroksi-2-metilbenzoil)amino]-4-(feniltio)butil]-3-izokvinolinkarboksamid Recommended compound of formula (9) [3S-[2(2S*,3S*),3 alpha, 4a beta, 8a beta]]-N-(1,1-dimethyl-2 hydroxyethyl) decahydro- 2-[2-hydroxy -3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide

[image] [image]

i njegove farmaceutski prikladne soli, kao i prolijekovi - analozi. Preporučeni prolijekovi mogu se dobiti zamjenom vodika jedne od alkoholnih skupina acilnom skupinom, još bolje aminokiselinskom acilnom skupinom. and its pharmaceutically acceptable salts, as well as prodrugs - analogs. The recommended prodrugs can be obtained by replacing the hydrogen of one of the alcohol groups with an acyl group, even better with an amino acid acyl group.

Ovaj izum također opisuje farmaceutske pripravke koji sadrže učinkovitu količinu spoja formule (9) ili njihove farmaceutski prikladne soli, u kombinaciji s farmaceutski prikladnim nosačem, kao što je sredstvo za razrjeđivanje ili ekscipijens. The present invention also describes pharmaceutical compositions comprising an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, such as a diluent or excipient.

Ovaj izum također opisuje postupak liječenja AIDS-a, koji obuhvaća primjenu na domaćina ili bolesnika, kao što je primat, učinkovite količine spoja ovog izuma. The present invention also describes a method of treating AIDS, which comprises administering to a host or patient, such as a primate, an effective amount of a compound of the present invention.

Ovaj izum također opisuje postupak inhibiranja replikacije HIV-a, koji obuhvaća primjenu na stanicu zaraženu HIV-om, stanicu podložnu infekciji HIV-om, u domaćina ili bolesnika, kao što je primat, učinkovite količine spoja ovog izuma. The present invention also describes a method of inhibiting HIV replication, which comprises administering to an HIV-infected cell, a cell susceptible to HIV infection, in a host or patient, such as a primate, an effective amount of a compound of the present invention.

Detaljan opis izuma Detailed description of the invention

Ovaj izum opisuje nove spojeve opisane formulom (9), kao što je ranije opisano, koji su korisni za liječenje infekcije HIV-om i/ili AIDS-a. This invention describes novel compounds described by formula (9), as previously described, which are useful for the treatment of HIV infection and/or AIDS.

Prijavitelji su kao reference obuhvatili SAD patent br. 5484926, SAD patentnu prijavu br. 08/708411 i 08/708607, kao i japansku patentnu prijavu br. JP 95-248183 i JP 95-248184, uz napomenu da su definicije preporučenih oblika, izraza, varijabli, oznaka i sličnog korištenog u svakoj pojedinoj prijavi primjenjive samo na odgovarajuće otkriće iz te prijave. The applicants included US patent no. 5484926, US patent application no. 08/708411 and 08/708607, as well as Japanese patent application no. JP 95-248183 and JP 95-248184, noting that the definitions of recommended forms, expressions, variables, symbols and the like used in each individual application are applicable only to the corresponding disclosure from that application.

Kako je svaka od gore nabrojenih prijava koje su uključene kao reference pripravljena posebno, izvorne prijave mogu u pojedinim slučajevima koristiti jednak izraz, oznaku ili varijablu za označavanje različitog pojma. Na primjer, varijabla “X” se koristi u svakoj prijavi, ali svaka prijava ima vlastitu definiciju supstituenta ili dijela koji ta varijabla predstavlja. Upućenima u struku bit će jasno da su izrazi, oznake i varijable u svakoj od prijava koje su uključene kao reference ograničeni samo na otkrića iz te prijave i mogu biti zamijenjeni drugim prikladnim izrazima, oznakama, varijablama ili sličnim koje će predstavljati pojedine supstituente ili dijelove. Očekuje se da će upućeni u struku uvidjeti da se bilo koji pogodni niz izraza, oznaka i varijabli može koristiti u svrhu generičkog ili specifičnijeg predstavljanja građe sadržane u ovoj prijavi, uključujući izraze, oznake, varijable i slično, koji su općenito primjenjivi na otkrića sadržana u gore navedenim prijavama, kao i slijedećeg otkrića. As each of the above applications incorporated by reference is prepared separately, the original applications may in some cases use the same term, label or variable to denote a different term. For example, the variable “X” is used in every application, but each application has its own definition of the substituent or part that the variable represents. Those skilled in the art will appreciate that the terms, labels and variables in each of the applications incorporated by reference are limited only to the disclosures of that application and may be replaced by other suitable terms, labels, variables or the like to represent individual substituents or moieties. It is expected that those skilled in the art will appreciate that any suitable series of terms, labels and variables may be used for the purpose of generically or more specifically representing the material contained in this application, including terms, labels, variables and the like, which are generally applicable to the disclosures contained in the above applications, as well as the following discovery.

Spojevi formule (9) mogu biti prolijekovi, koji mogu poslužiti poboljšanju farmaceutskih svojstava spojeva, kao što su farmakokinetička svojstva, na primjer bolja bioraspoloživost ili topljivost. Pripravci prolijekova mogu se priređivati standardnim postupcima koji su poznati upućenima u struku. Preporučeni prolijek može se dobiti aciliranjem ili alkiliranjem početnog alkohola pri čemu je R ili R’ CH(CH3)2CH2OH. Compounds of formula (9) can be prodrugs, which can serve to improve the pharmaceutical properties of the compounds, such as pharmacokinetic properties, for example better bioavailability or solubility. Prodrug preparations can be prepared by standard procedures known to those skilled in the art. The recommended prodrug can be obtained by acylation or alkylation of the starting alcohol where R or R' is CH(CH3)2CH2OH.

Sve spomenute temperature izražene su u stupnjevima Celsiusa (°C). Sve ovdje korištene mjerne jedinice su jedinice težine, osim tekućina koja je mjerena u volumnim jedinicama. All mentioned temperatures are expressed in degrees Celsius (°C). All units of measurement used here are units of weight, except for liquids which are measured in units of volume.

Izraz “alkil”, u značenju u kojem se ovdje primjenjuje, odnosi se na nerazgranate ili razgranate lančane skupine koje preporučljivo imaju jedan do osam, bolje jedan do šest, a najbolje od jedan do četiri atoma ugljika. Izraz “C1-C6 alkil” predstavlja nerazgranati ili razgranati alkilni lanac koji ima od jedan do šest atoma ugljika. Primjeri C1-C6 alkilnih skupina uključuju metil, etil, n-propil, izopropil, butil, izobutil, sek-butil, t-butil, pentil, neo-pentil, heksil, izoheksil i slični. Izraz “C1-C6 alkil” uključuje i izraz “C1-C4 alkil”. The term "alkyl", as used herein, refers to straight or branched chain groups preferably having one to eight, preferably one to six, and preferably one to four carbon atoms. The term "C1-C6 alkyl" represents a straight or branched alkyl chain having from one to six carbon atoms. Examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like. The term "C1-C6 alkyl" includes the term "C1-C4 alkyl".

Izraz “cikloalkil” predstavlja zasićeni ili djelomično zasićeni, mono- ili polikarbociklički prsten, koji preporučljivo ima 5-14 atoma ugljika u prstenu. Primjeri cikloalkila uključuju monocikličke prstene koji imaju 3-7, još bolje 3-6 atoma ugljika, kao što su ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil i slični. Primjer cikloalkila je C5-C7 cikloalkil, koji ima zasićenu ugljikovodičnu prstenastu strukturu koja sadrži od pet do sedam atoma ugljika. The term "cycloalkyl" represents a saturated or partially saturated, mono- or polycarbocyclic ring, which preferably has 5-14 carbon atoms in the ring. Examples of cycloalkyl include monocyclic rings having 3-7, more preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. An example of cycloalkyl is C5-C7 cycloalkyl, which has a saturated hydrocarbon ring structure containing from five to seven carbon atoms.

Izraz “alkoksil” predstavlja -O-alkil. Primjer alkoksil je C1-C6 alkoksil, koji prestavlja nerazgranati ili razgranati alkilni lanac koji ima od jedan do šest atoma ugljika vezanih s atomom kisika. Primjeri C1-C6 alkoksilnih skupina uključuju metoksil, etoksil, propoksil, izopropoksil, butoksil, sek-butoksil, t-butoksil, pentoksil, heksoksil i slične. C1-C6 alkoksil uključuje i C1-C4 alkoksil. The term "alkyl" represents -O-alkyl. An example of alkyl is C1-C6 alkyl, which represents an unbranched or branched alkyl chain having from one to six carbon atoms bonded to an oxygen atom. Examples of C1-C6 alkoxy groups include methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sec-butoxyl, t-butoxyl, pentoxyl, hexoxyl and the like. C1-C6 alkoxyl also includes C1-C4 alkoxyl.

Izraz “aril”, u značenju u kojem se ovdje koristi, odnosi se na karbociklički ili heterociklički, aromatski, 5-14-eročlani monociklički ili policiklički prsten. Primjeri arila uključuju fenil, naftil, antril, fenantril, tienil, pirolil, imidazolil, pirazolil, furil, izotiazolil, furazanil, izoksazolil, tiazolil, piridil, pirazinil, pirimidinil, piridazinil, triazinil, benzo[b]tienil, nafto[2,3-b]tiantrenil, izobenzofuranil, kromenil, ksantenil, fenoksatienil, indolizinil, izoindolil, indolil, indazolil, purinil, izokvinolil, kvinolil, ftalazinil, naftiridinil, kvinoksialinil, kvinzolinil, benzotiazolil, benzimidazolil, tetrahidrokvinolinil, kinolinil, pteridinil, karbazolil, beta-karbolinil, fenantridinil, akridinil, perimidinil, fenantrolinil, fenazinil, izotiazolil, fenotiazinil i fenoksazinil. The term "aryl", as used herein, refers to a carbocyclic or heterocyclic, aromatic, 5-14 membered monocyclic or polycyclic ring. Examples of aryl include phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3 -b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, quinolinyl, pteridinyl, carbazolyl, beta-carbolinyl , phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl and phenoxazinyl.

Izraz “ariloksil” predstavlja -O-aril. The term "aryloxyl" represents -O-aryl.

Izraz “hidrolizirajuća skupina” je skupina koja, kada je vezana na kisik, tvori ester, koji može biti hidroliziran in vivo do hidroksilne skupine. Primjeri hidrolizirajuće skupine, koje po želji mogu biti supstituirane, uključuju acilnu funkcijsku skupinu, sulfonatnu funkcijsku skupinu i fosfatnu funkcijsku skupinu. Na primjer, takve hidrolizirajuće skupine uključuju blokirane ili neblokirane aminokiselinske ostatke, hemisukcinatni ostatak i nikotinatni ostatak. The term "hydrolyzing group" is a group that, when attached to oxygen, forms an ester, which can be hydrolyzed in vivo to a hydroxyl group. Examples of hydrolyzable groups, which may optionally be substituted, include an acyl functional group, a sulfonate functional group, and a phosphate functional group. For example, such hydrolyzing groups include blocked or unblocked amino acid residues, a hemisuccinate residue, and a nicotinate residue.

Izraz “halogen” predstavlja klor, fluor, brom ili jod. Izraz “halo” predstavlja kloro, fluoro, bromo ili jodo. The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.

Izraz “karbocikl” predstavlja aromatski ili zasićeni ili djelomično zasićeni 5- do 14-eročlani monociklički ili policiklički prsten, kao što je 5- do 7-eročlani monociklički ili 7- do 10-eročlani biciklički prsten, s time da su svi članovi prstena atomi ugljika. The term "carbocycle" represents an aromatic or saturated or partially saturated 5- to 14-membered monocyclic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, with all members of the ring being atoms carbon.

Izraz “heterocikl” predstavlja aromatski ili zasićeni ili djelomično zasićeni, 5- do 14-eročlani, monociklički ili policiklički prsten, kao što je 5- do 7-eročlani monociklički ili 7- do 10-eročlani biciklički prsten, koji ima jedan do tri heteroatoma odabranih između dušika, kisika i sumpora, pri čemu svaki heteroatom dušika i sumpora može po želji biti oksidiran, a svaki dušik može biti kvaterniziran. Heterociklički prsten može biti pričvršćen na bilo koji pogodni heteroatom ili na ugljikov atom. Primjeri takvih heterocikla uključuju dekahidroizokvinolinil, oktahidro-tieno [3,2-c] piridinil, piperidinil, piperazinil, azepinil, pirolil, pirolidinil, pirazolil, pirazolidinil, imidazolil, izobenzofuranil, furazanil, imidazolinil, imidazolidinil, piridil, pirazinil, pirimidinil, piridazinil, oksazolil, oksazolidinil, izoksazolil, tiantrenil, triazinil, izoksazolidinil, morfolinil, tiazolil, tiazolidinil, izotiazolil, kvinuklidinil, izotiazolidinil, indolil, kvinolinil, kromenil, ksantenil, izokvinolinil, benzimidazolil, tiadiazolil, benzopiranil, benzotiazolil, benzoazolil, furil, tetrahidrofuril, tetrahidropiranil, tienil, benzotienil, benzo[b]tienil, nafto[2,3-b]tienil, tiamorfolinil, tiamorfolinilsulfoksid, tia morfolinil sulfon, oksadiazolil, triazolil, tetrahidrokvinolinil, tetrahidrizokvinolinil, fenoksatienil, indolizinil, izoindolil, indazolil, purinil, izokvinolil, kvinolil, ftalazinil, naftiridinil, kvinoksialinil, kvinzolinil, tetrahidrokvinolinil, kinolinil, pteridinil, karbazolil, beta-karbolinil, fenantridinil, akridinil, perimidinil, fenantrolinil, fenazinil, izotiazolil, fenotiazinil i fenoksazinil. The term "heterocycle" represents an aromatic or saturated or partially saturated, 5- to 14-membered, monocyclic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, having one to three heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each heteroatom of nitrogen and sulfur can optionally be oxidized, and each nitrogen can be quaternized. The heterocyclic ring can be attached to any suitable heteroatom or carbon atom. Examples of such heterocycles include decahydroisoquinolinyl, octahydro-thieno[3,2-c] pyridinyl, piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, isobenzofuranyl, furazanyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thianthrenyl, triazinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, chromenyl, xanthenyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thia morpholinyl sulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrizoquinolinyl, phenoxathienyl, indolizinyl, isoindolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, tetrahydroquinolinyl, quinolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl and phenoxazinyl.

Izraz “tioeter” uključuje S-aril, kao što je feniltio i naftiltio; S-heterocikl gdje je heterocikl zasićen ili djelomično zasićen; S-(C5-C7)-cikloalkil; i S-alkil, kao što je C1-C6 alkiltio. U tioeteru, -aril, -heterocikl, -cikloalkil i -alkil mogu po želji biti supstituirani. Primjer tioetera je “C1-C6 alkiltio”, a predstavlja nerazgranati ili razgranati alkilni lanac koji ima od jedan do šest ugljikovih atoma vezanih na sumporni atom. Primjeri C1-C6 alkiltio skupina uključuju metiltio, etiltio, propiltio, izopropiltio, butiltio, sek-butiltio, t-butiltio, pentiltio, heksiltio i slične. The term “thioether” includes S-aryl, such as phenylthio and naphthylthio; S-heterocycle wherein the heterocycle is saturated or partially saturated; S-(C5-C7)-cycloalkyl; and S-alkyl, such as C1-C6 alkylthio. In the thioether, -aryl, -heterocycle, -cycloalkyl and -alkyl may optionally be substituted. An example of a thioether is "C1-C6 alkylthio", which represents an unbranched or branched alkyl chain that has from one to six carbon atoms attached to a sulfur atom. Examples of C1-C6 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, t-butylthio, pentylthio, hexylthio and the like.

Izraz “merkapto” predstavlja -SH. The term "mercapto" represents -SH.

Izraz “amino” predstavlja -NL1L2, pri čemu su L1 i L2 preporučljivo neovisno odabrani između kisika, karbocikla, heterocikla, alkila, sulfonila i vodika; ili NC(O)L3, gdje je L3 preporučljivo alkil, alkoksil, vodik ili -NL1L2. Aril, alkil i alkoksil skupine mogu po želji biti supstituirane. Primjer za amino je C1-C4 alkilamino, koji predstavlja nerazgranati ili razgranati alkilni lanac koji ima od jedan do četiri ugljikova atoma vezana na amino skupinu. Primjeri C1-C4 alkilamino skupina uključuju metilamino, etilamino, propilamino, izopropilamino, butilamino, sek-butilamino i slični. Drugi primjer za amino je di(C1-C4) alkilamino, koji predstavlja dva nerazgranata ili razgranata alkilna lanca, od kojih svaki ima jedan do četiri ugljikova atoma vezana na zajedničku amino skupinu. Primjeri di(C1-C4) alkilamino skupina uključuju dimetilamino, etilmetilamino, metilpropilamino, etilizopropilamino, butilmetilamino, sek-butiletilamino i slične. Primjer za amino je C1-C4 alkilsulfonilamino, koji ima nerazgranati ili razgranati alkilni lanac s jednim do četiri ugljikova atoma vezana na sulfonilamino dio. Primjeri C1-C4 alkilsulfonilamino skupina uključuju metilsulfonilamino, etilsulfonilamino, propil sulfonilamino, izopropilsulfonilamino, butilsulfonilamino, sek-butilsulfonilamino, t-butilsulfonilamino i slični. The term "amino" represents -NL1L2, wherein L1 and L2 are preferably independently selected from oxygen, carbocycle, heterocycle, alkyl, sulfonyl and hydrogen; or NC(O)L 3 , where L 3 is preferably alkyl, alkoxy, hydrogen or -NL 1 L 2 . Aryl, alkyl and alkoxyl groups can be optionally substituted. An example of amino is C1-C4 alkylamino, which represents an unbranched or branched alkyl chain having from one to four carbon atoms attached to the amino group. Examples of C1-C4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like. Another example for amino is di(C1-C4)alkylamino, which represents two unbranched or branched alkyl chains, each having one to four carbon atoms attached to a common amino group. Examples of di(C 1 -C 4 ) alkylamino groups include dimethylamino, ethylmethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino and the like. An example of amino is C1-C4 alkylsulfonylamino, which has a straight or branched alkyl chain with one to four carbon atoms attached to the sulfonylamino moiety. Examples of C1-C4 alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, sec-butylsulfonylamino, t-butylsulfonylamino and the like.

Izraz “acil” predstavlja L6C(O)L4, gdje je L6 jednostruka veza, -O ili -N, a L4 je preporučljivo alkil, amino, hidroksil, alkoksil ili hidrogen. Alkil i alkoksil skupine mogu po želji biti supstituirane. Primjer za acil je C1-C4 alkoksikarbonil, koji je nerazgranati ili razgranati alkoksilni lanac koji ima jedan do četiri ugljikova atoma vezana na karbonilni dio. Primjeri za C1-C4 alkoksikarbonilnih skupina uključuju metoksikarbonil, etoksikarbonil, propoksikarbonil, izopropoksikarbonil, butoksikarbonil i slične. Drugi primjer za acil uključuje karboksi, gdje je L6 jednostruka veza, a L4 je alkoksil, vodik ili hidroksil. Daljnji primjer za acil je N-(C1-C4)alkilkarbamoil (L6 je jednostruka veza, a L4 je amino), koji je nerazgranati ili razgranati alkilni lanac, a sadrži jedan do četiri ugljikova atoma vezana za dušikov atom ili karbamoilni dio. Primjeri N-(C1-C4)alkilkarbamoilnih skupina uključuju N-metilkarbamoil, N-etilkarbamoil, N-propilkarbamoil, N-izo propil karbamoil, N-butilkarbamoil, N-t-butilkarbamoil i slične. Slijedeći primjer za acil je N,N-di(C1-C4)alkilkarbamoil, koji ima dva nerazgranata ili razgranata alkilna lanca, a svaki od njih ima jedan do četiri ugljikova atoma vezana za dušikov atom karbamoilnog dijela. Primjeri za N,N-di(C1-C4)alkilkarbamoilne skupine uključuju N,N-dimetilkarbamoil, N,N- etilmetilkarbamoil, N,N-metilpropilkarbamoil, N,N-etilizopropilkarbamoil, N,N-butilmetilkarbamoil, N,N-sek- butil etilkarbamoil i slični. The term "acyl" represents L 6 C(O) L 4 , where L 6 is a single bond, -O or -N, and L 4 is preferably alkyl, amino, hydroxyl, alkoxy or hydrogen. Alkyl and alkoxyl groups can be optionally substituted. An example of acyl is C1-C4 alkoxycarbonyl, which is an unbranched or branched alkyl chain having one to four carbon atoms attached to the carbonyl moiety. Examples of C1-C4 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like. Another example for acyl includes carboxy, where L 6 is a single bond and L 4 is alkoxy, hydrogen or hydroxyl. A further example of acyl is N-(C1-C4)alkylcarbamoyl (L6 is a single bond and L4 is amino), which is an unbranched or branched alkyl chain containing one to four carbon atoms attached to a nitrogen atom or carbamoyl moiety. Examples of N-(C1-C4)alkylcarbamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-t-butylcarbamoyl and the like. Another example for acyl is N,N-di(C1-C4)alkylcarbamoyl, which has two straight or branched alkyl chains, each having one to four carbon atoms attached to the nitrogen atom of the carbamoyl moiety. Examples of N,N-di(C1-C4)alkylcarbamoyl groups include N,N-dimethylcarbamoyl, N,N-ethylmethylcarbamoyl, N,N-methylpropylcarbamoyl, N,N-ethylisopropylcarbamoyl, N,N-butylmethylcarbamoyl, N,N-sec - butyl ethylcarbamoyl and the like.

Izraz “sulfinil” predstavlja -SO-L5, gdje je L5 preporučljivo alkil, amino, aril, cikloalkil ili heterocikl. Alkil, aril, cikloalkil i heterocikl mogu po želji biti supstituirani. The term "sulfinyl" represents -SO-L5, where L5 is preferably alkyl, amino, aryl, cycloalkyl or heterocycle. Alkyl, aryl, cycloalkyl and heterocycle may optionally be substituted.

Izraz “sulfonil” predstavlja -SO2-L5, pri čemu je L5 preporučljivo alkil, aril, cikloalkil, heterocikl ili amino. Alkil, aril, cikloalkil i heterocikl mogu po želji biti supstituirani. Primjer za sulfonil je C1-C4 alkilsulfonil, koji je nerazgranati ili razgranati alkilni lanac koji ima jedan do četiri ugljikova atoma vezana na sulfonilni dio. Primjeri C1-C4 alkilsulfonilnih skupina uključuju metilsulfonil, etilsulfonil, propilsulfonil, izopropilsulfonil, butilsulfonil, sek-butilsulfonil, t-butilsulfonil i slične. The term "sulfonyl" represents -SO2-L5, wherein L5 is preferably alkyl, aryl, cycloalkyl, heterocycle or amino. Alkyl, aryl, cycloalkyl and heterocycle may optionally be substituted. An example of sulfonyl is C1-C4 alkylsulfonyl, which is a straight or branched alkyl chain having one to four carbon atoms attached to the sulfonyl moiety. Examples of C1-C4 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl and the like.

Kao što je gore navedeno, mnoge su skupine po želji supstituirane. U stvari, ako nije drukčije naznačeno, sve skupine definirane izrazima iz ove prijave mogu biti supstituirane ili nesupstituirane. Na primjer, kada se koristi izraz “alkil” on uključuje i supstituirane i nesupstituirane alkile ukoliko jedni ili drugi nisu izrijekom isključeni. Primjeri supstituenata za alkil i aril uključuju merkapto, tioeter, nitro (NO2), amino, ariloksil, halogen, hidroksil, alkoksil i acil, kao i aril, cikloalkil i zasićene i djelomično zasićene heterocikle. Primjeri supstituenata za heterocikl i cikloalkil uključuju gore nabrojene primjere za alkil i aril, kao i za aril i alkil. As noted above, many groups are optionally substituted. In fact, unless otherwise indicated, all groups defined by the terms of this application may be substituted or unsubstituted. For example, when the term "alkyl" is used it includes both substituted and unsubstituted alkyl unless one or the other is expressly excluded. Examples of alkyl and aryl substituents include mercapto, thioether, nitro (NO 2 ), amino, aryloxy, halogen, hydroxyl, alkoxy, and acyl, as well as aryl, cycloalkyl, and saturated and partially saturated heterocycles. Examples of substituents for heterocycle and cycloalkyl include the examples listed above for alkyl and aryl, as well as for aryl and alkyl.

Primjeri za supstituirane arile uključuju fenilni ili naftilni prsten supstituiran s jednim ili više supstituenata, preporučljivo jedan do tri, neovisno odabranih između halo, hidroksi, morfolino(C1-C4)alkoksikarbonil, piridil(C1-C4)alkoksikarbonil, halo(C1-C4)alkil, C1-C4 alkil, C1-C4 alkoksi, karboksi, C1-C4 alkoksikarbonil, karbamoil, N-(C1-C4)alkilkarbamoil, amino, C1-C4 alkilamino, di(C1-C4)alkilamino ili skupina formule -(CH2)a-R7, pri čemu a može biti 1, 2, 3 ili 4; R7 je hidroksi, C1-C4 alkoksi, karboksi, C1-C4 alkoksikarbonil, amino, karbamoil, C1-C4 alkilamino ili di(C1-C4)alkilamino. Examples of substituted aryls include a phenyl or naphthyl ring substituted with one or more substituents, preferably one to three, independently selected from halo, hydroxy, morpholino(C1-C4) alkoxycarbonyl, pyridyl(C1-C4) alkoxycarbonyl, halo(C1-C4) alkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, N-(C1-C4)alkylcarbamoyl, amino, C1-C4 alkylamino, di(C1-C4)alkylamino or a group of the formula -(CH2 )a-R7, where a can be 1, 2, 3 or 4; R 7 is hydroxy, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonyl, amino, carbamoyl, C 1 -C 4 alkylamino or di(C 1 -C 4 )alkylamino.

Drugi supstituirani alkil je halo(C1-C4)alkil, koji predstavlja nerazgranati ili razgranati alkilni lanac koji ima jedan do četiri ugljikova atoma na koje je vezano 1-3 halogena atoma. Primjeri za halo(C1-C4)alkilne skupine uključuju klorometil, 2-bromoetil, 1-kloroizopropil, 3-fluoropropil, 2,3-dibromobutil, 3-kloroizobutil, jodo-t-butil, trifluorometil i slične. Another substituted alkyl is halo(C1-C4)alkyl, which represents an unbranched or branched alkyl chain having one to four carbon atoms to which 1-3 halogen atoms are attached. Examples of halo(C1-C4)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.

Drugi supstituirani alkil je hidroksi(C1-C4)alkil, koji predstavlja nerazgranati ili razgranati alkilni lanac koji ima jedan do četiri ugljikova atoma s hidroksi skupinom vezanom na nj. Primjeri za hidroksi(C1-C4)alkilne skupine uključuju hidroksimetil, 2-hidroksietil, 3-hidroksipropil, 2-hidroksiizopropil, 4-hidroksibutil i slične. Another substituted alkyl is hydroxy(C1-C4)alkyl, which is an unbranched or branched alkyl chain having one to four carbon atoms with a hydroxy group attached to it. Examples of hydroxy(C1-C4)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl and the like.

Slijedeći supstituirani alkil je C1-C4 alkiltio(C1-C4)alkil, koji je nerazgranata ili razgranata C1-C4 alkilna skupina na koju je vezana C1-C4 alkiltio skupina. Primjeri za C1-C4 alkiltio(C1-C4)alkilne skupine uključuju metiltiometil, etiltiometil, propiltiopropil, sek-butiltiometil i slične. The next substituted alkyl is C1-C4 alkylthio(C1-C4)alkyl, which is a straight or branched C1-C4 alkyl group to which a C1-C4 alkylthio group is attached. Examples of C1-C4 alkylthio(C1-C4)alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl and the like.

Slijedeći primjer za supstituirani alkil je heterocikl(C1-C4)alkil, koji je nerazgranati ili razgranati alkilni lanac koji ima jedan do četiri ugljikova atoma s heterociklom vezanim na nj. Primjeri za heterociklo(C1-C4)alkile uključuju pirolilmetil, kvinolinilmetil, 1-indoliletil, 2-furiletil, 3-tien-2-ilpropil, 1-imidazolilizopropil, 4-tiazolilbutil i slične. Another example of a substituted alkyl is heterocycle(C1-C4)alkyl, which is an unbranched or branched alkyl chain having one to four carbon atoms with a heterocycle attached to it. Examples of heterocyclo(C1-C4)alkyl include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl and the like.

Slijedeći primjer za supstituirani alkil je aril(C1-C4)alkil, koji je nerazgranati ili razgranati alkilni lanac koji ima jedan do četiri ugljikova atoma s arilnom skupinom vezanom na nj. Primjeri za aril(C1-C4)alkilne skupine uključuju fenilmetil, 2-feniletil, 3-naftil-propil, 1-naftilizopropil, 4-fenilbutil i slične. Another example of a substituted alkyl is aryl(C1-C4)alkyl, which is a straight or branched alkyl chain having one to four carbon atoms with an aryl group attached to it. Examples of aryl(C 1 -C 4 )alkyl groups include phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.

Heterocikl može, na primjer, biti supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana između halo, halo(C1-C4)alkil, C1-C4 alkil, C1-C4 alkoksi, karboksi, C1-C4 alkoksikarbonil, karbamoil, N-(C1-C4)alkilkarbamoil, amino, C1-C4 alkilamino, di(C1-C4)alkilamino ili skupine čija je struktura -(CH2)a-R7, pri čemu a može biti 1, 2, 3 ili 4, a R7 je hidroksi, C1-C4 alkoksi, karboksi, C1-C4 alkoksikarbonil, amino, karbamoil, C1-C4 alkilamino ili di(C1-C4)alkilamino. The heterocycle may, for example, be substituted with 1, 2 or 3 substituents independently selected from halo, halo(C1-C4)alkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, N-( C1-C4)alkylcarbamoyl, amino, C1-C4 alkylamino, di(C1-C4)alkylamino or groups whose structure is -(CH2)a-R7, where a can be 1, 2, 3 or 4, and R7 is hydroxy , C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino or di(C1-C4)alkylamino.

Primjeri supstituiranih heterocikla uključuju 3-N-t-butil karboksamid dekahidroizokvinolinil, 6-N-t-butil karboksamid oktahidro-tieno[3,2-c]piridinil, 3-metilimidazolil, 3-metoksipiridil, 4-klorokvinolinil, 4-aminotiazolil, 8-metilkvinolinil, 6-klorokvinoksalinil, 3-etilpiridil, 6-metoksibenzimidazolil, 4-hidroksifuril, 4-metilizokvinolinil, 6,8-dibromokvinolinil, 2-metil-1,2,3,4-tetrahidroizokvinolinil, N-metil-kvinolin-2-il, 2-t-butoksikarbonil-1,2,3,4-izokvinolin-7-il i slične. Examples of substituted heterocycles include 3-N-t-butyl carboxamide decahydroisoquinolinyl, 6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl, 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.

Primjeri heterocikličkih sustava prstenova prikazanih kao A i B uključuju (1) 5-eročlane monocikličke prstenske skupine poput tienil, pirolil, imidazolil, pirazolil, furil, izotiazolil, furazanil, izoksazolil, tiazolil i drugih, (2) 6-eročlane monocikličke skupine poput piridil, pirazinil, pirimidinil, piridazinil, triazinil i drugih; (3) policikličke heterocikličke prstenske skupine poput dekahidroizokvinolinil, oktahidro-tieno [3,2-c] piridinil, benzo[b]tienil, nafto[2,3-b]tiantrenil, izobenzofuranil, kromenil, ksantenil i njihovih potpuno ili djelomično zasićenih analoga. Examples of heterocyclic ring systems shown as A and B include (1) 5-membered monocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and others, (2) 6-membered monocyclic groups such as pyridyl , pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and others; (3) polycyclic heterocyclic ring groups such as decahydroisoquinolinyl, octahydro-thieno [3,2-c] pyridinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl and their fully or partially saturated analogues .

Cikloalkil može po želji biti supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana između halo, halo(C1-C4)alkil, C1-C4 alkil, C1-C4 alkoksi, karboksi, C1-C4 alkoksikarbonil, karbamoil, N-(C1-C4)alkilkarbamoil, amino, C1-C4 alkilamino, di(C1-C4)alkilamino ili skupine čija je struktura -(CH3)a-R7, pri čemu a može biti 1, 2, 3 ili 4, R7 je hidroksi, C1-C4 alkoksi, karboksi, C1-C4 alkoksikarbonil, amino, karbamoil, C1-C4 alkilamino ili di(C1-C4)alkilamino. Primjeri supstituiranih cikloalkilnih skupina uključuju 3-metilciklopentil, 4-etoksicikloheksil, 5-karboksiciklo-heptil, 6-klorocikloheksil i slične. Cycloalkyl can optionally be substituted with 1, 2 or 3 substituents independently selected from halo, halo(C1-C4)alkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, carbamoyl, N-(C1- C4)alkylcarbamoyl, amino, C1-C4 alkylamino, di(C1-C4)alkylamino or groups whose structure is -(CH3)a-R7, where a can be 1, 2, 3 or 4, R7 is hydroxy, C1- C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino or di(C1-C4)alkylamino. Examples of substituted cycloalkyl groups include 3-methylcyclopentyl, 4-ethoxycyclohexyl, 5-carboxycycloheptyl, 6-chlorocyclohexyl and the like.

Primjeri supstituiranih hidrolizirajućih skupina uključuju N-benzil glicil, N-Cbz-L-valil i N-metil nikotinat. Examples of substituted hydrolyzing groups include N-benzyl glycyl, N-Cbz-L-valyl and N-methyl nicotinate.

Spojevi ovog izuma imaju barem pet nesimetričnih središta koja su na slijedećoj formuli (9) označena zvjezdicom: The compounds of this invention have at least five asymmetric centers which are marked with an asterisk in the following formula (9):

[image] [image]

Posljedično postojanju ovih nesimetričnih središta, spojevi ovog izuma mogu se pojaviti u bilo kojem od mogućih stereoizomerijskih oblika, a mogu se koristiti u smjesama stereoizomera, koji mogu biti optički aktivni ili racemični, ili se mogu koristiti posebno, kao uglavnom čisti stereoizomeri, tj. najmanje 95%-tne čistoće. Svi nesimetrični oblici, pojedini stereoizomeri kao i njihove kombinacije pripadaju području ovog izuma. As a consequence of the existence of these asymmetric centers, the compounds of this invention can occur in any of the possible stereoisomeric forms, and can be used in mixtures of stereoisomers, which can be optically active or racemic, or can be used separately, as mainly pure stereoisomers, i.e. at least 95% pure. All unsymmetrical forms, individual stereoisomers as well as their combinations belong to the scope of this invention.

Pojedini stereoizomeri mogu se pripraviti od svojih odgovarajućih prethodnika, pomoću ranije opisanih postupaka, otapanjem racemičkih smjesa ili razdvajanjem dijastereomera. Razlučivanje se može provesti u nazočnosti sredstva za otapanje, kromatografiranjem ili opetovanim kristaliziranjem, ili pak nekom kombinacijom ovih tehnika koje su u struci poznate. Pojedinosti vezane uz otapanje mogu se naći u Jacques i sur., Enantiomers, Racemates, and Resolutions, John Wiley & Sons 1981. Individual stereoisomers can be prepared from their respective precursors, using previously described procedures, by dissolving racemic mixtures or by separating diastereomers. The resolution can be carried out in the presence of a solvent, by chromatography or repeated crystallization, or by some combination of these techniques known in the art. Details regarding dissolution can be found in Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley & Sons 1981.

Preporučuje se da spojevi ovog izuma budu uglavnom čisti, tj. čistoće veće od 50%. Bolje je da spojevi budu čistoće najmanje 75%. Još je bolje da su spojevi više od 90%-tne čistoće. Još je bolje da su spojevi najmanje 95% čisti, bolje najmanje 97%, a najbolje 99%. It is recommended that the compounds of this invention be substantially pure, i.e. greater than 50% pure. It is better for compounds to be at least 75% pure. It is even better if the compounds are more than 90% pure. It is even better that the compounds are at least 95% pure, better at least 97%, and best 99%.

Kao što je ranije spomenuto, izum uključuje farmaceutski prikladne soli spojeva određenih formulom (9). Spoj ovog izuma može imati dovoljno kiselu, dovoljno bazičnu ili obje ove funkcijske skupine, te prema tome reagirati s bilo kojom od brojnih neorganskih ili organskih baza, odnosno neorganskih ili organskih kiselina, čime se dobiju farmaceutski prikladne soli. As mentioned earlier, the invention includes pharmaceutically acceptable salts of the compounds of formula (9). The compound of this invention can have sufficiently acidic, sufficiently basic or both of these functional groups, and accordingly react with any of a number of inorganic or organic bases, i.e. inorganic or organic acids, thereby obtaining pharmaceutically suitable salts.

Izraz “farmaceutski prikladna sol”, u značenju u kojem se ovdje koristi, odnosi se na soli spojeva gornje formule koje su uglavnom neotrovne za žive organizme. Primjeri farmaceutski prikladnih soli uključuju one soli koje se pripravljaju reagiranjem spojeva ovog izuma s mineralnom ili organskom kiselinom, odnosno neorganskom bazom. Reaktanti se obično pomiješaju u zajedničkom otapalu, kao što je dietileter ili benzen, za kisele adicijske soli, odnosno voda i alkoholi za bazične adicijske soli. Soli normalno precipitiraju izvan otopine unutar razdoblja od jednog sata do oko deset dana, i mogu se izdvojiti filtriranjem ili kojim drugim uobičajenim postupkom. Ove su soli poznate kao kisele adicijske odnosno bazične adicijske soli. The term "pharmaceutically acceptable salt", as used herein, refers to salts of compounds of the above formula which are generally non-toxic to living organisms. Examples of pharmaceutically suitable salts include those salts which are prepared by reacting the compounds of this invention with a mineral or organic acid or an inorganic base. The reactants are usually mixed in a common solvent, such as diethyl ether or benzene, for acidic addition salts, or water and alcohols for basic addition salts. The salts normally precipitate out of solution within a period of one hour to about ten days, and can be separated by filtration or some other common method. These salts are known as acid addition or basic addition salts.

Kiseline koje se mogu upotrijebiti za dobivanje kiselih adicijskih soli su neorganske kiseline poput klorovodične, bromovodične, jodovodične, sumporne, fosforne i drugih kiselina, kao i organske kiseline poput p-toluensulfonske, metansulfonske, oksalne, p-bromofenilsulfonske, ugljične, jantarne, limunske, benzojeve, octene i sličnih kiselina. Acids that can be used to obtain acid addition salts are inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric and other acids, as well as organic acids such as p-toluenesulfonic, methanesulfonic, oxalic, p-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic and similar acids.

Primjeri farmaceutski prikladnih soli su sulfat, pirosulfat, bisulfat, sulfit, bisulfit, fosfat, monohidrogenfosfat, dihidrogenfosfat, metafosfat, pirofosfat, klorid, bromid, jodid, acetat, propionat, dekanoat, kaprilat, akrilat, format, izobutirat, kaproat, heptanoat, propiolat, oksalat, malonat, sukcinat, suberat, sebakat, fumarat, maleat, butin-1,4-dioat, heksin-1,6-dioat, benzoat, klorobenzoat, metilbenzoat, dinitrobenzoat, hidroksibenzoat, metoksibenzoat, ftalat, sulfonat, ksilensulfonat, fenilacetat, fenilpropionat, fenilbutirat, citrat, laktat, g-hidroksibutirat, glikolat, tartarat, metan-sulfonat, propansulfonat, naftalen-1-sulfonat, naftalen-2-sulfonat, mandelat i slični. Examples of pharmaceutically suitable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate , oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyn-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate , phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

Preporučene prikladne kisele adicijske soli su one koje nastaju od mineralnih kiselina, poput klorovodične i bromovodične, te od organskih kiselina, poput maleinske i metansulfonske kiseline. Recommended suitable acid addition salts are those formed from mineral acids, such as hydrochloric and hydrobromic, and from organic acids, such as maleic and methanesulfonic acids.

Bazične adicijske soli uključuju one koje se dobiju od neorganskih i organskih baza, kao što su hidroksidi, karbonati, bikarbonati i druge soli amonijaka ili alkali ili hidroksida zemnoalkalijskih kovina. Baze korisne za pripravu soli ovog izuma uključuju, prema tome, natrij hidroksid, kalij hidroksid, amonij hidroksid, kalij karbonat, natrij karbonat, natrij bikarbonat, kalij bikarbonat, kalcij hidroksid, kalcij karbonat i druge. Naročito se preporučuju natrijeve i kalijeve soli. Base addition salts include those obtained from inorganic and organic bases, such as hydroxides, carbonates, bicarbonates and other salts of ammonia or alkalis or hydroxides of alkaline earth metals. Bases useful in preparing the salts of this invention include, therefore, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and others. Sodium and potassium salts are especially recommended.

“Farmaceutski prikladan prolijek” označuje spoj koji se u fiziološkim uvjetima ili liziranjem otopine može prevesti u spoj formule 9. "Pharmaceutically suitable prodrug" means a compound that can be converted into a compound of formula 9 under physiological conditions or by solution lysis.

“Farmaceutski prikladna otopina” je otopina koja zadržava biološku učinkovitost i svojstva biološki aktivnih sastojaka spojeva formule 9. "Pharmaceutically suitable solution" is a solution that retains the biological effectiveness and properties of the biologically active ingredients of the compounds of formula 9.

Primjeri farmaceutski prikladnih otopina uključuju, ali nisu ograničeni na, spojeve formule 9 u kombinaciji s vodom, izopropanolom, etanolom, metanolom, DMSO, etil acetatom, octenom kiselinom ili etanolaminom. Examples of pharmaceutically suitable solutions include, but are not limited to, compounds of formula 9 in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.

Treba uvidjeti da pojedini protuion koji tvori dio bilo koje soli ovog izuma nije od ključnog značenja toliko dugo dok je sol u cijelosti farmakološki prikladna i dok protuion ne doprinosi neželjenim osobinama soli u cijelosti. It should be appreciated that the particular counterion forming part of any salt of this invention is not of critical importance so long as the salt as a whole is pharmacologically suitable and the counterion does not contribute to undesirable properties of the salt as a whole.

Preporučeni spoj je spoj 21 The recommended compound is compound 21

[image] [image]

[3S-[2(2S*,3S*),3alfa,4a beta,8a beta]]-N-(1,1-dimetil-2-hidroksietil)dekahidro-2-[2-hidroksi- 3-[(3-hidroksi-2- metil benzoil)amino]-4-(feniltio)butil]-3-izokvinolinkarboksamid. [3S-[2(2S*,3S*),3alpha,4a beta,8a beta]]-N-(1,1-dimethyl-2-hydroxyethyl)decahydro-2-[2-hydroxy- 3-[(3 -hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide.

Postupak priprave spoja 21 je opisan u daljnjem tekstu. Spoj 21 također je moguće dobiti kao metabolit iz plazme bolesnika kojima je davan [3S-(3R,4aR*,8aR*,2’S*, 3’S*)]-2-[2’-hidroksi-3’- feniltiometil-4’- aza-5’-okso- 5’-(2’’- metil-3’’-hidroksifenil)pentil] dekahidroizokvinolin-3-N-t-butilkarboksamid, sol metansulfonske kiseline, koji je opisan u SAD patentu br. 5484926. The procedure for the preparation of compound 21 is described below. Compound 21 can also be obtained as a metabolite from the plasma of patients who were given [3S-(3R,4aR*,8aR*,2'S*, 3'S*)]-2-[2'-hydroxy-3'-phenylthiomethyl-4'- aza-5'-oxo-5'-(2''-methyl-3''-hydroxyphenyl)pentyl]decahydroisoquinoline-3-N-t-butylcarboxamide, methanesulfonic acid salt, which is described in US Pat. 5484926.

Spojevi formule 9 mogu se pripraviti prema slijedećoj Reakcijskoj shemi I. Compounds of formula 9 can be prepared according to the following Reaction Scheme I.

REAKCIJSKA SHEMA I REACTION SCHEME I

Shema I. Opći put sinteze za dobivanje 9b i derivata Scheme I. General synthesis route for obtaining 9b and derivatives

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Spoj 1a, perhidroizokvinolin, na tržištu dostupan od NSC Technologies (Chicago, IL) ili od Procos SpA (Milano, Italija) izlaže se produljenoj kiseloj hidrolizi u koraku 1a, čime se dobije spoj 2a. Mogu se koristiti različite neorganske kiseline, bilo u smjesi vodeno/organsko otapalo, bilo samo u vodi, pri temperaturama iznad 50°C. Primjer ovakve neorganske kiseline je 6N vodena HCl. Supstituenti za spoj 1a uključuju odgovarajuće estere 1b, tioestere 1c ili druge amide 1d: Compound 1a, a perhydroisoquinoline, commercially available from NSC Technologies (Chicago, IL) or from Procos SpA (Milan, Italy) is subjected to extended acid hydrolysis in step 1a to afford compound 2a. Different inorganic acids can be used, either in a water/organic solvent mixture, or only in water, at temperatures above 50°C. An example of such an inorganic acid is 6N aqueous HCl. Substituents for compound 1a include the corresponding esters 1b, thioesters 1c or other amides 1d:

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gdje Z, Z1 i Z2 mogu svaki neovisno biti alkil, cikloalkil, heterocikl ili aril. where Z, Z1 and Z2 can each independently be alkyl, cycloalkyl, heterocycle or aryl.

Spoj 2a se potom zaštiti na aminskom dušiku, da bi se dobio spoj 2b u koraku 1b. Zaštitna skupina Rp definira se kao prikladna konjugirajuća skupina koja sprečava neželjenu razgradnju aktiviranih karboksilatnih derivata spoja 2b u Koraku 2. Ove zaštitne skupine tipično mogu biti karbamat po porijeklu, a opća im je struktura prikazana formulom 11: Compound 2a is then protected at the amine nitrogen to give compound 2b in step 1b. The protecting group Rp is defined as a suitable conjugating group that prevents unwanted decomposition of the activated carboxylate derivatives of compound 2b in Step 2. These protecting groups can typically be carbamate in origin, and their general structure is shown by formula 11:

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R’’ može u formuli 11 predstavljati alkil, cikloalkil, aril ili heterocikl, koji se lako mogu ukloniti deprotekcijskim korakom nakon Koraka 2. Primjeri R’’ uključuju, ali nisu ograničeni na, metil, etil, propil, izopropil, n-butil, izobutil, t-butil ili viši razgranati ili nerazgranati alkil, 2,2,2-trikloroetil, 2-trimetilsililetil, alil, fenil, supstituirani fenil, benzil, supstituirani benzil, 9-fluoroenilmetil, 9-antrilmetil i viši policiklički aromatski prstenski sustav. Slijedeće tvari, prikazane dolje, mogu se dobiti od Aldrich Chemical Co. (Sigma Aldrich Fluka): R'' may in formula 11 represent alkyl, cycloalkyl, aryl or heterocycle, which can be easily removed by a deprotection step after Step 2. Examples of R'' include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl or higher branched or unbranched alkyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, phenyl, substituted phenyl, benzyl, substituted benzyl, 9-fluoroenylmethyl, 9-anthrylmethyl and higher polycyclic aromatic ring system. The following substances, shown below, are available from Aldrich Chemical Co. (Sigma Aldrich Fluka):

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Ove zaštitne skupine tipično se postavljaju reakcijom aciliranja odgovarajućeg haloformatnog estera 12a ili dikarbonata 12b: These protecting groups are typically installed by an acylation reaction of the corresponding haloformate ester 12a or dicarbonate 12b:

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u nazočnosti odgovarajuće baze u tipičnim organskim otapalima za ove vrste reakcija, kao što su halogenirana otapala, eteri i ugljikovodici. Ove su baze tipično neorganske, kao što su kovinski hidroksidi, bikarbonati i karbonati, ili organske baze poput amina, na primjer trietilamina, dietilamina, dietil izopropilamina, 1,8-diazabiciklo[2.2.2]oktana (DABCO) ili srodni di- ili trialkilamini, kao i amidinske baze poput 1,8-diazabiciklo[5.4.0]undek-7-ena (DBU) i 1,8- diaza biciklo[4.3.0]non-5-ena (DBN). Slijedeće tvari, prikazane dolje, mogu se dobiti od Aldrich Chemical Co. (Sigma Aldrich Fluka): in the presence of a suitable base in typical organic solvents for these types of reactions, such as halogenated solvents, ethers and hydrocarbons. These bases are typically inorganic, such as metal hydroxides, bicarbonates and carbonates, or organic bases such as amines, for example triethylamine, diethylamine, diethyl isopropylamine, 1,8-diazabicyclo[2.2.2]octane (DABCO) or related di- or trialkylamines, as well as amidine bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,8-diazabicyclo[4.3.0]non-5-ene (DBN). The following substances, shown below, are available from Aldrich Chemical Co. (Sigma Aldrich Fluka):

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Ove se reakcije tipično provode u rasponu od ispod sobne temperature do približno 100°C. These reactions are typically carried out in the range from below room temperature to approximately 100°C.

Korak spajanja amida, Korak 2, može se postići brojnim putevima, ovisno o načinu aktiviranja karboksilne skupine. Skupina J postavlja se u Koraku 2, reakcijom karboksilne kiseline 2b kojom nastaje aktivirani derivat 2c. The amide coupling step, Step 2, can be accomplished in a number of ways, depending on how the carboxyl group is activated. Group J is placed in Step 2, by the reaction of carboxylic acid 2b, which produces the activated derivative 2c.

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Skupina J može biti bilo koja od različitih odlazećih skupina, kao što su alkoksi, hidroksi, halogen, pseudohalogen (uključujući azid, cijanid, izocijanat i izotiocijanat), alkil ili arensulfonat, aromatski heterocikl (vezan preko heteroatoma) i N-hidroksiheterocikl, uključujući hidroksisukcinimid ili hidroksibenzotriazolski ester. Gornji su pojmovi definirani na slijedeći način: Group J can be any of a variety of leaving groups, such as alkoxy, hydroxy, halogen, pseudohalogen (including azide, cyanide, isocyanate, and isothiocyanate), alkyl or arenesulfonate, aromatic heterocycle (bonded through a heteroatom), and N-hydroxyheterocycle, including hydroxysuccinimide or hydroxybenzotriazole ester. The above terms are defined as follows:

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Acil halidi (2c, J = halogen) mogu se pripraviti uporabom neorganskih halogenirajućih sredstava kao što su tionil klorid ili bromid, fosforni triklorid ili bromid, fosforni pentaklorid ili bromid, ili organska sredstva kao oksalil klorid ili triklorizocijanurična kiselina. Esteri (2c, J = OR’’) (R’’ je gore definiran) mogu se pripraviti na različite načine, od kiselog klorida 2c u kojem je J Cl kombiniranjem sa željenim alkoholom u nazočnosti orgaske ili neorganske baze prethodno određene za aciliranje spoja 12a ili spoja 12b. Ester se može pripraviti i na drugi način, kiselinom potaknutim esterificiranjem u nazočnosti željenog alkohola. Sulfonati (2c, J = OSO2W1, pri čemu je W1 alkil ili aril) se tipično dobiju reakcijom karboksilne kiseline 2b s alkil ili arilsulfonil kloridima u nazočnosti organske aminske baze kao što je trietilamin, u nepolarnom otapalu, na temperaturama ispod 0°C. Alkil i arilsulfonil određeni su na slijedeći način: Acyl halides (2c, J = halogen) can be prepared using inorganic halogenating agents such as thionyl chloride or bromide, phosphorus trichloride or bromide, phosphorus pentachloride or bromide, or organic agents such as oxalyl chloride or trichloroisocyanuric acid. Esters (2c, J = OR'') (R'' is defined above) can be prepared in various ways, from the acid chloride 2c in which J is Cl by combining with the desired alcohol in the presence of an organic or inorganic base previously determined to acylate compound 12a or compound 12b. The ester can be prepared in another way, by acid-induced esterification in the presence of the desired alcohol. Sulfonates (2c, J = OSO2W1, where W1 is alkyl or aryl) are typically obtained by reacting carboxylic acid 2b with alkyl or arylsulfonyl chlorides in the presence of an organic amine base such as triethylamine, in a nonpolar solvent, at temperatures below 0°C. Alkyl and arylsulfonyl are defined as follows:

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Pseudohalogenski derivati 2c (J = pseudohalogen) tipično se dobiju od kiselih halida 2c (J = halogen), reakcijom s neorganskim pseudohalidom, u nazočnosti baze. Baze koje se koriste uključuju, ali nisu ograničene , na kovinske hidrokside, bikarbonate i karbonate, ili organske baze poput amina, i to trietilamina, dietilamina, dietil izopropilamina, 1,8- diazabiciklo[2.2.2]oktana (DABCO) ili srodnih di- ili trialkilamina, kao i amidinske baze poput 1,8- diaza biciklo[5.4.0]undek-7-ena (DBU) i 1,8-diazabiciklo[4.3.0]non-5-ena (DBN). Osobito preporučena baza je trietilamin. Heteroaromatski derivati 2c također se dobiju od kiselih halida 2c (J = halogen), uporabom specifičnog heteroaromatskog spoja u nazočnosti aminske baze u nepolarnom otapalu. N-hidroksiheterociklički derivati 2c mogu se dobiti od kiselih halida kao što je gore opisano, a također se mogu pripraviti uporabom alkil karbodiimida (alkil-N=C=N-alkil, gdje alkilne skupine mogu biti jednake ili različite) ili aril karbodiimida (aril-N=C=N-aril, gdje arilne skupine mogu biti jednake ili različite) i aminske baze kao sredstva za zgušnjavanje. Pseudohalide derivatives 2c (J = pseudohalide) are typically obtained from acid halides 2c (J = halogen), by reaction with an inorganic pseudohalide, in the presence of a base. Bases used include, but are not limited to, metal hydroxides, bicarbonates and carbonates, or organic bases such as amines, namely triethylamine, diethylamine, diethyl isopropylamine, 1,8-diazabicyclo[2.2.2]octane (DABCO) or related di - or trialkylamines, as well as amidine bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,8-diazabicyclo[4.3.0]non-5-ene (DBN). A particularly recommended base is triethylamine. Heteroaromatic derivatives 2c are also obtained from acid halides 2c (J = halogen), using a specific heteroaromatic compound in the presence of an amine base in a nonpolar solvent. The N-hydroxyheterocyclic derivatives 2c can be obtained from acid halides as described above, and can also be prepared using alkyl carbodiimides (alkyl-N=C=N-alkyl, where the alkyl groups can be the same or different) or aryl carbodiimides (aryl -N=C=N-aryl, where the aryl groups can be the same or different) and amine bases as thickening agents.

Primarni ili sekundarni amin (prikazan nad strelicom u Koraku 2 Sheme I) korišten u postupku spajanja može sadržavati prikladne zaštitne skupine, ovisno o funkcijskoj skupini koja je nazočna u aminu, te o načinu spajanja koji se koristi. Različiti su načini spajanja 2c s primarnim ili sekundarnim aminom, ovisno o tome što označuje J. Kada se koristi slobodna kiselina (2c, J = OH), vezanje se provede korištenjem postupaka s karbodiimidom, s nekom od uobičajenih reagensa u ovoj skupini, uključujući dicikloheksilkarbodiimid ili srodne dialkilkarbodiimide, EDC (soli 1-(3-dimetilaminopropil)-3- etilkarbodiimida) ili srodne reagense topljive u vodi, zajedno s organskom aminskom bazom u polarnim organskim otapalima kao što su dioksan, DMF, NMP i acetonitril, u nazočnosti N-hidroksiheterocikličkog spoja kao što je N-hidroksisukcinimid ili 3-hidroksibenzotriazol. Na drugi način, haloformatni esteri poput 12d mogu se koristiti za privremeno aktiviranje kiseline, čime se dobiju miješani anhidridi opće formule 2d. The primary or secondary amine (shown above the arrow in Step 2 of Scheme I) used in the coupling process may contain suitable protecting groups, depending on the functional group present in the amine and the coupling method used. There are various ways to couple 2c with a primary or secondary amine, depending on what J denotes. When the free acid (2c, J = OH) is used, coupling is accomplished using carbodiimide procedures, with one of the common reagents in this group, including dicyclohexylcarbodiimide or related dialkylcarbodiimides, EDCs (salts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or related water-soluble reagents, together with an organic amine base in polar organic solvents such as dioxane, DMF, NMP, and acetonitrile, in the presence of N- of a hydroxyheterocyclic compound such as N-hydroxysuccinimide or 3-hydroxybenzotriazole. Alternatively, haloformate esters such as 12d can be used to temporarily activate the acid, yielding mixed anhydrides of the general formula 2d.

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Tipični haloformatni esteri prikazani su gore, kao 12d, a uključuju metil-, etil-, izopropil-, izobutil-, n-butil-, fenil- i srodne alkil i aril kloroformate, prikazane dolje. Typical haloformate esters are shown above, as 12d, and include methyl-, ethyl-, isopropyl-, isobutyl-, n-butyl-, phenyl-, and related alkyl and aryl chloroformates, shown below.

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Formula 2d predstavlja mogući međuspoj u koraku od formule 2b do formule 3. Formula 2d je međuspoj, ali ovdje opisanim postupkom nastaje spoj formule 3, bez izoliranja Formule 2d. Formula 2d represents a possible intermediate compound in the step from formula 2b to formula 3. Formula 2d is an intermediate compound, but the process described here produces a compound of formula 3, without isolating Formula 2d.

Ove se reakcije tipično izvode u različitim nepolarnim organskim otapalima, kao što su halougljici i eteri poput dietiletera, metil t-butiletera, diizopropil etera, dioksana i THF, na temperaturama ispod 0°C, zajedno s organskom aminskom bazom poput trietilamina, dietilamina, dietil izopropilamina, DABCO ili srodnih di- ili trialkilamina, kao i amidinskih baza poput DBU i DBN. These reactions are typically carried out in various non-polar organic solvents, such as halocarbons and ethers such as diethyl ether, methyl t-butyl ether, diisopropyl ether, dioxane and THF, at temperatures below 0°C, together with an organic amine base such as triethylamine, diethylamine, diethyl isopropylamine, DABCO or related di- or trialkylamines, as well as amidine bases such as DBU and DBN.

Kada je J u spoju 2c alkil ili arensulfonat (J = OSO2R ili OSO2Ar), spajanje se može provesti u različitim nepolarnim organskim otapalima, kao što su halougljici i eteri poput dietiletera, metil t-butiletera, diizopropil etera, dioksana i THF, na temperaturama ispod 0°C, zajedno s organskom aminskom bazom poput trietilamina, dietilamina, dietil izopropilamina, DABCO ili srodnih di- ili trialkilamina, kao i amidinskih baza poput DBU i DBN. When J in compound 2c is alkyl or arenesulfonate (J = OSO2R or OSO2Ar), the coupling can be carried out in various non-polar organic solvents, such as halocarbons and ethers such as diethyl ether, methyl t-butyl ether, diisopropyl ether, dioxane and THF, at temperatures below 0°C, together with an organic amine base such as triethylamine, diethylamine, diethyl isopropylamine, DABCO or related di- or trialkylamines, as well as amidine bases such as DBU and DBN.

Kada je J u spoju 2c halogen ili pseudohalogen, spajanje se može provesti u najčešćim organskim otapalima, kao što su THF, dietil eter, dioksan, metil t-butil eter ili drugi eteri; aceton, cikloheksanon, metil izobutilketon i drugi ketoni; esteri poput etil, metil i izopropil acetata; halogenirana otapala poput halogeniranih metana i etana, klorobenzena i drugih halogeniranih benzena; nitrila poput acetonitrila i propionitrila; nižih alkohola poput etanola, izopropanola, t-butanola i srodnih alkohola; i polarna organska otapala, kao što su dimetilformamid, dimetilsulfoksid, N-metil-2-pirolidon i srodna otapala koja sadrže amid. Često se koristi i baza, koja može biti bilo koja od brojnih neorganskih baza, poput kovinskih hidroksida, bikarbonata i karbonata, ili organskih baza poput amina, na primjer trietilamin, dietilamin, dietil izopropilamin, DABCO ili srodni di- ili trialkilamini, kao i amidinske baze poput DBU i DBN. When J in compound 2c is halogen or pseudohalogen, the coupling can be carried out in the most common organic solvents, such as THF, diethyl ether, dioxane, methyl t-butyl ether or other ethers; acetone, cyclohexanone, methyl isobutyl ketone and other ketones; esters such as ethyl, methyl and isopropyl acetate; halogenated solvents such as halogenated methane and ethane, chlorobenzene and other halogenated benzenes; nitriles such as acetonitrile and propionitrile; lower alcohols such as ethanol, isopropanol, t-butanol and related alcohols; and polar organic solvents, such as dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, and related amide-containing solvents. A base is also often used, which can be any of a number of inorganic bases, such as metal hydroxides, bicarbonates and carbonates, or organic bases such as amines, for example triethylamine, diethylamine, diethyl isopropylamine, DABCO or related di- or trialkylamines, as well as amidines bases like DBU and DBN.

Stručnjaci mogu izvesti Korak 2 spajanja amida s drugim mogućim J skupinama. Those skilled in the art can perform Step 2 coupling of the amide with other possible J groups.

U Koraku 3, uklanjanje zaštitne skupine može se postići bilo kojim standardnim postupkom deprotekcije za određen razred zaštitnih skupina. Jednostavni alkil- ili supstituirani alkil karbamati mogu se ukloniti vodenim otopinama baze, na temperaturama do oko 100°C, s nekim od čestih neorganskih kovinskih hidroksida, poput natrij, litij, kalij ili barij hidroksida, kao i hidroksida drugih kovina u najmanje stehiometrijskim količinama. Karbamatne zaštitne skupine koje sadrže benzil skupine vezane na kisik mogu se ukloniti hidrogenolizom s paladijem ili platinskim katalizatorom. Na drugi način, može se koristiti vodena bazična hidroliza, na temperaturama do oko 100°C s nekim od čestih neorganskih kovinskih hidroksida, poput natrij, litij, kalij ili barij hidroksida, kao i hidroksida drugih kovina u najmanje stehiometrijskim količinama. Za deprotekciju karbamata benzilske osnove se također mogu koristiti i različite bezvodne kiseline, uključujući HCl, HBr i HI. Lewisove kiseline bora i aluminija, kao što su AlCl3, BBR3, BCl3 u nepolarnim otapalima također su učinkovite. Također se mogu koristiti neke supstituirane benzil, aril ili alkil skupine, u kojima je specifični supstitucijski uzorak odabran prema svojoj sposobnosti da bude uklonjen u specifičnim uvjetima. Na primjer, 2-trimetilsililetilkarbonilna skupina (Teoc) je zaštitna skupina oblikovana na način da iskoristi specifičnu reaktivnost 2-trimetilsililetilne skupine u postupku deprotekcije. 2-trimetilsililetilkarbonil klorid se može koristiti za zaštitu aminskog dušika, a kasnije se može ukloniti izvorom fluoridnog iona, kao što su HF ili tetraalkilamonij fluoridne soli. In Step 3, removal of the protecting group can be achieved by any standard deprotection procedure for a particular class of protecting groups. Simple alkyl- or substituted alkyl carbamates can be removed by aqueous base solutions, at temperatures up to about 100°C, with some of the common inorganic metal hydroxides, such as sodium, lithium, potassium or barium hydroxide, as well as hydroxides of other metals in at least stoichiometric amounts. Carbamate protecting groups containing benzyl groups attached to oxygen can be removed by hydrogenolysis with a palladium or platinum catalyst. Alternatively, aqueous basic hydrolysis can be used, at temperatures up to about 100°C with some of the common inorganic metal hydroxides, such as sodium, lithium, potassium or barium hydroxide, as well as hydroxides of other metals in at least stoichiometric amounts. A variety of anhydrous acids, including HCl, HBr, and HI, can also be used to deprotect benzylic carbamates. Lewis acids of boron and aluminum such as AlCl3, BBR3, BCl3 in non-polar solvents are also effective. Some substituted benzyl, aryl, or alkyl groups may also be used, in which the specific substitution pattern is selected according to its ability to be removed under specific conditions. For example, the 2-trimethylsilylethylcarbonyl group (Teoc) is a protecting group designed to take advantage of the specific reactivity of the 2-trimethylsilylethyl group in the deprotection process. 2-trimethylsilylethylcarbonyl chloride can be used to protect the amine nitrogen and can later be removed with a source of fluoride ion, such as HF or tetraalkylammonium fluoride salts.

U Koraku 4, perhidroizokvinolinski dio formule 4 vezan je na kloroalkohol (spoj 5, Shema I) preko epoksidnog međuspoja (13) nastalog bazom potaknutim zatvaranjem susjedne klorohidrinske funkcijske skupine. In Step 4, the perhydroisoquinoline moiety of formula 4 is attached to a chloroalcohol (compound 5, Scheme I) via an epoxide intermediate (13) formed by base-promoted closure of an adjacent chlorohydrin functional group.

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Spoj 5 proizvodi Kaneka Industries, Japan. U prevođenju spoja 5 u spoj 13 pa u spoj 6, može se koristiti nekoliko otvori-zatvori postupaka. Epoksid 13 može se izolirati ili može reagirati s 4, koji se dodaje ili nakon oblikovanja 13, ili 4 može biti nazočan od početka slijeda. Epoksid 13 može se dobiti od neorganskih baza kao što su kovinski hidroksidi, karbonati i bikarbonati, u otapalima kao što su alkoholi, poput metanola, etanola ili izopropil alkohola, eteri poput THF i dioksana, ili mješavine oba spoja. Epoksid se također može dobiti u dvofaznom sustavu otapala, koji se sastoji od vode ili halougljičnog otapala, kao što je diklorometan s bazom. Katalizator prijelaza faze, poput tetraalkilamonijske soli, može se koristiti kako bi se postupak pospješio. Postupak otvaranja epoksida 13 spojem 4 provodi se u alkoholnim otapalima ili smjesama alkohola i drugog otapala, koje može biti eter ili dipolarno neprotonsko otapalo, poput dimetilformamida ili dimetilsulfoksida. Otvaranje epoksida 13 spojem 4 kako bi se dobio spoj 6 optimalno se provodi tijekom razdoblja od 2-7 sati, na 50-60°C. Compound 5 is produced by Kaneka Industries, Japan. In converting compound 5 to compound 13 and then to compound 6, several open-close procedures can be used. The epoxide 13 can be isolated or it can be reacted with 4, which is added either after the formation of 13, or 4 can be present from the beginning of the sequence. Epoxide 13 can be obtained from inorganic bases such as metal hydroxides, carbonates and bicarbonates, in solvents such as alcohols such as methanol, ethanol or isopropyl alcohol, ethers such as THF and dioxane, or mixtures of both compounds. The epoxide can also be prepared in a two-phase solvent system, consisting of water or a halocarbon solvent, such as dichloromethane with a base. A phase transition catalyst, such as a tetraalkylammonium salt, can be used to speed up the process. The process of opening epoxy 13 with compound 4 is carried out in alcoholic solvents or mixtures of alcohol and another solvent, which can be ether or a dipolar aprotic solvent, such as dimethylformamide or dimethylsulfoxide. Opening of epoxide 13 with compound 4 to give compound 6 is optimally carried out over a period of 2-7 hours at 50-60°C.

U Koraku 5, uklanja se karbobenziloksi skupina, čime se dobije slobodni amin 7. Ovo se može provesti pomoću HBr u octenoj kiselini uz suotapala, kao što su halougljici. Također je moguće koristiti halide bora, poput BBr3 i BCl3 ili alkil supstituirane borne halide, kao što je dimetilbor bromid u halougljičnim otapalima poput kloroforma i diklorometana, na temperaturama u rasponu od 0°C do temperature okoline. Karbobenziloksi skupina može biti uklonjena i na drugi način, hidrolizom s vodenim/alkoholnim otopinama kovinskih hidroksida, kao što su barij, natrij, litij ili kalij hidroksid, na temperaturama iznad sobne, tijekom višesatnog razdoblja. In Step 5, the carbobenzyloxy group is removed, yielding the free amine 7. This can be carried out using HBr in acetic acid with co-solvents such as halocarbons. It is also possible to use boron halides, such as BBr3 and BCl3 or alkyl substituted boron halides, such as dimethylboron bromide in halocarbon solvents such as chloroform and dichloromethane, at temperatures ranging from 0°C to ambient temperature. The carbobenzyloxy group can be removed in another way, by hydrolysis with aqueous/alcoholic solutions of metal hydroxides, such as barium, sodium, lithium or potassium hydroxide, at temperatures above room temperature, over a period of several hours.

Korak 6a je spajanje derivata benzojeve kiseline formule 8, čime se dobije 9a. U Formuli 8, Q može biti odlazeća skupina. Q može biti bilo koja od odlazećih skupina o kojima se govorilo ranije u svezi sa Skupinom J. Spojevi formule 8, u kojima je Q = OH ili Cl dostupni su na tržištu od EMS Dottikon, Lenzburg, Švicarska i od Sugai Chemical Industries, Ltd. u Japanu. Načini spajanja su različiti, a ovisni su o tome što označuje Q. Kada se koristi slobodna kiselina (Q = OH), vezanje se provede korištenjem postupaka s karbodiimidom, s nekom od uobičajenih reagensa u ovoj skupini, uključujući dicikloheksilkarbodiimid ili srodne dialkilkarbodiimide, EDC (soli 1-(3-dimetilaminopropil)-3-etilkarbodiimida) ili srodne reagense topljive u vodi, zajedno s organskom aminskom bazom u polarnim organskim otapalima kao što su dioksan, DMF, NMP i acetonitril, u nazočnosti N-hidroksiheterocikličkog spoja kao što je N-hidroksisukcinimid ili 3-hidroksibenzotriazol. Kada je Q = halogen ili pseudohalogen, spajanje se može provesti u najčešćim organskim otapalima, kao što su THF, dietil eter, dioksan, metil t-butil eter ili drugi eteri; aceton, cikloheksanon, metil izobutilketon i drugi ketoni; esteri poput etil, metil i izopropil acetata; halogenirana otapala poput halogeniranih metana i etana, klorobenzena i drugih halogeniranih benzena; nitrila poput acetonitrila i propionitrila; nižih alkohola poput etanola, izopropanola, t-butanola i srodnih alkohola; i polarna organska otapala, kao što su dimetilformamid, dimetilsulfoksid, N-metil-2-pirolidon i srodna otapala koja sadrže amid. Često se koristi i baza, koja može biti bilo koja od brojnih neorganskih baza, poput kovinskih hidroksida, bikarbonata i karbonata, ili organskih baza poput amina, na primjer trietilamin, dietilamin, dietil izopropilamin, DABCO ili srodni di- ili trialkilamini, kao i amidinske baze poput DBU i DBN. Step 6a is the coupling of the benzoic acid derivative of formula 8 to give 9a. In Formula 8, Q can be a leaving group. Q may be any of the leaving groups discussed earlier in connection with Group J. Compounds of formula 8, wherein Q = OH or Cl are commercially available from EMS Dottikon, Lenzburg, Switzerland and from Sugai Chemical Industries, Ltd. in Japan. Coupling methods are varied, depending on what Q stands for. When a free acid (Q = OH) is used, coupling is accomplished using carbodiimide procedures, with one of the common reagents in this group, including dicyclohexylcarbodiimide or related dialkylcarbodiimides, EDC ( salts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) or related water-soluble reagents, together with an organic amine base in polar organic solvents such as dioxane, DMF, NMP, and acetonitrile, in the presence of an N-hydroxyheterocyclic compound such as N -hydroxysuccinimide or 3-hydroxybenzotriazole. When Q = halogen or pseudohalogen, the coupling can be carried out in the most common organic solvents, such as THF, diethyl ether, dioxane, methyl t-butyl ether or other ethers; acetone, cyclohexanone, methyl isobutyl ketone and other ketones; esters such as ethyl, methyl and isopropyl acetate; halogenated solvents such as halogenated methane and ethane, chlorobenzene and other halogenated benzenes; nitriles such as acetonitrile and propionitrile; lower alcohols such as ethanol, isopropanol, t-butanol and related alcohols; and polar organic solvents, such as dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, and related amide-containing solvents. A base is also often used, which can be any of a number of inorganic bases, such as metal hydroxides, bicarbonates and carbonates, or organic bases such as amines, for example triethylamine, diethylamine, diethyl isopropylamine, DABCO or related di- or trialkylamines, as well as amidines bases like DBU and DBN.

Uklanjanje acetata provodi se u koraku 6b, vodenim ili alkoholnim otopinama neorganskih baza, kao što su kovinski hidroksidi, karbonati i bikarbonati, na temperaturama okoline, do 100°C. Postoji li zaštićena funkcijska skupina na karboksamidnoj skupini vezanoj na perhidroizokvinolinskom sustavu prstena, najbolje ju je ukloniti u ovoj fazi (tijekom ili nakon koraka 6b). Priroda ovog koraka ovisi o pojedinoj zaštitnoj skupini. Acetate removal is carried out in step 6b, with aqueous or alcoholic solutions of inorganic bases, such as metal hydroxides, carbonates and bicarbonates, at ambient temperatures up to 100°C. If there is a protected functional group on the carboxamide group attached to the perhydroisoquinoline ring system, it is best to remove it at this stage (during or after step 6b). The nature of this step depends on the individual protecting group.

Preporučeni postupak za provedbu cjelokupnog procesa prikazanog na Shemi I prikazan je na Shemi II. The recommended procedure for implementing the entire process shown in Scheme I is shown in Scheme II.

Aminokiselina 15 zaštićena Cbz-om spaja se s aminom 22, čime se dobije amid 16. Cbz skupina se ukloni hidrogeniranjem, čime se dobije amin 17. On se spoji The Cbz-protected amino acid 15 is coupled with amine 22 to give amide 16. The Cbz group is removed by hydrogenation to give amine 17. It is coupled

Shema II. Sinteza amida 21 Scheme II. Amide synthesis 21

[image] [image]

s kloroalkoholom preko epoksida, postupkom in situ, čime se dobije spoj 18. Uobičajenom deprotekcijom bazom i spajanjem slobodnog primarnog amina s kiselim kloridom 20 dobije se amid 21. Potankosti ovog postupka izložene su u nastavku, Primjerima 1 A do F. Slovne oznake A do F na Shemi II odgovaraju Primjerima 1 A do F koji slijede. with chloroalcohol via epoxide, an in situ procedure, which gives compound 18. The usual deprotection with a base and coupling of the free primary amine with acid chloride 20 gives amide 21. The details of this procedure are shown below, in Examples 1 A to F. Letter designations A to F in Scheme II correspond to Examples 1 A to F which follow.

Slijedeći Primjeri opisuju oblike ozuma. Primjeri su izloženi u svrhu pojašnjenja, a nije im namjena ograničavanje područja izuma. The following Examples describe the forms of ozum. The examples are presented for the purpose of clarification and are not intended to limit the scope of the invention.

Kratice za pojmove točka tališta, spektri nuklearne magnetske rezonance, maseni spektri zbijanja elektrona, maseni spektri desorpcije polja, maseni spektri bombardiranja brzim atomima, infracrveni spektri, ultraljubičasti spektri, analiza elemenata, high preformance tekuća kromatografija i tankoslojna kromatografija su, istim poretkom: t.t., NMR, EIMS, MS(FD), MS(FAB), IC, UV, analiza, HPLC i TLC. K tome, navedeni su apsorpcijski maksimumi za IC spektar koji su od interesa, a ne svi zamijećeni maksimumi. Abbreviations for the terms melting point, nuclear magnetic resonance spectra, electron compaction mass spectra, field desorption mass spectra, fast atom bombardment mass spectra, infrared spectra, ultraviolet spectra, elemental analysis, high performance liquid chromatography and thin layer chromatography are, in the same order: m.p., NMR, EIMS, MS(FD), MS(FAB), IC, UV, analysis, HPLC and TLC. In addition, the absorption maxima for the IR spectrum that are of interest are listed, not all observed maxima.

U svezi s NMR spektrima, korištene su slijedeće kratice: singlet (s), dublet (d), dublet ili dubleti (dd), triplet (t), kvartet (q), multiplet (m), dublet multipleta (dm), široki singlet (br.s), široki dublet (br.d), široki triplet (br.t) i široki multiplet (br.m). J označuje konstantu spajanja izraženu u hercima (Hz). Ukoliko nije drukčije naznačeno, NMR podaci se odnose na slobodnu bazu promatranog spoja. In connection with NMR spectra, the following abbreviations are used: singlet (s), doublet (d), doublet or doublets (dd), triplet (t), quartet (q), multiplet (m), doublet of multiplets (dm), broad singlet (br.s), wide doublet (br.d), wide triplet (br.t) and wide multiplet (br.m). J denotes the coupling constant expressed in Hertz (Hz). Unless otherwise indicated, NMR data refer to the free base of the observed compound.

NMR spektri određivani su na General Electric QE-300 300 MHz instrumentu. Kemijske smjene izražene su δ vrijednostima u ppm. Maseni spektri dobiveni su na VG ZAB-3 spektrometru u Scripps Research Institute, La Jolla, CA. Infracrveni spektri zabilježeni su na Midac Corporation spektrometru. UV spektri dobiveni su pomoću Varian Cary 3E instrumenta. Tankoslojna kromatografija provedena je na silika pločicama tvrtke E.Merck. Točke tališta mjerene su na Mettler FP62 instrumentu i nisu ispravljane. NMR spectra were determined on a General Electric QE-300 300 MHz instrument. Chemical shifts are expressed as δ values in ppm. Mass spectra were obtained on a VG ZAB-3 spectrometer at Scripps Research Institute, La Jolla, CA. Infrared spectra were recorded on a Midac Corporation spectrometer. UV spectra were obtained using a Varian Cary 3E instrument. Thin-layer chromatography was performed on silica plates from E.Merck. Melting points were measured on a Mettler FP62 instrument and are uncorrected.

Primjer 1 Example 1

Postupci sinteze amida Formule 21 Procedures for the synthesis of amides of Formula 21

[3S-[2(2S*,3S*),3alfa,4a beta,8a beta]]-N-(1,1-dimetil-2-hidroksietil)dekahidro-2-[2-hidroksi-3- [(3-hidroksi-2-metil benzoil)amino]-4-(feniltio)butil]-3-izokvinolinkarboksamid [3S-[2(2S*,3S*),3alpha,4a beta,8a beta]]-N-(1,1-dimethyl-2-hydroxyethyl)decahydro-2-[2-hydroxy-3- [(3 -hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide

[image] [image]

A. Perhidroizokvinolin (26.4 g, 111 mmol) (na tržištu dostupan od NSC Technologies (Chicago, IL) ili Procos SpA (Milano, Italija)) se suspendira u vodi (200 ml) i koncentriranoj vodenoj HCl (200 ml). Ova se smjesa grije do refluksa i miješa 3 dana, tijekom kojih se pretvori u otopinu. Otapala se uklone pri smanjenom tlaku, čime se dobije svjetložuta kruta tvar. Kruta tvar se otopi u 2-propanolu (200 ml) i filtrira. Filtrat se ispari pri smanjenom tlaku do ulja. Dodaju se EtOAc (100 ml) i voda (100 ml), i pH otopine se dovede do 8.0 dodavanjem 2 N vodenog KOH. Kap po kap, tijekom 30 minuta, doda se benzil kloroformat (15.8 ml, 111 mmol) uz održavanje pH između 7 i 8, dodavanjem 2 N vodenog KOH. Smjesa se miješa na sobnoj temperaturi tijekom 18 h. Doda se EtOAc (200 ml) i organski sloj se ispire 1 N vodenom HCl (100 ml) i otopinom soli (100 ml). Organski sloj se suši (MgSO4), filtrira i ispari pri smanjenom tlaku do ulja. Proizvod se prčisti kromatografijom na silika gelu, ispiranjem s 1:1 40-60 petrolej eter/EtOAc, nakon toga 100%-tnim EtOAc. Frakcije koje sadrže proizvod se prikupe i ispare pri smanjenom tlaku, čime se dobije spoj 15 (11.3 g, 32%) u obliku bezbojnog ulja: 1H NMR (300 MHz, CDCl3) δ: 7.43-7.28 (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). A. Perhydroisoquinoline (26.4 g, 111 mmol) (commercially available from NSC Technologies (Chicago, IL) or Procos SpA (Milan, Italy)) was suspended in water (200 mL) and concentrated aqueous HCl (200 mL). This mixture is heated to reflux and stirred for 3 days, during which time it turns into a solution. The solvents were removed under reduced pressure to give a pale yellow solid. The solid was dissolved in 2-propanol (200 ml) and filtered. The filtrate is evaporated under reduced pressure to an oil. EtOAc (100 mL) and water (100 mL) were added, and the pH of the solution was adjusted to 8.0 by addition of 2 N aqueous KOH. Benzyl chloroformate (15.8 mL, 111 mmol) was added dropwise over 30 minutes while maintaining the pH between 7 and 8 by adding 2 N aqueous KOH. The mixture is stirred at room temperature for 18 h. EtOAc (200 mL) was added and the organic layer was washed with 1 N aqueous HCl (100 mL) and brine (100 mL). The organic layer is dried (MgSO4), filtered and evaporated under reduced pressure to an oil. The product was purified by silica gel chromatography, eluting with 1:1 40-60 petroleum ether/EtOAc, followed by 100% EtOAc. Fractions containing the product were collected and evaporated under reduced pressure to give compound 15 (11.3 g, 32%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ: 7.43-7.28 (m, 5H), 5.17 ( no 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. 1-hidroksibenzotriazol (4.2 g, 31.4 mmol) i EDC (6.0 g, 31.4 mmol) se dodaju u otopinu kiseline 15 (8.3 g, 26.2 mmol) u DMF (128 ml), na temperaturi okoline. Smjesa se grije na 80°C tijekom 10 minuta. Doda se 1,1-dimetil-2-trimetilsililoksietilamin (5.1 g, 31.4 mmol, pripravljen od 1,1-dimetil-2-hidroksietilamina (Aldrich Chemical Co.) i heksametildisilazana (Aldrich Chemical Co.)) grijanjem smjese pod refluksom, nekoliko sati, nakon čega slijedi isparavanje para sastojaka, i otopina se grije na 80°C tijekom 17 sati. Žuta otopina se ulije u EtOAc (250 ml) i 2 N vodenu HCl (250 ml). Nakon desetominutnog miješanja, doda se EtOAc (750 ml) i smjesa se ispire vodom (3 x 500 ml) i otopinom soli (1 x 250 ml). Pomiješani vodeni slojevi se ekstrahiraju pomoću EtOAc (1 x 250 ml). Pomiješani organski slojevi se suše (Na2SO4) i pročiste plamenom kromatografijom (50/50 EtOAc/heksani), čime se dobije spoj 16 u obliku bezbojnog ulja (7.9 g, 78%): 1H NMR (300 MHz, CD3OD) B. 1-Hydroxybenzotriazole (4.2 g, 31.4 mmol) and EDC (6.0 g, 31.4 mmol) were added to a solution of acid 15 (8.3 g, 26.2 mmol) in DMF (128 mL), at ambient temperature. The mixture is heated to 80°C for 10 minutes. 1,1-dimethyl-2-trimethylsilyloxyethylamine (5.1 g, 31.4 mmol, prepared from 1,1-dimethyl-2-hydroxyethylamine (Aldrich Chemical Co.) and hexamethyldisilazane (Aldrich Chemical Co.)) was added by heating the mixture under reflux, for several hours, followed by evaporation of the vapors of the ingredients, and the solution is heated at 80°C for 17 hours. The yellow solution was poured into EtOAc (250 mL) and 2 N aqueous HCl (250 mL). After stirring for ten minutes, EtOAc (750 mL) was added and the mixture was washed with water (3 x 500 mL) and brine (1 x 250 mL). The combined aqueous layers were extracted with EtOAc (1 x 250 mL). The combined organic layers were dried (Na2SO4) and purified by flash chromatography (50/50 EtOAc/hexanes) to give compound 16 as a colorless oil (7.9 g, 78%): 1H NMR (300 MHz, CD3OD)

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). 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. Smjesa karbamata 16 (7.9 g, 20.4 mmol) i 5%-tnog paladija na ugljiku (Pd/C)(1.6 g) se hidrogenira pri 50 psi vodika u apsolutnom EtOH (110 ml) na temperaturi okoline, tijekom 18 sati. Smjesa se filtrira kroz celit i ispari in vacuo, čime se dobije amin 17 u obliku bijele, kristalne krute tvari: 1H NMR (300 MHz, CD3OD) δ 3.63 (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). C. A mixture of carbamate 16 (7.9 g, 20.4 mmol) and 5% palladium on carbon (Pd/C) (1.6 g) was hydrogenated at 50 psi hydrogen in absolute EtOH (110 mL) at ambient temperature for 18 h. The mixture was filtered through celite and evaporated in vacuo to give amine 17 as a white, crystalline solid: 1H NMR (300 MHz, CD3OD) δ 3.63 (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. Vodeni 10.2 N NaOH (2.4 ml, 24.5 mmol) se doda toploj (27°C) suspenziji kloroalkohola (dobije se od Kaneka Industries iz Japana) (10.4 g, 28.6 mmol) u izopropanolu (IPA) (104 ml) uz mehaničko miješanje. Nakon 1 h se doda 1 N vodena HCl u IPA (pripravljena dodavanjem 1 ml koncentrirane vodene HCl u 12 ml IPA), približno (ca.) 1 ml) radi neutraliziranja (pH = 7). Doda se amin 17 (5.2 g, 20.4 mmol) u obliku otopine u IPA (50 ml) i rijetka suspenzija se grije na 60°C tijekom 10 h. IPA se uklanja in vacuo. Ostatak se razrijedi s EtOAc (150 ml) i ispire vodom (2 x 50 ml), zasićenim vodenim NaHCO3 (1 x 50 ml) i otopinom soli (1 x 50 ml). Pomiješani vodeni slojevi se ekstrahiraju pomoću EtOAc (1 x 25 ml). Pomiješani organski slojevi se suše (Na2SO4) i pročiste plamenom kromatografijom (75/25 EtOAc/heksani, potom EtOAc), čime se dobije spoj 18 u obliku bijele krute tvari (8.98 g, 76%): 1H NMR 300 MHz, CD3OD) δ 7.33 (m, 10H), 5.08 (AB, JAB=12.2Hz, ΔUAB=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). D. Aqueous 10.2 N NaOH (2.4 mL, 24.5 mmol) was added to a warm (27°C) suspension of chloroalcohol (obtained from Kaneka Industries, Japan) (10.4 g, 28.6 mmol) in isopropanol (IPA) (104 mL) with mechanical stirring. mixing. After 1 h, 1 N aqueous HCl in IPA (prepared by adding 1 ml of concentrated aqueous HCl to 12 ml of IPA), approximately (ca.) 1 ml) is added for neutralization (pH = 7). Amine 17 (5.2 g, 20.4 mmol) was added as a solution in IPA (50 ml) and the dilute suspension was heated at 60°C for 10 h. The IPA is removed in vacuo. The residue was diluted with EtOAc (150 mL) and washed with water (2 x 50 mL), saturated aqueous NaHCO 3 (1 x 50 mL) and brine (1 x 50 mL). The combined aqueous layers were extracted with EtOAc (1 x 25 mL). The combined organic layers were dried (Na2SO4) and purified by flash chromatography (75/25 EtOAc/hexanes, then EtOAc) to give compound 18 as a white solid (8.98 g, 76%): 1H NMR 300 MHz, CD3OD) δ 7.33 (m, 10H), 5.08 (AB, JAB=12.2Hz, ΔUAB=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. 50%-tni vodeni NaOH (2.7 g, 1.8 ml, 33.6 mmol) se doda suspenziji karbamata 18 (6.75 g, 11.6 mmol) u IPA (34 ml), na temperaturi okoline. Smjesa se grije u refluksu tijekom 12 sati. Nakon hlađenja na sobnu temperaturu, smjesa se razrijedi metil t-butil eterom (MTBE)(600 ml) i ispire vodom (2 x 250 ml) i otopinom soli (1 x 125 ml). Pomiješani vodeni slojevi se ekstrahiraju pomoću MTBE (1 x 150 ml). Pomiješani organski slojevi se suše (Na2SO4) i ispare in vacuo, čime se dobije smjesa spoja 19 i benzil alkohola u obliku uljaste bijele krute tvari: 1H NMR (300 MHz, CD3OD) δ 7.34 (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). E. 50% aqueous NaOH (2.7 g, 1.8 mL, 33.6 mmol) was added to a suspension of carbamate 18 (6.75 g, 11.6 mmol) in IPA (34 mL), at ambient temperature. The mixture is heated under reflux for 12 hours. After cooling to room temperature, the mixture is diluted with methyl t-butyl ether (MTBE) (600 ml) and washed with water (2 x 250 ml) and brine (1 x 125 ml). The combined aqueous layers were extracted with MTBE (1 x 150 ml). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to give a mixture of compound 19 and benzyl alcohol as an oily white solid: 1H NMR (300 MHz, CD3OD) δ 7.34 (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. Trietilamin (3.2 g, 4.3 ml, 31.2 mmol) se doda otopini smjese amina 19 (4.7 g, 10.4 mmol teorijski od 18) i benzil alkohola u EtOH (23 ml) na temperaturi okoline. Doda se otopina 3-acetoksi-2-metilbenzoil klorid (20) (dobije se prema postupku iz SAD patentne prijave serij. br. 08/708411 od 5. rujna 1996, koja je ovdje specifično uključena kao referenca) (2.4 g, 11.5 mmol) u THF (4 ml). Nakon 2 sata, doda se 50%-tni vodeni NaOH (4.1 g, 2.8 ml, 52.2 mmol) i smjesa se grije uz refluks 1 sat. Nakon hlađenja na temperaturu okoline, smjesa se neutralizira do pH = 7 pomoću 2 N vodene HCl (26 ml). Ova se smjesa razrijedi s EtOAc (500 ml) i ispire vodom (1 x 250 ml), zasićenim vodenim NaHCO3 (2 x 250 ml), H2O (1 x 250 ml) i otopinom soli (1 x 125 ml). Organski sloj se suši (Na2SO4) i pročisti plamenom kromatografijom (75/25 EtOAc/heksani), čime nastaje amid 21 u obliku bijele pjene (1173-57A, 1.39 g, 23%). 1H NMR pokazala je nazočnost 11 mas.% EtOAc koji nije mogao biti uklonjem in vacuo. F. Triethylamine (3.2 g, 4.3 mL, 31.2 mmol) was added to a solution of a mixture of amine 19 (4.7 g, 10.4 mmol theoretical from 18 ) and benzyl alcohol in EtOH (23 mL) at ambient temperature. A solution of 3-acetoxy-2-methylbenzoyl chloride (20) (obtained according to the procedure of US Patent Application Serial No. 08/708411 dated September 5, 1996, which is specifically incorporated herein by reference) is added (2.4 g, 11.5 mmol ) in THF (4 mL). After 2 hours, 50% aqueous NaOH (4.1 g, 2.8 ml, 52.2 mmol) was added and the mixture was heated under reflux for 1 hour. After cooling to ambient temperature, the mixture was neutralized to pH = 7 using 2 N aqueous HCl (26 ml). This mixture was diluted with EtOAc (500 mL) and washed with water (1 x 250 mL), saturated aqueous NaHCO 3 (2 x 250 mL), H 2 O (1 x 250 mL), and brine (1 x 125 mL). The organic layer is dried (Na2SO4) and purified by flash chromatography (75/25 EtOAc/hexanes) to give amide 21 as a white foam (1173-57A, 1.39 g, 23%). 1H NMR showed the presence of 11 wt.% EtOAc which could not be removed in vacuo.

Analiza: Analysis:

1H NMR (300 MHz, CD3OD) δ 7.53 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.0 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 7.06 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 4.42 (m, 1H), 4.08 (m, 1H), 3.61 (dd, J=13.6, 4.0 Hz, 1H), 3.45 (AB, JAB=11.0 Hz, ΔUAB=18.0 Hz, 2H), 3.29 (dd, J=13.6, 10.3 Hz, 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). 1H NMR (300 MHz, CD3OD) δ 7.53 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.0 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 7.06 (t, J =8.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 4.42 (m, 1H), 4.08 (m, 1H), 3.61 (dd, J =13.6, 4.0 Hz, 1H), 3.45 (AB, JAB=11.0 Hz, ΔUAB=18.0 Hz, 2H), 3.29 (dd, J=13.6, 10.3 Hz, 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 (75.5 MHz, CD3OD) δ 175.7, 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. 13c NMR (75.5 MHz, CD3od) Δ 175.7, 172.5, 155.9, 138.8, 136.7, 129.8, 128.9, 126.3, 126.0, 122.4, 115.9, 70.3, 69.9, 68.2, 59.3, 58.8, 54.9, 53.0, 36.2, 34.2, 34.2 , 34.1, 31.1, 30.7, 26.4, 26.0, 23.1, 23.0, 20.8, 12.1.

Primjer 2 Example 2

Inhibicijska aktivnost proteaze HIV-a i protu-HIV aktivnost spoja 21 u kulturi stanica HIV protease inhibitory activity and anti-HIV activity of compound 21 in cell culture

Analiza kinetike čvrstog vezanja upotrijebljena je kako bi se odredila magnituda Ki vrijednosti spoja 21. Ki = 5.6 ± 0.91 nM. Tight binding kinetics analysis was used to determine the magnitude of the Ki value of compound 21. Ki = 5.6 ± 0.91 nM.

Metode Methods

Ekspresija HIV-1 proteaze Expression of HIV-1 protease

Gen HIV-1 proteaze izoliran je iz virusnog soja IIIB (Ratner, L. i sur., Nature, 316, 227-284 (1985)). Da bi se povećala postojanost pročišćene proteaze (Rose, J.R. i sur., J. Biol. Chem., 268, 11939-11945 (1993)), glutaminski ostatak na položaju 7 (Q7) mutiran je u serin (S) zamjenom odsječka od 33 parova baza između NdeI i BstEII mjesta u slijedu gena proteaze sintetičkim oligonukleotidom koji kodira Q7S mutaciju. Promijenjeni genski slijed umetnut je u plazmidski vektor pGZ (Menge, K.L. i sur., Biochemistry, 34:15934-15942 (1995) pod kontrolom fagnog T7 promotora. Dobiveni proizvod, pGZ/HP-19Q7S#9, transformira se u soj E. coli BL21 (DE3), kupljen od Novagen, Inc. The HIV-1 protease gene was isolated from the virus strain IIIB (Ratner, L. et al., Nature, 316, 227-284 (1985)). To increase the stability of the purified protease (Rose, J.R. et al., J. Biol. Chem., 268, 11939-11945 (1993)), the glutamine residue at position 7 (Q7) was mutated to serine (S) by replacing a segment of 33 base pairs between the NdeI and BstEII sites in the sequence of the protease gene by a synthetic oligonucleotide encoding the Q7S mutation. The altered gene sequence was inserted into the plasmid vector pGZ (Menge, K.L. et al., Biochemistry, 34:15934-15942 (1995) under the control of the phage T7 promoter. The resulting product, pGZ/HP-19Q7S#9, was transformed into strain E. coli BL21 (DE3), purchased from Novagen, Inc.

Ekspresija HIV-1 PR: Kulture se uzgajaju u 2YT mediju (1.6% triptikazni pepton, 1% ekstrakt plijesni, 0.5% NaCl pri početnom pH 7.5) koji sadrži 200 μg/L ampicilina u 100-litrenom fermentatoru (Biolafitte SA) na 37°C, tijekom 5 sati, potom se induciraju dodavanjem 1 mM IPTG (izopropil-β-D-tiogalaktopiranozid). Temperatura kulture tijekom induciranja podigne se na 42°C kako bi se povećalo nakupljanje rekombinantne HIV-1 proteaze u obliku netopljivih inkluzijskih tjelešaca. Nakon 2 h na 42°C, stanice se prikupe filtracijom kružnim tijekom, uporabom Pellicon 0.1 μm VVPP000C5 kazete #10 (Millipore), i stanična pasta se pohrani zamrznuta na -70°C. Expression of HIV-1 PR: Cultures are grown in 2YT medium (1.6% trypticase peptone, 1% mold extract, 0.5% NaCl at initial pH 7.5) containing 200 μg/L ampicillin in a 100-liter fermenter (Biolafitte SA) at 37°. C, for 5 hours, then they are induced by adding 1 mM IPTG (isopropyl-β-D-thiogalactopyranoside). The temperature of the culture during induction was raised to 42°C to increase the accumulation of recombinant HIV-1 protease in the form of insoluble inclusion bodies. After 2 h at 42°C, cells are collected by circular flow filtration using Pellicon 0.1 μm VVPP000C5 cassette #10 (Millipore), and the cell paste is stored frozen at -70°C.

Pročišćavanje rekombinantne HIV-proteaze: svi su koraci, osim ako nije drukčije naznačeno, provedeni na 4°C. Koncentracije proteina određene su pomoću BioRad otopine za određivanje proteina s goveđim serumskim albuminom (BioRad, Richmond, CA) kao standarda. Kromatografski koraci i čistoća HIV PR analizirani su elektroforezom na natrij dodecilsulfat poliakrilamidnom gelu (SDS-PAGE). Konačna čistoća HIV-PR bila je >98%. Tipični konačni prinos svake stolitrene kulture bio je ~120 mg. Purification of recombinant HIV-protease: All steps, unless otherwise indicated, were performed at 4°C. Protein concentrations were determined using BioRad protein assay solution with bovine serum albumin (BioRad, Richmond, CA) as a standard. Chromatographic steps and purity of HIV PR were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The final purity of HIV-PR was >98%. The typical final yield of each one-liter culture was ~120 mg.

Stanična pasta iz stolitrene kulture ponovno se suspendira u 300 ml pufera za liziranje (50 mM Tris-Cl pH 8.0, 25 mM NaCl, 20 mM 2-merkaptoetanola) i mikrofluidizira u fluidizatoru tvrtke Microfluidics Corporation, pri 22000 psi. Sirovi stanični lizat se izbistri centrifugiranjem na 14000 okr./min. 20 minuta. HIV PR nađena je uglavnom u peleti, u obliku inkluzijskih tjelešaca. Inkluzijska tjelešca su uzastopno ispirana više puta u puferu za liziranje koji je sadržavao dodatnih 0.1% Trition-X100 i 1 M ureje, a nakon svakog postupka za ispiranje inkluzijska tjelešca su peletirana centrifugiranjem na 5000 okr./min. tijekom 20 minuta. Pročišćena inkluzijska tjelešca otopljena su u puferu koji je sadržavao 50 mM Tris-Cl, pH 8.0, 25 mM NaCl, 20 mM 2-merkaptoetanola i 8 M ureje. Otopina je izbistrena centrifugiranjem na 14000 okr./min. i stavljena, na sobnoj temperaturi, na 300 ml Fast Flow Q-Sepharose stupcu (Pharmacia, Piscataway, NJ), uravnoteženom pomoću istog pufera. Pod ovim uvjetima HIV PR se nije vezala za stupac, pa je u protočnim frakcijama nađen gotovo čist enzim. Da bi se renaturirao protein, frakcije sa Fast Flow Q-Sepharose stupca dijalizirane su protiv tri izmjene pufera koji sadrži 25 mM NaH2PO4 pH 7.0, 25 mM NaCl, 10 mM DTT i 10% glicerola. Nakon prikupljanja, male se količine precipitirane tvari uklone centrifugiranjem i nastali se pripravak enzima koncentrira, dijalizira protiv 0.5 M NaCl, 50 mM MES pH 5.6, 10 mM DTT, zamrzne u malim alikvotima od ~2 mg/ml i pohrani na -70°C. The cell paste from the one-liter culture was resuspended in 300 ml of lysis buffer (50 mM Tris-Cl pH 8.0, 25 mM NaCl, 20 mM 2-mercaptoethanol) and microfluidized in a Microfluidics Corporation fluidizer at 22,000 psi. The crude cell lysate is clarified by centrifugation at 14,000 rpm. 20 minutes. HIV PR was found mainly in the pellet, in the form of inclusion bodies. Inclusion bodies were sequentially washed several times in lysis buffer containing additional 0.1% Trition-X100 and 1 M urea, and after each washing procedure inclusion bodies were pelleted by centrifugation at 5000 rpm. during 20 minutes. Purified inclusion bodies were dissolved in a buffer containing 50 mM Tris-Cl, pH 8.0, 25 mM NaCl, 20 mM 2-mercaptoethanol and 8 M urea. The solution was clarified by centrifugation at 14,000 rpm. and loaded, at room temperature, on a 300 ml Fast Flow Q-Sepharose column (Pharmacia, Piscataway, NJ) equilibrated with the same buffer. Under these conditions, HIV PR did not bind to the column, so almost pure enzyme was found in the flow-through fractions. To renature the protein, fractions from the Fast Flow Q-Sepharose column were dialyzed against three changes of buffer containing 25 mM NaH2PO4 pH 7.0, 25 mM NaCl, 10 mM DTT, and 10% glycerol. After collection, small amounts of the precipitated substance are removed by centrifugation and the resulting enzyme preparation is concentrated, dialyzed against 0.5 M NaCl, 50 mM MES pH 5.6, 10 mM DTT, frozen in small aliquots of ~2 mg/ml and stored at -70°C .

Test i analiza kinetike čvrstog vezanja Assay and analysis of tight binding kinetics

Proteolitička aktivnost pročišćene HIV-1 proteaze mjerena je pomoću preinačenog kromogenog testa koji su razvili Richards i sur. (Richards, A.D. i sur., J. Biol. Chem., 256, 773-7736 (1990)). Sintetički peptid His-Lys-Ala-Arg- Val-Leu-Phe(paraNO2)-Glu-Ala-Nle-Ser-NH2 (American Peptide Company) (Nle je norleucin) upotrijebljen je kao supstrat. Test je proveden u 0.5 M NaCl, 50 mM MES pH 5.6, 5 mM DDT i 2% DMSO, na 37°C. Kidanje veze između leucina i paranitro-fenilalanina (Phe para-NO2) ispitivano je spektrofotometrijskim praćenjem pada apsorbancije na 305 nm. Početna brzina određena je kao brzina pada apsorbancije tijekom prvih 100 sekundi enzimske reakcije. Pod ovim uvjetima, uz Q7S HIV-1 proteazu, Michaelisova konstanta (Km) ovog supstrata je 59 ± 17 μM. Proteolytic activity of purified HIV-1 protease was measured using a modified chromogenic assay developed by Richards et al. (Richards, A.D. et al., J. Biol. Chem., 256, 773-7736 (1990)). The synthetic peptide His-Lys-Ala-Arg-Val-Leu-Phe(paraNO2)-Glu-Ala-Nle-Ser-NH2 (American Peptide Company) (Nle is norleucine) was used as a substrate. The test was performed in 0.5 M NaCl, 50 mM MES pH 5.6, 5 mM DDT and 2% DMSO, at 37°C. The breaking of the bond between leucine and paranitro-phenylalanine (Phe para-NO2) was investigated by spectrophotometric monitoring of the drop in absorbance at 305 nm. The initial rate was determined as the rate of decrease in absorbance during the first 100 seconds of the enzymatic reaction. Under these conditions, with Q7S HIV-1 protease, the Michaelis constant (Km) of this substrate is 59 ± 17 μM.

Za određivanje inhibicije spoja 21, korištena je koncentracija zasićenja supstrata od 200 μM. Između 13 i 20 koncentracije inhibitora su procijenjene i brzina reakcije je mjerena za svaku koncentraciju, kako je gore opisano. Očiti Ki (Ki app.), koji je ranije izložen, određen je nelinearnim sparivanjem najmanjih kvadrata podataka uz pomoć računala, prema Morrisonovoj jednadžbi (Morrison, J.F., Biochem. Biophys. Acta, 185, 269-286 (1963)). To determine the inhibition of compound 21, a saturating substrate concentration of 200 μM was used. Between 13 and 20 inhibitor concentrations were evaluated and the reaction rate was measured for each concentration, as described above. Apparent Ki (Ki app.), set forth earlier, was determined by computer-aided nonlinear least-squares fitting of the data, according to Morrison's equation (Morrison, J.F., Biochem. Biophys. Acta, 185, 269-286 (1963)).

Primjer 3 Example 3

Protuvirusno djelovanje spoja 21 protiv HIV-1 u kulturi stanica Antiviral activity of compound 21 against HIV-1 in cell culture

Stanice i sojevi virusa: Virus cells and strains:

CEM-SS i MT-2 linije ljudskih T stanica i sojevi HIV-a RF i IIIB dobiveni su od AIDS Research and Reference Program, Division of AIDS, NIAID, i NIH. CEM-SS and MT-2 human T cell lines and HIV strains RF and IIIB were obtained from the AIDS Research and Reference Program, Division of AIDS, NIAID, and NIH.

Testovi zaštite stanica: Cell protection tests:

Inhibicijski učinci pojedinog sredstva na replikaciju HIV-1 mjereni su redukcijskim postupkom s MTT bojenjem (Alley, M.C. i sur., Cancer Res. 48: 589-601 (1988)). Spojevi su otopljeni u DMSO u koncentraciji od 40 mg/ml, potom razrijeđeni 1:200 u mediju za kultiviranje (RPMI, opremljen s 10% fetalnog goveđeg seruma). Iz svakog razrijeđenog punjenja, 100 μL je dodano u ploču s 96 jamica i pripravljena su polulogaritamska razrjeđenja. U posebnim epruvetama, MT-2 stanice i CEM-SS stanice inficirane su s HIV-1 IIIB ili HIV-1 RF mnogostrukošću infekcija (m.i.) od 0.01, odnosno 0.03. Nakon četverosatnog razdoblja adsorpcije, 100 μL inficiranih ili neinficiranih stanica dodano je u jamice ploče koja sadrži lijek, do konačne koncentracije od 1 x 104 stanica po jamici. Nakon 6 (CEM-SS stanice), odnosno 7 dana (MT-2 stanice), testnim pločama je dodan MTT (5 mg/ml) i određena je količina nastalog formazana spektrofotometrijski, na 570 nm. Podaci su izraženi kao postotak formazana nastalog u stanicama izloženih lijeku u odnosu na formazan koji je nastao u jamicama neinficiranih, lijeku neizloženih stanica. ED50 je izračunata kao koncentracija lijeka koja je smanjila postotak nastalog formazana u inficiranim, lijeku izloženim stanicama na 50% one količine koja je nastala u neinficiranim, lijeku neizloženim stanicama. Citotoksičnost (TC50) je izračunata kao koncentracija lijeka koja smanjuje postotak formazana nastalog u neinficiranim, lijeku izloženim stanicama na 50% vrijednosti proizvedene u neinficiranim, lijeku neizloženim stanicama. Terapijski indeks (TI) izračunat je dijeljenjem citotoksičnosti (TC50) s protuvirusnom učinkovitošću (ED50). The inhibitory effects of each agent on HIV-1 replication were measured by the reduction method with MTT staining (Alley, M.C. et al., Cancer Res. 48: 589-601 (1988)). Compounds were dissolved in DMSO at a concentration of 40 mg/ml, then diluted 1:200 in culture medium (RPMI, supplemented with 10% fetal bovine serum). From each diluted load, 100 μL was added to a 96-well plate and half-log dilutions were prepared. In separate tubes, MT-2 cells and CEM-SS cells were infected with HIV-1 IIIB or HIV-1 RF at a multiplicity of infection (m.i.) of 0.01 and 0.03, respectively. After a four-hour adsorption period, 100 μL of infected or uninfected cells were added to the wells of the drug-containing plate, to a final concentration of 1 x 10 4 cells per well. After 6 (CEM-SS cells) or 7 days (MT-2 cells), MTT (5 mg/ml) was added to the test plates and the amount of formed formazan was determined spectrophotometrically at 570 nm. Data are expressed as the percentage of formazan formed in cells exposed to the drug relative to formazan formed in the wells of uninfected, drug-unexposed cells. The ED50 was calculated as the drug concentration that reduced the percentage of formazan formed in infected, drug-exposed cells to 50% of the amount formed in uninfected, drug-exposed cells. Cytotoxicity (TC50) was calculated as the concentration of drug that reduced the percentage of formazan produced in uninfected, drug-exposed cells to 50% of the value produced in uninfected, unexposed cells. Therapeutic index (TI) was calculated by dividing cytotoxicity (TC50) by antiviral efficacy (ED50).

Tablica 1 Table 1

Procjena protuvirusnog djelovanja i citotoksičnosti spoja 21 u akutnoj infekciji CEM-SS stanica virusom HIV-1 RF Evaluation of antiviral activity and cytotoxicity of compound 21 in acute infection of CEM-SS cells with HIV-1 RF virus

[image] [image]

a terapijski indeks = citotoksičnost (TC50) ÷ protuvirusna aktivnost (ED50). and therapeutic index = cytotoxicity (TC50) ÷ antiviral activity (ED50).

Tablica 2 Table 2

Procjena protuvirusnog djelovanja i citotoksičnosti spoja 21 u akutnoj infekciji MT-2 stanica virusom HIV-1 IIIB Assessment of antiviral activity and cytotoxicity of compound 21 in acute infection of MT-2 cells with HIV-1 IIIB virus

[image] [image]

a terapijski indeks = citotoksičnost (TC50) ÷ protuvirusna aktivnost (ED50). and therapeutic index = cytotoxicity (TC50) ÷ antiviral activity (ED50).

Kao što je ranije navedeno, spojevi ovog izuma korisni su za inhibiranje proteaze HIV-a, enzima povezanog sa stvaranjem i sklapanjem čestica virusa. Ovaj izum donosi postupak liječenja infekcije HIV-om koji uključuje primjenu na domaćina ili bolesnika, kao što je primat, učinkovite količine spoja formule (9) ili njegove farmaceutski prikladne soli. Ovaj izum također donosi postupak liječenja AIDS-a koji uključuje primjenu na domaćina ili bolesnika učinkovite količine spoja formule (9) ili njegove farmaceutski prikladne soli. Ovaj izum donosi i postupak inhibiranja proteaze HIV-a koji uključuje primjenu na stanicu zaraženu HIV-om, ili na domaćina ili bolesnika, kao što je primat, zaraženog HIV-om, učinkovite količine spoja formule (1) ili njegove farmaceutski prikladne soli. As noted earlier, the compounds of this invention are useful for inhibiting HIV protease, an enzyme involved in the formation and assembly of virus particles. The present invention provides a method of treating HIV infection comprising administering to a host or patient, such as a primate, an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof. The present invention also provides a method of treating AIDS comprising administering to a host or patient an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof. The present invention also provides a method of inhibiting HIV protease comprising administering to an HIV-infected cell, or to a host or patient, such as a primate, infected with HIV, an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof.

Izraz “učinkovita količina” znači količinu spoja formule (9), ili njegove farmaceutski prikladne soli, koja je učinkovita u proteazom HIV-a posredovano inhibiranje stvaranja i sklapanja virusnih čestica. Razumljivo je da je specifična doza spoja primijenjenog prema ovom izumu, u svrhu postizanja terapijskih ili inhibicijskih učinaka, određena prema posebnim okolnostima pojedinog slučaja primjene, a te okolnosti uključuju, na primjer, pojedini primijenjeni spoj, način primjene, stanje koje se liječi, kao i pojedini domaćin ili bolesnik koji se liječi. Primjera radi, dnevna doza (koja se primjenjuje odjednom ili podijeljena u više obroka) je u rasponu od oko 0.01 do oko 50 mg spoja ovog izuma/kg tjelesne težine. Preporučene dnevne doze općenito su od oko 0.05 mg/kg do oko 40 mg/kg, još bolje od oko 1.0 mg/kg do oko 30 mg/kg. The term "effective amount" means an amount of a compound of formula (9), or a pharmaceutically acceptable salt thereof, which is effective in inhibiting HIV protease-mediated production and assembly of viral particles. It is understood that the specific dose of the compound administered according to this invention, for the purpose of achieving therapeutic or inhibitory effects, is determined according to the particular circumstances of the individual case of application, and these circumstances include, for example, the particular compound administered, the method of administration, the condition being treated, as well as individual host or patient being treated. For example, a daily dose (administered at once or divided into several meals) is in the range of about 0.01 to about 50 mg of the compound of this invention/kg of body weight. Recommended daily doses are generally from about 0.05 mg/kg to about 40 mg/kg, more preferably from about 1.0 mg/kg to about 30 mg/kg.

Spojevi ovog izuma mogu se primjenjivati na različite načine, uključujući peroralni, rektalni, transdermalni, supkutani, intravenski, intramuskularni i intranazalni. Spojevi ovog izuma preporučljivo se pripravljaju uoči primjene. Stoga ovaj izum donosi i farmaceutski pripravak koji sadrži učinkovitu količinu spoja formule (9) ili njegove farmaceutski prikladne soli i farmaceutski prikladnog nosača, kao što su sredstva za razrjeđivanje ili ekscipijensi. The compounds of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds of this invention are preferably prepared before use. Therefore, the present invention also provides a pharmaceutical composition containing an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, such as diluents or excipients.

Aktivni sastojak preporučljivo zauzima od 0.1% do 99.9% ukupne mase pripravka. “Farmaceutski prikladan” znači da je nosač, kao što su sredstvo za razrjeđivanje ili ekscipijens, kompatibilan s ostalim sastojcima pripravka, a pritom nije štetan za domaćina ili bolesnika. The active ingredient preferably occupies from 0.1% to 99.9% of the total mass of the preparation. "Pharmaceutically acceptable" means that the carrier, such as a diluent or excipient, is compatible with the other ingredients of the formulation while not being harmful to the host or patient.

Farmaceutski pripravci mogu se pripraviti od spojeva ovog izuma poznatim postupcima, uporabom poznatih i lako dostupnih sastojaka. Prilikom izrade pripravaka ovog izuma, aktivni sastojak se obično primiješa nosaču, ili se razrijedi nosačem, ili se obloži nosačem, koji može biti u obliku kapsule, vrećice, papirića ili drugog prikladnog spremnika. Kada nosač služi kao razrjeđivač, on može biti kruta, polukruta ili tekuća tvar koja se ponaša kao vehikulum, ekscipijens ili medij za aktivni sastojak. Prema tome, pripravci mogu biti u obliku tableta, pilula, prašaka, pastila, vrećica, cacheta, eliksira, suspenzija, emulzija, otopina, sirupa, aerosola (u krutom stanju ili u tekućem mediju), masti (u kojima aktivni sastojak zauzima, na pr., do 10% ukupne težine), mekih i tvrdih želatinskih kapsula, supozitorija, sterilnih otopina za injiciranje, sterilno pakiranih prašaka i sličnog. Pharmaceutical preparations can be prepared from the compounds of this invention by known procedures, using known and readily available ingredients. When preparing the preparations of this invention, the active ingredient is usually mixed with a carrier, or diluted with a carrier, or coated with a carrier, which may be in the form of a capsule, sachet, paper or other suitable container. When a carrier serves as a diluent, it may be a solid, semi-solid or liquid substance that acts as a vehicle, excipient or medium for the active ingredient. Therefore, preparations can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in a solid state or in a liquid medium), ointments (in which the active ingredient occupies, on e.g., up to 10% of the total weight), soft and hard gelatin capsules, suppositories, sterile injection solutions, sterile packaged powders and the like.

Primjeri pripravaka koji slijede prikazani su samo radi ilustracije, a nisu namijenjeni ograničavanju područja izuma. Izraz “aktivni sastojak” predstavlja spoj formule (9) ili njegovu farmaceutski prikladnu sol. The examples of preparations that follow are presented for illustration purposes only and are not intended to limit the scope of the invention. The term "active ingredient" represents a compound of formula (9) or a pharmaceutically acceptable salt thereof.

Pripravak 1 Preparation 1

Tvrde želatinske kapsule pripravljaju se od slijedećih sastojaka: Hard gelatin capsules are prepared from the following ingredients:

[image] [image]

Pripravak 2 Preparation 2

Tableta se pripravlja od dolje nabrojanih sastojaka: The tablet is prepared from the ingredients listed below:

[image] [image]

Sastojci se izmiješaju i stlače, čime se dobiju tablete težine 665 mg. The ingredients are mixed and pressed, resulting in tablets weighing 665 mg.

Pripravak 3 Preparation 3

Aerosolska otopina se pripravi od slijedećih sastojaka: The aerosol solution is prepared from the following ingredients:

[image] [image]

Aktivni spoj se pomiješa s etanolom i smjesa se doda dijelu potisnog plina 22, ohladi na -30°C i prenese u napravu za punjenje. Potrebna količina se potom stavi u spremnik od nerđajućeg čelika i razrijedi s ostatkom potisnog plina. Na spremnik se potom pričvršćuju ventili. The active compound is mixed with ethanol and the mixture is added to the propellant gas portion 22, cooled to -30°C and transferred to the filling device. The required amount is then placed in a stainless steel container and diluted with the rest of the propellant gas. Valves are then attached to the tank.

Pripravak 4 Preparation 4

Tablete, od kojih svaka sadrži 60 mg aktivnog sastojka, slijedećeg su sastava: The tablets, each of which contains 60 mg of the active ingredient, have the following composition:

[image] [image]

Aktivni sastojak, škrob i celuloza propuste se kroz SAD sito br. 45 i dobro pomiješaju. Vodena otopina koja sadrži polivinilpirolidon se pomiješa s dobivenim praškom i smjesa se potom propusti kroz SAD sito br. 14. Tako dobivena zrnca suše se na 50°C i propuste kroz SAD sito br. 18. Natrij karboksimetil škrob, magnezij stearat i talk, prethodno propušteni kroz SAD sito br. 60, se dodaju zrncima, a nakon miješanja se vrši stlačivanje na stroju za tablete, čime se dobiju tablete pojedinačne težine 150 mg. The active ingredient, starch and cellulose are passed through USA sieve no. 45 and mix well. An aqueous solution containing polyvinylpyrrolidone is mixed with the resulting powder and the mixture is then passed through a USA sieve no. 14. The grains obtained in this way are dried at 50°C and passed through SAD sieve no. 18. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through USA sieve no. 60, are added to the granules, and after mixing, they are compressed on a tablet machine, which results in tablets with a single weight of 150 mg.

Pripravak 5 Preparation 5

Kapsule, od kojih svaka sadrži 80 mg aktivnog sastojka, priprave se od slijedećeg: Capsules, each of which contains 80 mg of the active ingredient, are prepared from the following:

[image] [image]

Aktivni sastojak, celuloza, škrob i magnezij stearat se pomiješaju, propuste kroz SAD sito br. 45 i pune u kapsule od tvrde želatine, po 200 mg. The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through USA sieve no. 45 and filled in hard gelatin capsules, 200 mg each.

Pripravak 6 Preparation 6

Supozitoriji, od kojih svaki sadrži po 225 mg aktivnog sastojka, sastavljeni su od slijedećeg: Suppositories, each of which contains 225 mg of the active ingredient, are composed of the following:

[image] [image]

Aktivni sastojak se propušta kroz SAD sito br. 60 i suspendira u gliceridima zasićenih masnih kiselina koji su prethodno rastaljeni uz korištenje minimalne potrebne topline. Smjesa se potom lijeva u kalupe za supozitorije nominalnog kapaciteta od 2 g, te se ostavi hladiti. The active ingredient is passed through US sieve no. 60 and suspended in glycerides of saturated fatty acids that have been previously melted using the minimum necessary heat. The mixture is then poured into suppository molds with a nominal capacity of 2 g and left to cool.

Pripravak 7 Preparation 7

Suspenzije, od kojih svaka sadrži 50 mg aktivnog sastojka na 5 ml doze , su sastavljene od slijedećeg: The suspensions, each of which contains 50 mg of the active ingredient per 5 ml dose, are composed of the following:

[image] [image]

Aktivni sastojak se propušta kroz SAD sito br. 45 i miješa s natrij karboksimetilcelulozom i sirupom, čime se dobije glatka pasta. Otopina benzojeve kiseline, aroma i boja se razrijede s dijelom vode i dodaju uz miješanje. Potom se doda dovoljno vode da bi se postigao traženi volumen. The active ingredient is passed through US sieve no. 45 and mixed with sodium carboxymethylcellulose and syrup, resulting in a smooth paste. The benzoic acid solution, aroma and color are diluted with a portion of water and added while stirring. Then enough water is added to reach the required volume.

Pripravak 8 Preparation 8

Intravenski pripravak pripravi se na slijedeći način: The intravenous preparation is prepared as follows:

[image] [image]

Otopina gornjeg sastava se primjenjuje intravenski na primatelja brzinom od 1 ml na minutu. The solution of the above composition is administered intravenously to the recipient at a rate of 1 ml per minute.

Pripravak 9 Preparation 9

Tableta se priprema od ovih sastojaka: The tablet is prepared from these ingredients:

[image] [image]

Claims (37)

1. Spoj formule (9): [image] naznačen time, što su: R i R’ neovisno odabrani između H, supstituirane ili nesupstituirane alkil-OR1 skupine, cikloalkilne skupine supstituirane (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, heterociklo skupine supstituirane (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, alkil-NR2R3 skupine ili alkil-S(X)(Y)R4 skupine, pri čemu R1 je H, supstituirana ili nesupstituirana alkilna skupina, ili acilna skupina; R2 i R3 su svaki neovisno odabran između H, supstituirane ili nesupstituirane alkil, cikloalkil, heterociklo i arilne skupine, i acilne i sulfonilne skupine; R4 je H, supstituirana ili nesupstituirana alkil, cikloalkil, heterociklo ili arilna skupina; a X i Y su svaki neovisno odabran između =O i ničega; ili njegov farmaceutski prikladan prolijek, sol ili otopina.1. Compound of formula (9): [image] characterized by the fact that they are: R and R' are independently selected from H, a substituted or unsubstituted alkyl-OR1 group, a cycloalkyl group substituted by a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, a heterocyclo group substituted by a (C1-C6)alkyl group or ( C1-C6)alkyl-OH group, alkyl-NR2R3 group or alkyl-S(X)(Y)R4 group, whereby R 1 is H, a substituted or unsubstituted alkyl group, or an acyl group; R 2 and R 3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, heterocyclo and aryl groups, and acyl and sulfonyl groups; R 4 is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocyclo or aryl group; And X and Y are each independently selected from =O and nothing; or a pharmaceutically acceptable prodrug, salt or solution thereof. 2. Spoj prema zahtjevu 1, naznačen time, što je R H, ili njegov farmaceutski prikladan prolijek, sol ili otopina.2. A compound according to claim 1, characterized in that R is H, or a pharmaceutically acceptable prodrug, salt or solution thereof. 3. Spoj prema zahtjevu 1, naznačen time, što je najmanje jedan od R i R’ alkil-OR1 skupina, R1 je H, ili njegov farmaceutski prikladan prolijek, sol ili otopina.3. The compound according to claim 1, characterized in that at least one of R and R' is an alkyl-OR1 group, R1 is H, or its pharmaceutically suitable prodrug, salt or solution. 4. Spoj prema zahtjevu 1, naznačen time, što je najmanje jedan od R i R’ alkil-OR1 skupina, s time da je spomenuta alkil-OR1 skupina odabrana između -C(CH3)2CH2OH, -CH(CH3)CH2OH, -CH2CH2OH, -C(CH3)(CH2OH)2, -C(CH3)2-O-CH2-O-CH3, -C(CH3)2CH2-O-CH2-O-CH3, -C(CH3)2CH2-O-acil, -C(CH3)2-S-CH2-O-CH3-, -C(CH3)2CH2-S-CH2-O-CH3-, -C(CH3)2-O-CH2-S-CH3, -C(CH3)2CH2-O-CH2-S-CH3 i -C(CH3)2CH2-S-acil ili njegovog farmaceutski prikladnog prolijeka, soli ili otopine.4. The compound according to claim 1, characterized in that at least one of R and R' is an alkyl-OR1 group, with the said alkyl-OR1 group being selected from -C(CH3)2CH2OH, -CH(CH3)CH2OH, - CH2CH2OH, -C(CH3)(CH2OH)2, -C(CH3)2-O-CH2-O-CH3, -C(CH3)2CH2-O-CH2-O-CH3, -C(CH3)2CH2-O -acyl, -C(CH3)2-S-CH2-O-CH3-, -C(CH3)2CH2-S-CH2-O-CH3-, -C(CH3)2-O-CH2-S-CH3, -C(CH3)2CH2-O-CH2-S-CH3 and -C(CH3)2CH2-S-acyl or a pharmaceutically acceptable prodrug, salt or solution thereof. 5. Spoj prema zahtjevu 1, naznačen time, što je najmanje jedan od R i R’ cikloalkilna skupina supstituirana s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, s time da je spomenuta cikloalkilna skupina odabrana između: [image] ili njegov farmaceutski prikladan prolijek, sol ili otopina.5. A compound according to claim 1, characterized in that at least one of R and R' is a cycloalkyl group substituted with a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, with the said cycloalkyl group being selected from : [image] or a pharmaceutically acceptable prodrug, salt or solution thereof. 6. Spoj prema zahtjevu 1, naznačen time, što je najmanje jedan od R i R’ heterociklo skupina supstituirana s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, s time da je spomenuta heterociklo skupina odabrana između: [image] pri čemu je R3 H, supstituirani ili nesupstituirani alkil, cikloalkil, heterociklo ili arilna skupina, ili acilna ili sulfonilna skupina, ili njegov farmaceutski prikladan prolijek, sol ili otopina.6. Compound according to claim 1, characterized in that at least one of the R and R' heterocyclo groups is substituted with a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, with the said heterocyclo group being selected from : [image] wherein R 3 is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocyclo or aryl group, or an acyl or sulfonyl group, or a pharmaceutically acceptable prodrug, salt or solution thereof. 7. Spoj prema zahtjevu 1, naznačen time, što ima formulu 21: [image] ili njegov farmaceutski prikladan prolijek, sol ili otopina.7. The compound according to claim 1, characterized in that it has the formula 21: [image] or a pharmaceutically acceptable prodrug, salt or solution thereof. 8. Spoj prema zahtjevu 2, naznačen time, što je R’ cikloalkilna skupina supstituirana s (C1-C6)alkilnom skupinom ili (C1-C6)alkil-OH skupinom, s time da je spomenuta cikloalkilna skupina odabrana između: [image] ili njegov farmaceutski prikladan prolijek, sol ili otopina.8. A compound according to claim 2, characterized in that R' is a cycloalkyl group substituted with a (C1-C6)alkyl group or a (C1-C6)alkyl-OH group, with the said cycloalkyl group being selected from: [image] or a pharmaceutically acceptable prodrug, salt or solution thereof. 9. Sol prema zahtjevu 1, naznačen time, što ima formulu (9b): [image] 9. Salt according to claim 1, characterized in that it has the formula (9b): [image] 10. Farmaceutski pripravak, naznačen time, što sadrži: (a) učinkovitu količinu spoja iz zahtjeva 1; i (b) farmaceutski prikladan nosač za njega.10. Pharmaceutical preparation, characterized by the fact that it contains: (a) an effective amount of the compound of claim 1; and (b) a pharmaceutically acceptable carrier therefor. 11. Farmaceutski pripravak, naznačen time, što sadrži: (a) učinkovitu količinu spoja iz zahtjeva 7; i (b) farmaceutski prikladan nosač za njega.11. Pharmaceutical preparation, characterized by the fact that it contains: (a) an effective amount of the compound of claim 7; and (b) a pharmaceutically acceptable carrier therefor. 12. Postupak inhibiranja proteaze HIV-a, naznačen time, što obuhvaća primjenu na domaćina učinkovite količine spoja iz zahtjeva 1 ili njegovog farmaceutski prikladnog prolijeka, soli ili otopine.12. A method of inhibiting HIV protease, characterized in that it comprises administering to the host an effective amount of the compound of claim 1 or its pharmaceutically suitable prodrug, salt or solution. 13. Postupak inhibiranja proteaze HIV-a, naznačen time, što obuhvaća primjenu na domaćina učinkovite količine spoja iz zahtjeva 7 ili njegovog farmaceutski prikladnog prolijeka, soli ili otopine.13. A method of inhibiting HIV protease, characterized in that it comprises administering to the host an effective amount of the compound of claim 7 or its pharmaceutically suitable prodrug, salt or solution. 14. Spoj prema zahtjevu 1, naznačen time e, što mu je čistoća veća od 90%.14. Compound according to claim 1, indicated by e, which has a purity greater than 90%. 15. Spoj prema zahtjevu 1, naznačen time, što mu je čistoća najmanje 95%.15. Compound according to claim 1, characterized in that its purity is at least 95%. 16. Spoj prema zahtjevu 1, naznačen time, što mu je čistoća najmanje 97%.16. Compound according to claim 1, characterized in that its purity is at least 97%. 17. Spoj prema zahtjevu 1, naznačen time, što mu je čistoća najmanje 99%.17. Compound according to claim 1, characterized in that its purity is at least 99%. 18. Spoj prema zahtjevu 7, naznačen time, što mu je čistoća veća od 90%.18. Compound according to claim 7, characterized in that its purity is greater than 90%. 19. Spoj prema zahtjevu 7, naznačen time, što mu je čistoća najmanje 95%.19. Compound according to claim 7, characterized in that its purity is at least 95%. 20. Spoj prema zahtjevu 7, naznačen time, što mu je čistoća najmanje 97%.20. The compound according to claim 7, characterized in that its purity is at least 97%. 21. Spoj prema zahtjevu 7, naznačen time, što mu je čistoća najmanje 99%.21. The compound according to claim 7, characterized in that its purity is at least 99%. 22. Farmaceutski pripravak prema zahtjevu 10, naznačen time, što je čistoća spoja veća od 90%.22. Pharmaceutical preparation according to claim 10, characterized in that the purity of the compound is greater than 90%. 23. Farmaceutski pripravak prema zahtjevu 10, naznačen time, što je čistoća spoja najmanje 95%.23. Pharmaceutical preparation according to claim 10, characterized in that the purity of the compound is at least 95%. 24. Farmaceutski pripravak prema zahtjevu 10, naznačen time, što je čistoća spoja najmanje 97%.24. Pharmaceutical preparation according to claim 10, characterized in that the purity of the compound is at least 97%. 25. Farmaceutski pripravak prema zahtjevu 10, naznačen time, što je čistoća spoja najmanje 99%.25. Pharmaceutical preparation according to claim 10, characterized in that the purity of the compound is at least 99%. 26. Farmaceutski pripravak prema zahtjevu 11, naznačen time, što je čistoća spoja veća od 90%.26. Pharmaceutical preparation according to claim 11, characterized in that the purity of the compound is greater than 90%. 27. Farmaceutski pripravak prema zahtjevu 11, naznačen time, što je čistoća spoja najmanje 95%.27. Pharmaceutical preparation according to claim 11, characterized in that the purity of the compound is at least 95%. 28. Farmaceutski pripravak prema zahtjevu 11, naznačen time e, što je čistoća spoja najmanje 97%.28. Pharmaceutical preparation according to claim 11, characterized in that the purity of the compound is at least 97%. 29. Farmaceutski pripravak prema zahtjevu 11, naznačen time, što je čistoća spoja najmanje 99%.29. Pharmaceutical preparation according to claim 11, characterized in that the purity of the compound is at least 99%. 30. Postupak prema zahtjevu 12, naznačen time, što je čistoća spoja veća od 90%.30. The method according to claim 12, characterized in that the purity of the compound is greater than 90%. 31. Postupak prema zahtjevu 12, naznačen time, što je čistoća spoja najmanje 95%.31. The method according to claim 12, characterized in that the purity of the compound is at least 95%. 32. Postupak prema zahtjevu 12, naznačen time, što je čistoća spoja najmanje 97%.32. The method according to claim 12, characterized in that the purity of the compound is at least 97%. 33. Postupak prema zahtjevu 12, naznačen time, što je čistoća spoja najmanje 99%.33. The method according to claim 12, characterized in that the purity of the compound is at least 99%. 34. Postupak prema zahtjevu 13, naznačen time, što je čistoća spoja veća od 90%.34. The method according to claim 13, characterized in that the purity of the compound is greater than 90%. 35. Postupak prema zahtjevu 13, naznačen time, što je čistoća spoja najmanje 95%.35. The method according to claim 13, characterized in that the purity of the compound is at least 95%. 36. Postupak prema zahtjevu 13, naznačen time, što je čistoća spoja najmanje 97%.36. The method according to claim 13, characterized in that the purity of the compound is at least 97%. 37. Postupak prema zahtjevu 13, naznačen time, što je čistoća spoja najmanje 99%.37. The method according to claim 13, characterized in that the purity of the compound is at least 99%.
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