BG63540B1 - Hiv protease inhibitors - Google Patents

Abstract

HIV protease inhibitors are obtained by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. The compounds, as well as the pharmaceutical compositions that contain them, and optionally other anti-viral agents as active ingredients are suitable for treating patients or hosts infected with the HIV virus which is known to cause AIDS. 37 claims

Description

The present invention relates to a new series of chemical compounds useful as HIV protease inhibitors and to the administration of such compounds as antiviral agents.

BACKGROUND OF THE INVENTION

Acquired immune deficiency syndrome (AIDS) is a relatively new disease or condition. AIDS causes increasing destruction of the body's immune system, as well as progressive deterioration of the central and peripheral nervous systems. Since its inception in the early 80's, AIDS has spread rapidly and has now reached epidemic proportions in a relatively limited segment of the population. Intensive research has led to the discovery of the causative agent, human T-lymphotrol retrovirus III (HTLV-III), now more commonly referred to as human immunodeficiency virus or HIV. HIV is a member of a class of viruses known as retroviruses. The retroviral genome is made up of a retroviral RNA that is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into the host cell chromosome and, using a process of replication of the host cells, produces new retroviral particles and the infection progresses to other cells. HIV seems to have a special affinity for human T-4 lymphocyte cells, which play a vital role in the body's immune system. The HIV infection of these white blood cells depletes their population. Finally, the immune system is rendered inoperative and ineffective against various pathogenic conditions, such as, among others, Plasma Cell Carini pneumonia, Kaposi's sarcoma and lymphatic cancer.

Although the exact mechanism of HIV virus formation and action has not been understood, identification of the virus has led to some progress in controlling the disease. For example, azidothymidine (AZT) has been found to be effective in inhibiting the imaging transcription of the HIV retroviral genome, thus giving an idea, though not treatment, for patients affected by AIDS. It continues to take drugs that can cure, or at least provide, an improved view of controlling the deadly HIV virus.

Retroviral replication is usually the post-transglacial development of polyproteins. This development is accomplished by a virus-encoded HIV protease enzyme. This results in the development of advanced polypeptides that will further aid in the formation and function of the infectious virus. If this molecular development is stifled, then normal development of HIV is interrupted. Therefore, HIV poetase inhibitors may function as anti-HIV viral agents.

HIV protease is one of the translated products of the HIV structural protein ro! gen. This retroviral protease specifically cleaves other structural poly'G '' peptides at separate sites until the release of these newly activated structural proteins and enzymes, making the violin replication able to transform. Thus, the inhibition of HIV poetase by potent compounds can prevent proviral integration of infected T-lymphocytes during the early phase of the HV-1 life cycle, and also inhibit viral proteolytic development during its late stage. Additionally, protease inhibitors may have more readily available, longer-lived, and less toxic than currently available drugs, possibly due to their specificity for retroviral protease.

In accordance with this invention, is provided a new class of compounds that can inhibit and / or block the activity of HIV protease, which halt the proliferation of HIV virus, pharma pharmaceutical compositions _? containing these compounds, and using the compounds as HIV protease inhibitors.

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SUMMARY OF THE INVENTION

The present invention relates to compounds falling within the general formula (9) below, and their pharmaceutically acceptable salts, prodrugs and solvates thereof, which inhibit ^- the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1 ) or HIV 2. These compounds are useful in the treatment of HIV infection and the treatment of Acquired Immune Deficiency Syndrome (AIDS). Compounds ^- ehnite pharmaceutically acceptable salts and pharmaceutical compositions of the present invention may be used alone or in combination with other anti ^- iviousni agents, immunomodulators, antibiotics or vaccines. The compounds of us ^- oyashtoto invention may also be used as prodrug sredstEE. Methods for treating AIDS, methods for treating HIV infection, and methods for inhibiting HIV protease have been disclosed.

The compounds of the present invention are of the formula (9):

in which R and R 'are independently selected from H, a substituted or unsubstituted alkyl-OIT group, a cycloalkyl group substituted with a (C 1 -C ₆ ) alkyl group or (C 1 -C ₆ ) alkyl-OH group, a heterocyclic group, a substituted is a (C 1 -C 4 alkyl group or (C 1 -C ₆ ) alkyl-OH group, an alkyl-C 1-3 group or an alkyl-8 (X) (Y) P ₄ group, in which:

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, heterocyclic and aoyl groups and acyl or sulfonyl groups;

R ₄ is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic or aryl group; and

X and Y are each independently selected from = 0 and nothing;

or a pharmaceutically acceptable prodrug, salt or solvate thereof.

Preferably in the compounds of formula 9, R is H. More preferably, R is H 5 and R 'is a cycloalkyl group selected from:

OH CH ₃ CHjOH

Preferably in the compounds of formula 9, when at least one of R and R 'is alkyl-OR, a group, Rt is H. In particular, when at least one of R and R' is alkyl-OR! a group alkyl-OR- is selected from: -C (CH ₃ ) ₂ CH ₂ OH, -CH (CH ₃ ) CH ₂ OH, -CH ₂ CH ₂ OH, SO C (CH ₃ ) (CH ₂ OH) ₂ , -C (CH ₃ ) ₂ -O-CH ₂ -O-CH ₂ , -C (CH ₃ ) ₂ CH ₂ -O-CH ₂ -O-CH _3, and -C (CH ₂ ) ₂ -O-acyl , or a pharmaceutically acceptable prodrug, salt or solvate thereof.

Preferably, at least one of R and R 'is a cycloalkyl group _; substituted by a (C ₁ -C ₆ ) alkyl group or a (C 1 -C ₆ ) alkyl-OH group, the cycloalkyl group is selected from:

Preferably, when at least one of R and R 'is a heterocyclic group substituted by a (C 1 -C ₆ ) alkyl group or a (C 1 -C ₆ ) alkyl-OH group, the heterocyclic group is selected from:

wherein R ₃ is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic or aryl group, or an acyl or sulfonyl group.

A preferred form of formula (9) is (3S- [2 (2S *, 3S *), 3 alpha, 4a beta, 8a or 5 Ta]] - N- (1,1-dimethyl-2-hydroxyethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2methylbenzoyl) amino] -4- (phenylthio) boogyl] -3-isoquinolinecarboxamide

and its pharmaceutically acceptable salts and prodrug analogues. Preferred prodrugs can be prepared by substituting hydrogen in one of the alcohol groups with an acyl group and more preferably. with an amino acid acyl group.

The present invention further provides pharmaceutical formulations ₇ containing an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, 15 such as diluent or excipient.

The present invention further provides a method of treating AIDS.

comprising administering to the host or patient, such as a primate, an effective amount of a compound of the present invention.

The present invention further provides a method of inhibiting HIV replication comprising prescribing an HIV-infected cell, a cell susceptible to HIV infection or a host or patient, such as a primate, to an effective amount of a compound of the present invention.

Examples of carrying out the invention

The present invention provides novel compounds within the scope of the general formula (9) as described above that are useful for treating HIV infection and / or AIDS.

Applicants include, by reference, U.S. Patent No. 5,484,926, U.S. Patent Application No. 08/708 411 and 08/708 607, and Japan Patent Application JP 95248183 and JP 95-248184, with the warning that the definitions of preferences, terms, the variables, designations, and the like used in each query are only applicable to the corresponding disclosure of that query.

In particular, since each of the above-referenced queries included by reference has been prepared separately, the original queries may in some cases use the same terms, designations or variables to indicate something different. For example, the variable "X" is used in each query, but each query has its own different definition of the substituent or residue represented by that variable. It will be appreciated by those skilled in the art that the terms, designations, and variables in any reference incorporated by reference are limited solely to the disclosure of that application and may be substituted by other appropriate terms, designations, and variables, or the like, representing specific substituents or residues. Those of skill in the art will understand, of course, that any suitable group of terms, designations, and variables may be used to summarize or specify the matter disclosed herein, including terms, designations, variables, and the like. / 04735 to the disclosures included in the above identified claims and subsequent disclosure.

The compounds of formula (9) may be prodrugs that can serve to improve the pharmaceutical properties of the compounds, such as pharmacokinetic properties, for example, improved bioavailability or solubility. The preparation of the prodrugs can be accomplished by standard methods known to those skilled in the art. A preferred prodrug may be prepared by acylation or alkylation of the starting alcohol, with R or R 'being CH (CH ₃ ) ₂ CH ₂ OH.

All temperatures indicated here are in degrees Celsius (° C), all units used here are in units of weight except for liquids that are in units of volume.

The term "alkyl" as used herein refers to straight or branched chain groups, preferably having from one to eight, more preferably having from one to six, and most preferably having from one to four carbon atoms. The term "C <C _alkyl means a straight or branched alkyl chain having from one to six carbon atoms. Exemplary C 1 -C 8 alkyl groups include methyl, ethyl, npropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like. The term "C ₁ -C ₆ alkyl" includes in its definition the term "C ₁ -C ₄ alkyl".

The term "cycloalkyl" means a saturated or partially saturated, mono- or polycarbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings _; having from 3 to 7, preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. An exemplary cycloalkyl is C ₅ -C ₇ cycloalkyl, which is a saturated hydrocarbon ring system containing from five to seven carbon atoms.

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The term "alkoxyl" means N-alkyl. An example of apcoxyl is a C 1-6 alkoxy, which means a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Exemplary C1- _C6 alkoxyl groups include methoxy, ethoxy, propoxy, isopropoxy, bugoxy, sec-butoxy, tert, butoxy, pentoxy, hexoxy and the like. C ₁ -C ₆ alkoxyl includes C ₁ -C ₆ alkoxy within the scope of its definition.

The term "aryl" _? as used herein refers to a carbocyclic or heterocyclic, aromatic, 5-14 membered monocyclic or polycyclic ring. Exemplary aryls include phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, lridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazinyl, triazinyl, triazinyl, triazinyl ] thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl , acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl. : «

The term "aryloxy" means -O-aryl.

The term "hydrolysable group" is a group which, when attached to oxygen, forms an ester which can be hydrolyzed in vivo to a hydroxyl group. Exemplary hydrolysable groups which are optionally substituted include acyl function, sulfonate function and phosphate function. For example, such hydrolysable groups include blocked or unblocked amino acid residues, a hemisuccinate residue and a nicotine residue.

The term "halogen" means chlorine, fluorine, bromine or iodine. The term "halo" means chloro, fluoro, bromo or iodo.

The term "carbocycle" means an aromatic or saturated or partially saturated 5-14 membered monocyclic or polycyclic ring, such as a 5- to 7 membered monocyclic or 7- to 10 membered bicyclic ring, in which all the ring members are carbon atoms.

The term "heterocycle" means an aromatic or saturated or partially saturated 5-14 membered, monocyclic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered: bicyclic ring having from one to three heteroatoms selected from nitrogen, oxygen and xiao, and in which any nitrogen or sulfur heteroatom may be optionally oxidized, ζ any nitrogen heteroatom may be quaternized if desired. The heterocyclic ring may be attached to any suitable heteroatom or carbon atom. Examples of such heterocycles include decahydroisoquinolinyl, octahydrothieno-3,2-c] pyridinyl, piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, isobenzolidan, fidrazolidin, fidrazolidin , pyridazinyl, oxazolyl, saxazolidinyl, isoxazolyl, thiantrenyl, triazinyl, isoxazolidinyl, morpholines. ^- . thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl. quinolinyl, chromenyl, xanthenyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolil, furyl, tetrahydrofuryl, tetrahydopyrid / wounded, thienyl, benzothienyl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thiamorpholinyl, ^_ iamoroolinilsulfoksid, thiamorpholinyl , oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenoxathienyl, indolizinyl, isoindolyl. indazolin, isoquinolin, quinolin, indolinol, indolent, indolent

The term "thioether includes S-aryl such as phenylthio and naphthylthio; Sheterotsikal in which x is ^m erotsikylat is saturated or partially saturated, S- (C ₅ -C ₇₎ cycloalkyl; and S-alkyl, such as C1-C8 alkylthio. In the thioether, -aryl, -heterocycle, -cycloalkyl and -alkyl may be optionally substituted. An example of a thioether is "C 1 -C 6 alkylthio" which means straight or branched alkyl chain _? having from one to six carbon atoms attached to a sulfur atom. Exemplary C _1-6 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

L-.r-rA-lOSTL ' ⁷

The term "mercapto" means-SH.

The term "amino" means -NLL ₂ , where L and _1-2 are preferably independently selected from oxygen, carbocycle, heterocycle, alkyl, sulfonyl and hydrogen; or NC (O) L ₃ , wherein L ₃ is preferably alkyl, alkoxyl, hydrogen or -NLZ The aryl, alkyl and alkoxyl groups may be optionally substituted. An example of an amino is C -, - C ₄ alkylamino, which means a straight or branched alkyl chain having from one to four carbon atoms _? attached to an amino group. Exemplary alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, boogylamino, sec-butylamino and the like. Another example of an amino is di (C <SDalkilamino, which represents two straight or branched alkyl chains, each having from one to four carbon _atoms? Attached to a common amino group. Examples of di--SDalkilamino groups include dimethylamino, ethylmethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino and the like Example of an amino is C 1 -C ₄ alkylsulfonylamino having a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfonylamine moiety Exemplary C 1 -C ₄ alkylsulfonylamino other groups include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino and the like.

The term &quot; acyl &quot; means 1-C (O) C, where C is a single, bond, -O or -N, and additionally where _1-4 is preferably alkyl, amino, hydroxy, alkoxyl or hydrogen. The alkyl and alkoxyl groups may be optionally substituted. An exemplary acyl is a C, -C ₄ alkoxycarbonyl, which is a straight or branched alkoxyl chain having from one to four carbon atoms attached to a carbonyl moiety. Exemplary C 1 -C ₄ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like. Another exemplary acyl is carboxy, where C is a single bond and _1-4 is alkoxyl, hydrogen or hydroxyl. An additional exemplary acyl is 1- (C 1 -C ₄ ) alkylcarbamoyl (C 1 is a single bond and 1- ₄ is amino) which is a straight or branched alkyl chain having from one to four carbon atoms attached to the nitrogen atom of the carbamoyl

PCI / US98 / 047; 5

-rA-1C3727 residue. Exemplary N- (C 1 -C ₄ ) alkylcarbamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl and N-tert-butylcarbamoyl and the like. Another exemplary acyl is N, N-fln (C ₁ -C ₄ ) alkylcarbamoyl having two straight or branched alkyl chains, each having from one to four carbon atoms attached to the nitrogen atom of the carbamoyl moiety. Exemplary N-di-C 1 -C 6 alkylcarbamoyl groups include N, N-dimethylcarbamoyl, N, N-ethylmethyl carbamoyl, N, N-methylpropylcarbamoyl,

N, N-Ethylisopropyl-carbamoyl, N, N -butylmethylcarbamoyl, N, N-sec, butylethylcarbamoyl and the like.

The term "sulfinyl" means -SO-L ₅ where L- is preferably alkyl, amino, aryl, cycloalkyl or heterocycle. The alkyl, aryl, cycloalkyl and heterocycle can all be optionally substituted.

The term "sulfonyl" means -SO ₂ -L, wherein L- is preferably alkyl, aryl, cycloalkyl, heterocycle or amino. The alkyl, aryl, cycloalkyl and heterocycle can all be optionally substituted. An example of sulfonyl is C 1 -C ₄ alkylsulfonyl, which is a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfonyl moiety. Exemplary C _1-4 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, boilsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.

As noted above, many of the groups are optionally substituted. In fact, unless specifically noted, all of the groups defined by the terms defined in this application may be substituted or unsubstituted. For example, when the term "alkyl" is used, it should be understood that it covers both substituted and unsubstituted alkyl unless it is specifically stated that one or the other is excluded. Examples of alkyl and aryl substituents include mercapto, thioether, nitro (NO ₂ ), amino, aryloxy, halogen, hydroxy, alkoxy and acyl, as well as aryl, cycloalkyl and saturated or partially saturated heterocycles. Examples of heterocycle and cycloalkyl substituents include those listed above for alkyl and aryl as well as aryl and alkyl.

Exemplary substituted aryls include a phenyl or naphthyl ring _? substituted with one or more substituents, preferably one to three substituents, independently selected from halo, hydroxy, morpholino (C ₁ -C ₄ ) alkoxy carbonyl, pyridyl (C 1 -C ₄ ) alkoxycarbonyl, halo (C 3 -C ₄ ) alkyl, C-C ₄ alkyl, C 1 -C ₄ alkoxy, carboxy, C 1 -C ₄ alkoxycarbonyl, carbamoyl, N- (C 1 -C ₄ ) alkyl-carbamoyl, amino, C 1 -C ₄ alkylamino, di (C 3 -C ₄ ) alkylamino or a group of formula - (CH ₂ ) _a- N ⁷ where a is 1,2, 3 or 4; and R ⁷ is hydroxy, C _D C ₄ alkoxy, carboxy, C - C ₄ alkoxycarbonyl, amino, carbamoyl, C <C ₄ alkylamino or di (C <C ₄₎ alkylamino.

Another substituted alkyl is halo (C-O) alkyl, which means a straight or branched alkyl chain having from one to four carbon atoms having 1 to 3 halogen atoms attached thereto. Exemplary halo (C - _C4) alkyl groups include chloromethyl, 2bromoetil, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobugil, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.

Another substituted alkyl is hydroxy (C - SD alkyl which means a straight or branched _alkyl chain having from Oedipus to four carbon atoms with a hydroxy group attached to it. Exemplary hydroxy (C, _-C4) alkyl groups include hydroxymethyl,

2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl and the like.

Yet another substituted alkyl is 0 - C _e alkylthio (C - _C4) alkyl which is straight or branched C <C ₄ alkyl group having a C - C ₄ alkylthio group attached to it. Exemplary O, O, alkylthio-C 1 -C 6 alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl and the like.

Another exemplary substituted alkyl is heterocycle (C 1 -C ₄ ) alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with het. a bicycle attached to it. Exemplary heterocycle (C 1 -C ₄ ) alkyls include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl and the like.

Another exemplary substituted alkyl is arylC 1-6 alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms, with an aryl group attached thereto. Exemplary aryl (C 1 -C ₄ ) alkyl groups include phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.

The heterocycle may, for example, be substituted by 1,2 or 3 substituents independently selected from halo, halo (C ₁ -C ₄ ) alkyl, C 1-6 alkyl, C ₁ -C ₄ alkoxy, carboxy, C-CL alkoxycarbonyl, carbamoyl, M- (C-C ₄ ) alkylcarbamoyl, amino, C 1 -C ₄ alkylamino, di (C 1 -C ₄ ) alkylamino or a group having the structure - (CH ₂ ) _a -R ⁷ where a is 1,2, 3 or 4 and 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.

Examples of substituted heterocycles include 3-N-tert-butylcarboxamide decahydroisoquinolinyl, β-N-tert-butylcarboxamide octahydro-thieno [3,2-c] pyridinyl,

3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethyl pyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 4-6-methylisoquinolinyl, 4-6-methylisoquinolinyl, , 2,3,4tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-tert-butoxycarbonyl-1,2,3,4 isoquinolin-7-yl and the like.

Exemplary heterocyclic ring systems, labeled A or B _in vkpyuchvat (1)

5-membered monocyclic ring groups such as cotenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like; (2) 6 membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like; and (3) polycyclic heterocyclic ring groups such as decahydroisoquinolinyl, oxahydro-thieno [3,2-c] pyridinyl, benzo [b] thienyl, naphtho [2,3-b] thiantrenyl, isobenzofuranyl, chromenyl, xanthenyl and in whole or in part saturated their analogues.

The cycloalkyl may optionally be substituted by 1, 2 or 3 substituents independently selected from halo, halo (C 1 -C ₄ ) alkyl, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy, carboxy, C 1 -C ₄ alkoxycarbonyl, carbamoyl, C ₁ -C ₄ -alkylcarbamoyl, amino, C 1 -C ₄ alkylamino, di (C 1 -C ₄ ) alkylamino or a group having the structure - (CH ₂ ) _a- R ⁷ where a is 1,2, 3 or 4 and 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 6 alkylamino. Exemplary substituted cycloalkyl groups include 3-methylcyclopentyl, N-ethoxycyclohexyl, 5-carboxycycloheptyl, 6-chlorocyclohexyl and the like.

Exemplary substituted hydrolysable groups include N-benzyl glycyl, N-Cbz-L-valyl and N-methylnicotine

The compounds of the present invention have at least five asymmetry centers marked with an asterisk in the fsomule (9) below:

As a consequence of these purposeful ^_ oove of asymmetry, the compounds of the present invention can occur in any of the possible stereoisomeric forms, and can be used in mixtures h ~ stereoisomers, which can be optically active or racemic, or can 'be used alone as substantially pure stereoisomers, i. at least 95% pure. All asymmetric forms, individual stereoisomers and combinations thereof are within the scope of the present invention.

Individual stereoisomers may be obtained from their respective precursors by the methods described above, by re-dissolving the racemic mixture or by separating the diastereomers. Re-dissolving may be carried out in the psyche of a re-dissolving agent, by chromatography or by repeated crystallization, or by any combination of those techniques known in the art. Further details regarding resolutions can be ^- found in Jacques et al., Enantiomers, Racemates , and Resolutions, John Wiley & Sons , 1981.

Preferably the compounds of the present invention are substantially pure, i.e. over 50% pure. More preferably, the compounds are at least 75% pure. More preferably, the compounds are more than 90% pure. More preferably, the compounds are at least 95% pure, more preferably at least 97% pure and most preferably at least 99% pure.

As mentioned above, the invention includes pharmaceutically acceptable salts of the compounds defined by formula (9). A compound of this invention can have enough acidic, basic enough, or both types of functional groups, and react with any of a large number of inorganic or organic bases and inorganic or organic acids, respectively, to form a pharmaceutically acceptable salt.

The term pharmaceutically acceptable salt as used herein refers to salts of the compounds of the above formula that are substantially non-toxic to living organisms. Exemplary pharmaceutically acceptable salts include those salts obtained by reacting the compounds of the present invention with a mineral or organic acid or inorganic base. The reagents are generally mixed in a common solvent, such as diethylethe or benzene, for the acid addition salts, or water or alcohol for the basic addition salts. The salts are usually precipitated from the solution within one hour to ten days and can be isolated by filtration or other conventional methods. Such salts are known as acid addition or basic addition salts.

The acids that can be used to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like, and organic acids such as ρ-toluenesulfonic acid, methanesulfonic acid , p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.

Examples of pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, formate, formate, formate, propate propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malead butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalenate, phthalenate, phthalenate, phthalenate , phenylpropionate, phenylbutyrate, citrate, Act, γ-hidroksibugirat, glycollate, tartrate, methanesulfonate, prolansulfonat, naphthalene-1-sulfonate, naphthalene-2-suloonat, mandelate like.

Preferred pharmacists — for acceptable acid addition salts, are those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and those formed with organic acids, such as maleic acid and methanesulfonic acid.

The basic addition salts include those derived from inorganic and organic bases, such as ammonium or alkaline or alkaline earth metal hydroxides, carbonates, bicarbonates, and ^- approved. Such bases useful in the preparation of the salts of this invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydrox / d, calcium carbonate and the like. In particular, the potassium and sodium salts formed are preferred.

"Pharmaceutically acceptable: a prodrug" is intended to mean a compound that can be converted under physiological conditions or by solvolysis to a compound of sormula 9.

"Pharmaceutically acceptable oolvate" is intended to mean a solvate that retains the biologically effective: ^- and properties of the biologically active components of the compounds of formula 9.

Examples of biologically acceptable solvates include, but are not limited to, compounds of formula 9 in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or e ^- anolamine.

It is to be understood that the specific oppositely charged ion forming part of each salt of this invention is not of a critical nature, insofar as the salt is generally pharmaceutically acceptable and insofar as the oppositely charged ion does not give undesirable qualities to the salt as a whole.

A preferred compound is compound 21:

[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-isoquinoline-carboxamide.

Method for preparing compound 21 is shown below. Compound 21 can be obtained as a metabolite from plasma of patients receiving [3S- (3R, 4aR *, 8aR *, 2 ', S *, 3', 3 *)] - 2- [2'-hydroxy-3 ' -phenylthiomethyl-4'-aza-5'-oxo-5 '- (2-methyl3-hydroxyphenyl) pentyl] decahydroisoquinoline-3-N-tert-butylcarboxamide, a methanesulfonic acid salt, which is described in U.S. Patent No. 5,448,426.

The compounds of formula 9 can be prepared according to the following Reaction Scheme I:

Reaction Scheme I

Scheme I. General synthesis pathway for the preparation of 9b and derivatives

OONHiBu

FOCUS x ^ cclmza fcian la

ODQH

2ft

Eran and b

JriUlMlU not a mine

ft * 'N'

H amic <<mzape £ t «ni

R

Ο N.

-r ·

2bR

CtxHN

chloroazjol = amino-amine group □ nKN et ux <Lnoren-shutter nocjieuotia> ennocT

Removing c: b?

Ethane 5

R

removal not

3eiliiv ia ia im amima

Total »3

awiyjho spursian Ethanba £ tan A

Compound 1a, perhydroisoquinoline commercially available from NSC 'Technologies (Chicago, IL) or Procos SpA (Milan, Italy) was subjected to prolonged acidal hydrolysis in step 1a to give compound 2a. A variety of inorganic 5 acids can be used both in a mixture of an aqueous / organic solvent and only in water at temperatures above 50 ° C. An example of such inorganic acid is 6N aqueous HCl. Substituents for compound 1a include the corresponding esters

1b, thioesters 1c or other amides 1d:

cosz

wherein Ζ, Z-, and Ζ ₂ may each independently be alkyl, cycloalkyl, heterocycle or aryl.

Compound 2a is then protected under nitrogen from the amine to obtain compound 2b in step 1b. The protecting group R _p is defined as a suitable conjugated group to avoid the unwanted decomposition of the activated carboxylate derivatives of the compounds 2b in Step 2. Such protecting groups can typically be 5 carbamates of parentage having the general structure of formula 11:

R'oX

The nature of R may be any alkyl, cycloalkyl, aryl or heterocycle that can be easily removed in the 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-fluorenylmethyl, 9-anthrylmethyl and the like - Higher polycyclic aromatic ring systems. The following substances, as defined below, can be obtained from Aldich Chemical Co. (Sigma Aldrich Fluka):

□

2,2,2 Griyuritil ® - CHg-C ^ Cl

O ipMMciKrcwwttiwi = - O ^ -C-Si — CH3 H 0 + j aria

OblzLg

3

Such protecting groups can usually be added by acylating the corresponding haloformate ester 12a or dicarbonate 12b:

ftcAx

12a

X = halogen

12b

Y = OCO2G in the presence of a suitable base in a conventional organic solvent for these types of reactions, such as halogenated solvents, ethers and hydrocarbons. Such bases are typically inorganic such as metal hydroxides, bicarbonates and carbonates or organic bases such as amines such as 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-pH (DBU) and 1,8-diazabicyclo [4.3.0] non-5-ene (DBN). The following substances, as defined below, can be obtained from Aldich Chemical Co. (Sigma Aldrich Fluka);,.

CABCO =

DBU =

These reactions are typically carried out at a temperature from below room temperature to about 100 ° C.

The amide coupling of Step 2 can be accomplished in any way, depending on how the carboxyl group was activated. In Step 2, group J is added by carboxylic acid 2b reaction to give

of activated derivative 2c:

Stage 2

Rp “amlszashipA group

2c J - calving group

Group J may be any of a variety of leaving groups such as alkoxy, hydroxy, halogen, pseudohalogen (including azide, cyanide, isocyanate and isothiocyanate), alkyl or areulfonate, aromatic heterocycle (linked via heteroatom) and N-hydroxycyclohexyl or hydroxybenzotriazole ester. The following definitions apply to the terms above:

azide having isocyanate isotope cyan at - “See —L-C-0-C-S 0 £ alcoolonate "O-S-" kyl ό 0 aresulfonate 0 N-chrocaverotrocm KO.Q Nitrogen heterocycle N-hypoxysuccinimics hydroxybenzatriazole huh? OH

The acyl halides (2c, J = halogen) can be prepared using inorganic halogenating agents such as thionyl chloride or bromide, phosphorus trichloride or bromide, phosphorous pentachloride or bromide, or organic reagents such as oxalyl chloride or. Esters (2c, J = OR) (R 'as defined above) can be prepared in a variety of ways, starting from acid chloride 2c, where J is Cl, by combining it with the desired alcohol in the presence of an organic or inorganic base mentioned above for the acylation of compound 12a or compound 12b. Alternatively, the ester may be prepared by acid-promoted esterification in the presence of the desired alcohol. The sulfonates (2c, J = OSOjA / A, where θ alkyl or aryl) are usually prepared by reacting the carboxylic acid 2b with alkyl or arylsulfonyl chlorides in the presence of an organic amine base such as triethylamine in a non-polar solvent at a temperature below 0 ° C. Alkyl and arylsulfonates are defined as follows:

alkylsulfonate "

Oh

And O-S-alkyl

II about arensuphonipsloria "Q-aryl

The pseudohalogen derivatives of 2c (J = pseudohalogen) are usually prepared from the acid halides 2c (J = halogen) by reaction with an inorganic pseudohalogen in the presence of a base. Such bases include, but are not limited to, metal hydroxides, bicarbonates, and carbonates or organic bases such as amines such as triethylamine, diethylamine, diethylisopropylamine, 1,8diazabicyclo [2.2.2] octane (DABCO), or related di- or trialkylamines, and so also amidine bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,8diazabicyclo [4.3.0] non-5-ene (DBN). A particularly preferred base is triethylamine. The heteroaromatic derivatives of 2c were also prepared from the acid halides 2c (J = halogen) using a specific heteroaromatic compound in the presence of an amine base in a non-polar solvent. The N-hydroxyheterocyclic derivatives of 2c can be prepared from the acid halides as above and can also be generated using alkyl carbodiimides (alkyl-M = C = alkyl, where the alkyl groups may be the same or different) or arylcarbodiimides (aryl-N = C = N-aryl, where the aryl groups may be the same or different) and an amine base as a condensing agent.

The primary or secondary amine (shown above the arrow in Step 2 of Scheme 1) _; used in the coupling process may include appropriate protecting groups, depending on the functionality present in the amine and the method of coupling used. The mode of coupling of 2c with a primary or secondary amine can be accomplished in different ways depending on the nature of J. When free acid (2c, J = OH) is used, the coupling can be carried out using carbodiimide-based methods employing any of the general reagents of this class, including dicyclohexylcarbodiimide or related dialkylcarbodiimides, EDCs (salts of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) or coupled water-soluble reagents together with an organic amine base in a polar organic solvent, akav as dioxane, DMF, NMP and acetonitrile in the presence of Nhidroksiheterotsikleno compound such as N-hydroxysuccinimide or 3hidroksibenzotriazol. Alternatively, haloformate esters such as 12d may be used to temporarily activate the acid to produce mixed anhydrides of the general formula 2d.

lid X = halogen

Such haloformate esters are generally as shown above in 12d and include methyl-, ethyl-, isopropyl-, isobutyl-, n-butyl-, phenyl- and related alkyl and aryl chloroformates, as defined below.

alloyl chloroform alkyl

arylproformate aryl formula 2d is a possible intermediate in the step from formula 2b to formula 3. formula 2d is an intermediate, but the process described here leads to formula 3 without isolating formula 2d.

These reactions are usually carried out in a variety of non-polar organic solvents such as halocarbons and ethers, such as diethyl ether, methyl tert, butyl ether, diisopropylether, dioxane and THF at a temperature below 0 ° C accompanied by an organic amine base such as triethylamine, diethylamine, diethylamine, diethylamine, diethylamine DABCO or related di- or dialkylamines, as well as amidine bases such as DBU and DBN. i

When J in compound 2c is apkyl or arerenesulfonate (J = OSO ₂ R or OSOgAr), the coupling can be carried out in a variety of non-polar organic solvents such as halocarbons and ethers, such as diethyl ether, methyl t-butyl ether, diisopropylether, dioxane and THF. temperatures below 0 ° C, accompanied by an organic amine base such as triethylamine, diethylamine, diethylisopropylamine, DABCO or related di- or trialkylamines, as well as amidine bases such as DBU and DBN.

When J in compound 2c is hapogen or pseudohalogen, the coupling can - be effected in a general limited solvent such as THF, diethyl ether, dioxane, methyl t-butyl ether or up to. ethers; acetone, cyclohexanone, methyl isobutyl ketone and others. ketones; esters such ka ^t o ethyl, methyl and isopropyl acetate, halogenated solvents such as halogenated methanes and ethanes, 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. Often a base is used and it can be any of a variety of inorganic bases such as metal hydroxides, bicarbonates and carbonates or organic bases such as amines such as triethylamine, diethylamine, diethylisopropylamine, DABCO or related di- or trialkylamines, attack also amidine bases such as DBU and DBN.

The skilled artisan will be able to carry out the amidine coupling in Step 2 and other possible J groups.

In Step 3, deprotection can be accomplished ₇ using any of the standard deprotection methods for a particular class of protecting groups. Simple alkyl and substituted alkyl carbamates can be removed with aqueous base solutions at temperatures up to about 100 ° C using any of the common inorganic metal hydroxides such as sodium, lithium, potassium or barium hydroxide or hydroxides of other metals in at least stoichiometric amount. Carbamate protecting groups containing oxygen-linked benzyl groups may be removed by hydrogenolysis with palladium or platinum catalysts. Alternatively, aqueous hydrolysis at temperatures up to about 100 ° C may be used, using any of the common inorganic metal hydroxides such as sodium, lithium, potassium or barium hydroxide or other metals in at least stoichiometric amounts. Multiple anhydro acids can also be used to deprotect benzyloxy carbamates, including HCl, Hb2 and HJ. Lewis boron and aluminum acids, such as AICI ₃ , BBr ₃ , BCI, in non-polar solvents are also effective. Certain substituted benzyl, aryl or alkyl groups in which a specific substitution structure is selected because of its ability to be removed under specific conditions may also be used. For example, the 2-trimethylsilylethylcarbonyl group (Theos) is a protecting group designed to take advantage of the specific reactivity of the 2-trimethylsilylethyl group in the process of deprotection. ' 2-Trimethylsilylethylcarbonyl chloride may, however, be used to protect amine nitrogen and may subsequently be removed using fluoride ion sources such as HF or tetraalkylammonium fluorine salts.

In Step 4, the perhydroisoquinoline moiety of Formula 4 is bonded to the Chloroalcohol (compound 5, Scheme I) by an epoxy intermediate (13) created by base-induced closure of the vicinal chlorhydrin functionality.

SPh

CbzHN

Compound 5 was manufactured by Kaneka Industries, Japan. Several closing-opening processes may be used in the treatment of compound 5 - compound 1 · 3 - compound 6. The epoxide 13 may be isolated or may react with 4, added or subsequently to form 13, or 4 may be present by the beginning of the sequence. Can Epoxy 13 be Created _? using 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 thereof. The epoxide may also be formed in a two-phase solvent system consisting of water and a halocarbon solvent, such as dichloromethane, together with a base. A phase transfer catalyst such as a tetraalkylammonium salt may be used to facilitate the process. The process of opening epoxide 13 with compound 4 is carried out in alcoholic solvents or mixtures of alcohol and another solvent, which may be an ether or bipolar aprotic solvent, such as dimethylformamide or dimethylsulfoxide. Opening the epoxide 13 with compound 4 to give compound 6 is optimally carried out for 2 - 7 hours at 50-60 ° C.

In Step 5, the carbobenzyloxy group can be removed to give the free amine 7. This can be accomplished using HBr in acetic acid using co-solvents such as halocarbons. It can also be carried out using boron halides such as BBr ₃ and BCl ₃ or alkyl substituted boron halides such as dimethyl boro bromide in halogenated solvents such as chloroform and dichloromethane at temperatures ranging from 0 ° C to ambient temperature. Alternatively, the carbobenzyloxy group may be removed by hydrolysis using aqueous / alcoholic solvents of metal hydroxides such as barium, sodium, lithium or potassium hydroxide at ambient temperature for a period of hours.

Step 6a is the coupling of the benzoic acid derivatives of formula 8 to give 9a. In Formula 8, Q may be a leaving group. Q may be any of the leaving groups discussed further for Group J. The compounds of formula 8 wherein Q = OH or CI are commercially available from EMS Dottikon, Lenzburg, Switzerland and Sugai Chemical Industries, Ltd., Japan. The coupling can be accomplished in a variety of ways, depending on the nature of Q. When free acid (Q = OH) is used, the coupling can be accomplished ₇ using carbodiimide-based methods, using any of the common reagents for this class, including dicyclohexylcarbodiimide or related dialkylcarbodiimides, EDCs (salts of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), or coupled water-soluble reagents together with an organic amine base in a polar organic solvent such as dioxane, DMF, NMP and acetone in the presence of Nhidroksiheterotsikal, including 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 benzene; nitriles such as acetonitrile and propionitrile; lower alcohols such as ethanol, isopropanol, tert-butanol and related alcohols, and polar organic solvents such as dimethylformamide, dimethylsulfoxide, N-methyl-228 pyrrolidone, and amide-containing solvents. A base is often used and it can be any of the inorganic bases such as metal hydroxides, bicarbonates and carbonates or organic bases such as amines such as triethylamine, diethylamine, diethyl isopropylamine, DABCO or related di- or trialkylamines, and 5 as well as amidine bases such as DBU and DBN.

The removal of the aneta is performed 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 functionality on the carboxamide group bonded to the isoquinoline ring system -perhydro-, yu is best for it to be r ^_ oanena at this time (in time or after step 6b). The nature at this stage depends on the particular nature of the protecting group.

A preferred method of performing the entire process shown in Scheme I is shown in Scheme II.

Scheme II. Synthesis of Amide 21

CDNUtat

fission hydrolysis

Flag 1a

UNC

Zzhitsh pa a mine

Ggap ib

and

Ammonia Linking Bran 2.

n

sgtstr.mman ¹ L, ^cape .SLiuiwiaia ua amna Stage 3 o 4

eghasitz sgythorsma-forToreia noslshupe ιβπκοΓΓ

chloroalcohol

2b “the amino-group група πΗΝ

E ran 5

Removal of C bz

^ MIDN1> P.11brSh1> f

Eiarnba

Stage 4

Ewi> (ib iC '-? ..- K) 3727

The Cbz-protected amino acid 15 was coupled to the amine 22 to form the amide

16. The Cbz group was removed by hydrogenation to afford the amine 17. It was bound to the chloroalcohol by epoxide using an in situ procedure to give the compound 18. Normally deprotecting the base and linking the liberated primary amine to the acidic acid. ^- chloride 20 gave the amide 21. Details of this process are given below in Examples 1 A to F. The letters A to F of Scheme II correspond to Examples 1 A to F below.

The following examples illustrate aspects of the invention. These examples are for purposes of illustration and are not intended to limit the scope of the invention.

Abbreviations for term (melting point) melting point, nuclear magnetic resonance spectrum, electron shock mass spectrum, field desorption mass spectrum, fast atom bombardment spectrum, infrared spectrum, ultraviolet spectrum, elemental analysis, high performance liquid chromatography, high performance liquid chromatography : mp (m.p.), NMR, EIMS, MS (FD), MS (FAB), IR, UV, Analysis, HPLC and TLC. In addition, the absorption maxima indicated for the IR spectra are those of interest and not all observed.

The following abbreviations were used in relation to NMR spectra: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), multiplet (t), doublet of multiplets (dm), wide singlet (br.s), wide doublet (br.d). J stands for Hertz coupling constant (Hz). Unless otherwise indicated, NMR data refer to the free base of the target compound.

NMR spectra were obtained on a General Electric QE-300 MHz device. The chemical shifts are expressed in δ values in ppm. The mass spectra were obtained on a VG ZAB-3 Spectrometer at Scripps Research Institute, La Jolla, Ca. The infrared spectra were recorded on a Midac Corporation spectrometer. The UV spectra were obtained on a Varian Cary 3E device. Thin layer chromatography was performed using 30

BG-PA-103727 wax silica tiles from E. Merck. Melting points were measured on a Mettler FP62 device and not adjusted.

Example 1

Methods of Preparation for the Preparation of the Amide of Formula 21 (3S- [2 (2S *, 3S *) 3 alpha, 4a beta, 8a beta]] - N - (1,1-dimethyl-2-hydroxy-ethyl) decahydro-

2- [2-hydroxy-3 - [(3-hydroxy-2-methylbenzoyl)] amino-4- (phenyl-thio) butyl] -3-isoquinolinecarboxamide

A. Perhydroisoquinoline (26.4g, 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). The mixture was heated to reflux and stirred for 3 days, during which time it passed into solution. The solvents were removed under reduced pressure to give a pale yellow solid. The solid was suspended in 2-propanol (200 mL) and filtered. The filtrate was 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 the addition of 2N aqueous KOH. Benzyl chloroformate (15.8 mL, 111 mmol) was added dropwise over 30 minutes and the pH was maintained between 7 and 8 by the addition of 2N aqueous KOH. The mixture was stirred at room temperature for 18 hours. EtOAc (200 mL) was added and the organic layer was washed with 1N aqueous HCl (100 mL) and saturated brine (100 mL). The organic layer was dried (MgSO ₄ ), filtered and evaporated under reduced pressure to an oil. The product was purified by chromatography on silica gel eluting with 1: 1 40-60 petroleum ether / EtOAc followed by 100% EtOAc. The fractions containing the product were

PCLOS9W4735 combined and evaporated under reduced pressure to give compound 15 (11.3 g, 32%) as a colorless oil: ¹ H NMR (300MHz, CDCI ₃ ) 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) , 1,881.15 (m, 10H).

B. 1-Hydroxybenzotriazole (4.2 g, 31.4 mmol) and EDC (6.0 g, 31.4 mmol) were added to acid 15 (8.3 g, 26.2 mmol) in DMF (128 mL) at ambient temperature. The mixture was heated at 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 pure under reflux for several hours, followed by evaporation of the volatiles, after which the solution was heated at 80 ° C for 17 hours. The yellow solution was poured into EtOAc (250 mL) and 2N aqueous HCl (250 mL). After stirring for 10 minutes was added EtOAC (750 mL) and the mixture was washed with H ₂ O (3 x 500 mL) and concentrated salt diff ^m aperture (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%): ¹ H NMR (300MHz, CD3OD) δ 7.36 ( m, 5H), 5.20 (d, J = 8.1 Hz, 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. Carbamate mixture 16 (7.9 g, 20.4 mmol) and 5% palladium on carbon (Pd / C) (1.6

g) was hydrogenated at 345 kN / m ² (50 psi) H2 in absolute ethanol (110 mL) at ambient temperature for 18 hours. The mixture was filtered on celite and evaporated in vacuo to give amine 17 as a white crystalline substance: ¹ H NMR (300MHz, CD3OD) δ 3.63 (g, 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. 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. After 1 hour approximately 1 mL of 1N HCl in iPA (obtained by adding 1 mL of concentrated aqueous HCl to 12 mL of IPA) was added to neutralize (pH = 7). Amine 17 (5.2 g, 20.4 mmol) was added as a solution in IPA (50 mL) and the rare suspension was heated at 60 ° C for 10 minutes. Isopropanol was removed in vacuo. The residue was diluted with EtOAc (150 mL) and washed with water (2x 50 mL), saturated aqueous NaHCO ₃ (1 x 50 mL) and concentrated brine (1 x 50 mL). The combined aqueous layers were extracted with EtOAc (1 x 25 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and purified by flash chromatography (75/25 EtOAc / hexanes, then EtOAc) to give compound 18 as a white solid (8.98 g, 76%): ¹ H NMR (300MHz) , CD ₃ OD) δ 7.33 (m, 10H), 5.08 (AB, J _ae = 12.2Hz, AU _ab = 12.1Hz, 2H), 3.96, (m, 2H), 3. 56 (g, 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% 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 was refluxed for 12 hours. After cooling to ambient temperature, the mixture was diluted with methyl t-butyl ether (MTBE) (600 mL) and washed with H ₂ O (2x 250 mL) and concentrated brine (1 x 125 mL). The combined aqueous layers were extracted with MTBE (1 x 150 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a mixture of compound 19 and benzyl alcohol as an oily white solid: ¹ H NMR (300MHz, CD ₃ OD) 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. To a solution of a mixture of amine 19 (4.7 g, 10.4 mmol theoretically of 18) and benzyl alcohol in EtOH (23 mL) at ambient temperature was added triethylamine (3.2 g, 4.3 mL, 31.2 mmol). A solution of 3-acetoxy-2methylbenzoyl chloride (20) was added (obtained according to the method set out in U.S. Patent Application No. 08/708 411, filed September 5, 1996, which is specifically incorporated herein by reference) (2.4 g, 11.5 mmol ) in THF (4 mL). After two hours, 50% aqueous NaOH (4.1 g, 2.8 mL, 52.2 mmol) was added and the mixture was refluxed for 1 hour. After cooling to ambient temperature, the mixture was neutralized to pH = 7 with 2N aqueous HCl (26 mL). This mixture was diluted with EtOAc (500 mL) and washed with H ₂ O (1 x 250 mL), saturated aqueous NaHCO ₃ (2 x 250 mL), H ₂ O (1 x 250 mL) and concentrated brine (1 x 125 mL). The organic layer was dried (Na ₂ SO ₄ ) and purified by flash chromatography (75/25 EtOAc / hexanes) to give amide 21 as a white foam (1173-57A, 1.39 g, 23%). Ή NMR indicated the presence of 11 wt% EtOAc that could not be removed in vacuo.

Analysis:

¹ H NMR (300MHz, CD ₃ OD) δ 7.53 (0, J = 7.3Hz, 2H), 7.32 (t, J = 7.0Hz, 2H), 7.20 (t, J = 7 , 3Hz,

1H), 7.06 (t, J = 8.1Hz, 1H), 6.92 (d, J = 8.1Hz, 1H), 6.83 (d, J = 8.1Hz, 1H), 4. 42 (m, 1H),

4.08 (m, 1H), 3.61 (dd, J = 13.6, 4.0Hz, 1H), 3.45 (AB, J _A = 11.0Hz, AU _ab = 18.0Hz, 2H ),

3.29 (dd, J = 13.6, 10.3Hz, 1H), 3.10 (m, 1H), 2.66 (m, 2H), 2.28 (s, 3H), 2.22 ( m, 2H), 2.04 (m, 1H), 1.86-1.20 (m, 11H), 1.19 (s, 3H), 1.18 (s, 3H).

NMR (75.5MHz, CD ₃ OD) δ 175.7,172.5, 155.9,138.8,136.7,129.8,128.9,126.3,126.0,

Example 2

HIV protease inhibitory activity and anti-HIV activity in cell culture of compound 21.

An analysis of the kinetics of tight binding was used to determine the magnitude of K, the values of compound 21. K = 5.6 ± 0.91 nM.

Methods

Expression of HIV-1 protease

The HIV-1 protease gene was isolated from viral strain IIIB (Ratner, L. et al., Nature, 316, 227-284 (1985)). To enhance the stability of the purified protease (Rose, JR et al., J. Biol. Chem., 268, 11939 - 11945 (1993)), the glutamine residue at position 7 (Q7) was mutated to serine (S) by substitution of a segment of 33 base pairs between the Ndel and BstEII sites of the protease gene sequence with synthetic oligonucleotides converting the Q7S mutation. The modified gene sequence was inserted into the plasmid vector pGZ (Menge, K. L. et al., Biochemistry, 34: 15934-15942

BG-PA-103727

1995)) under the control of the phageT7 promoter. The resulting construct, pGZ / HP-19Q7S # 9, was transformed into E. coli strain BL21 (DE3) purchased from Novagen, Inc.

HIV-1 protease expression: Cultures containing 200 pg / L ampicillin in 100 L fermenter (Biolafitte SA) were grown in 2YT medium (1.6% Trypticase Pepton, 1% yeast extract, 0.5% NaCI at initial pH 7.5). 37 ° C for .5 hours and then stimulated by the addition of 1 mM IPTG (isopropyl-β-otiogalactopyranoside). The culture temperature during stimulation was raised to 42 ° C to increase the accumulation of recombinant HIV-1 protease as insoluble inclusion bodies. After 2 hours at 42 ° C. cells were collected by cross-flow filtration using a Pellicon 0.1 µm WPP000C5 cassette # 10 (Millipore) and the cell paste was stored frozen at -70 ° C.

Purification of recombinant HIV-1 protease: All steps, unless otherwise noted, were performed at 4 ° C. Protein concentrations were determined using the BioRad Protein Analytical Solution with Bovine Serum Albumin (BioRad, Richmond, CA) as a standard. The chromatographic steps and purity of HIV protease were analyzed by polyacrylamide gel electrophoresis with sodium dodecyl sulfate (SDS-PAGE). The ultimate purity of HIV protease was> 98%. The usual final yield of each 100 L culture was 120 mg.

The 100 L culture cell paste was resuspended in 300 mL of lysis buffer (50 mM Tris-CI pH 8.0, 25 mM NaCl, 20 mM 2-mercaptoethanol) and microfluidized in a Microfluidics Corporation fluidizer at 151 800 kN / m ² (22,000 dogs). The crude cell lysate was clarified by centrifugation at 14,000 rpm for 20 minutes. HIV protease has been found predominantly in pellets in the form of inclusive bodies. The inclusion bodies were subsequently washed repeatedly in lysis buffer containing in addition 0.1% Trition-XOO and 1M urea, and after each washing process, the inclusion bodies were pelleted by centrifugation at 5,000 rpm for 20 minutes. The purified inclusion bodies were dissolved in 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 applied

BG-PA-! 03727 at room temperature in a 300 mL Fast Flow Q-Sepharose column (Pharmacia, Piscataway, NJ) equilibrated with the same buoy. Under these conditions, HIV protease was not bound to the column and a substantially pure enzyme was found in the effluent fractions. To recover the protein, phoacids from the Fast Flow Q-Sepharose column were dialyzed against three changes of buffer containing 25 mM NaH ₂ PO ₄ , pH 7.0, 25 mM NaCl, 10 mM DTT, and 10% gly ^ ool. After refolding, small amounts of precipitated material were removed (by centrifugation and the resulting enzyme preparation was concentrated, dialyzed against 0.5 M NaCl, 50 mM MES pH 5.6, 10 mM DTT, frozen in small aliquots at ~ 2 mg / mL and stored at -70 ° C.

Study kinetics ^_ and of g.ga ^- -o binding and analysis.

The proteolytic activity of the purified HIV-1 protease was measured using a modified homo-e-assay developed by Richards et al. (Richards, A. D. et al. J. Biol. Chem. 256, 773-7736 ('990)). The synthetic peptide His-Lys-Ala-Arg-ValLeu-Phe (paraNO2) -Glu-Ala-N e-Ser -′.- l; (American Peptide Company) (Nle is norleucine) was used as a substrate. A-al / z was carried out in 0.5 M NaCl, 50 mM MES, pH

5.6, 5 mM DDT and 2% DMSO pr / 37 ^C C. The cleavage of the cleavage linkage between leucine and paranoid-Peg-NO2 was analyzed by spectrophotometric monitoring of the absorption decrease at 305 nm. The initial velocity was about as fast as the rate of absorption decline during the first 100 seconds of the winter reaction. Under these conditions, and using the G7S HIV-1 protease, the Michaelis (Km) constant for this substrate is 59 ± 17 μΜ.

Compound 21, a compound saturation concentration of 200 cM, was used to determine inhibition of ^- : -a compound 21. Between 13 and 20 inhibitor concentrations were evaluated and the reaction rate was measured at each concentration as described above. The apparent <(Ki arr) found above was determined by a computer using the nonlinear least squares distribution method for the Morrison tight coupling equation (Morrison, JF, Biochem. Biophys. Acta, 185 , 269-286 (1963).

3b-l · A-10.G27

Example 3

Antiviral activity of Compound 21 against HIV-1 in cell culture '

Cells and viral strains:

CEM-SS and MT-2 human cell lines and HIV-1 strains RF and ΙΙΙΒ were obtained 5 from the AIDS Research and Reference Program, Division of AIDS, NIAID, and NIH.

Cell protection assays

The inhibitory effects of each agent on HIV-1 replication were measured by the MTT color reduction method (Alley, MS et al., Cancer Res. 48: 589-601 (1988)). The compounds were dissolved in DMSO at a concentration of 40 mg / mL, then diluted 1: 200 in culture medium (RPMI supplemented with 10% fetal calf serum). From each diluted crude material, 100 μΙ were added to a 96-well plate and serial semi-logarithmic dilutions were prepared. In individual tubes, MT-2 cells and CEM-SS cells were infected with HIV-1 ΙΙΙΒ or HIV-1 RF at a multiplicity of infection (moi) of 0.01 to 0.03, respectively. Following a 4-hour ad15 sorption period, 100 μΙ of infected or uninfected cells were added to the wells containing drug on the plate until a final concentration of 1 x 10 ⁴ cells / well was obtained. Six days (CEM-SS) or 7 days (MT-2 cells) later, MTT (5 mg / ml) was added to the test plates and the amount of formazan produced was measured spectrophotometrically at 570 nm. Data were expressed as pro20 cents produced by formazan from drug-treated cells versus the produced formazan in wells from uninfected, drug-free cells. ED ₅₀ was calculated as the concentration of a drug that increases the percentage of formazan produced in infected drug-treated cells by up to 50% compared to that produced by uninfected drug-free cells. Cytotoxicity (TC ₅₀ ) was 25 calculated as the drug concentration that reduced the percentage of formazan produced in uninfected drug-treated cells to 50% of that produced in uninfected drug-free cells. The therapeutic index (TI) was calculated by dividing cytotoxicity (TC ₆₀ ) by antiviral efficacy (ED ₅₀ ).

Table 1

Evaluation of Antiviral Activity and Cytotoxicity of Compound 21 in Acute Infection of CEM-SS Cells with HIV-1 Protease

Compound ED ₆₀ (nM) ED ₉₅ (nM) TC ₆₀ (μΜ) Therapeutic Index * 21 34.2 154.1 96.6 2825 Azidothymidine (AZT) 52.3 543.1 > 374.5 > 7161 Dideoxycytes- 94.70 142.0 37.69 398 din (ddC)

^a Therapeutic index = Cytotoxicity (TC ₆₀ ) / Antiviral activity (ED ₅₀ ) Table 2

Evaluation of the Antiviral Activity and Cytotoxicity of Compound 21 in Acute Infection of MT-2 Cells with HIV-1 IIIB

Compound ED ₆₀ (nM) ED _% (nM) TC ₆₀ (μΜ) Therapeutic Index * 21 85.6 ND 92.6 1082 ΑΖΤ 430.7 ND 109.4 254 ddC 5924 ND 176.3 30

yu ^a Therapeutic index = Cytotoxicity _(TC50) / Antiviral activity (ED ₅₀₎

As noted above, the compounds of the present invention are useful for inhibiting HIV protease, which is an enzyme linked to the viral component of production and clustering. An embodiment of the present invention is 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

Bi -ij.-: ί * 2 ⁷ pharmaceutically acceptable salt. Another embodiment of the present invention is 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. A further embodiment of the present invention is a method of inhibiting HIV protease comprising administering to an HIV-infected cell or host or a patient, such as an HIV-infected primate, an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof .

The term "effective amount" means an amount of a compound of formula (9), or a pharmaceutically acceptable salt thereof, that is effective in inhibiting HIV protease-mediated production and clustering of viral components. The specific dose of a compound prescribed according to this invention for producing therapeutic or inhibitory effects will of course be determined by the particular circumstances of the case, including, for example, the prescribed compound, the route of administration, the condition being treated, and the individual host or patient, undergoing treatment. An exemplary daily dose (administered once or in divided doses) contains a dose level of about 0.01 mg / kg to about 50 mg / kg body weight of a compound of the invention. Preferred daily doses are generally from about 0.05 mg / kg to about 40 mg / kg and more preferablyP, from about 1.0 mg / kg to about 30 mg / kg.

The isobetene compounds can be administered in a variety of ways, including orally, octally, transdermally, subcutaneously, intravenously, intramuscularly, and intranasally. The compounds of the present invention are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical composition or formulation comprising an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier such as diluent or excipient.

Preferably, the active ingredient comprises from 0.1 wt% to 99.9 wt% of the formulation. By "pharmaceutically acceptable" is meant that a carrier such as a diluent or excipient is compatible with the other ingredients of the formulation and is not harmful to the host or patient.

the pharmaceutical formulations can be prepared from the compounds of the invention by known procedures using known, readily available ingredients. In the preparation of the compositions of the present invention, the active ingredients will typically be mixed with a carrier, or diluted with a carrier, or enclosed within a carrier, which may be below the capsule, bag, paper or other suitable container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a solvent, excipient or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, candies, bags, hollow wafers containing the composition, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of active compound), soft or hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.

The following exemplary formulations are illustrative only and are not intended to limit the invention. The term "active ingredient" is a compound of formula (9) or a pharmaceutically acceptable salt thereof.

Formulation 1

Hard gelatin capsules are prepared using the following components:

Amount (mg / capsule)

Active ingredient250

Starch, dry200

Magnesium stearate 10

A total of 460mg

Formulation 2

One tablet is prepared using the ingredients below:

Amount (mg / tablet) Active ingredient 250 Cellulose, microcrystalline 400 Colored silica 10 Stearic acid 5 Total 665 mg

The components are mixed and compacted to form tablets, each weighing 665 mg.

Formulation 3

An aerosol solution containing the following components is prepared:

Weight

Active ingredient 0.25 Methanol 25.75 Propellant 22 (chlorodifluoromethyl-1 74.00 Total 100.00

The active compound was mixed with ethanol and the mixture was added to a portion of propellant 22, cooled to -30 C and transferred to a filling apparatus. The required amount is then placed in a stainless steel container and diluted with the propellant residue. The valve elements are then mounted on the container.

Formulation 4

Tablets, each containing 60 mg of the active ingredient, are made as follows:

Active ingredient

Quantity (td / tablet)

Starch

Microcrystalline cellulose35

Polyvinylpyrrolidone (as 10% solution in water) 4

Carboxymethyl sodium starch 4.5

Magnesium stearate 0.5

Talc 1

150 in total

The active ingredient ^- starch and cellulose are passed through a N 6 US mesh sieve and mixed thoroughly. Aqueous solution containing polyvinylpyrrolidone. is mixed with the resultant powder, and ^_ Ogawa mixture is passed through a N 14 mesh US sieve. The granules thus obtained were dried at 50 ° C and passed through a N 18 US mesh sieve. Carboxymethyl sodium starch, magnesium stearate and talc pre-passed through a sieve of N 60 ^ 8 mesh were then added to the granules which, after being mixed, were sealed in a pelletizing machine to give tablets, each weighing 150 mg.

Formulation N 5

Capsule (s), each containing 80 mg of active ingredient, is prepared as follows:

Amount (mg / capsule)

Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg

The active ingredient ^- cellulose, starch and magnesium stearate are mixed, passed through a K 45 US mesh sieve and filled into hard gelatin capsules in quantities of 200 mg.

Formulation 6

E. D27

Suppositories, each containing 225 mg of active ingredient, are prepared as follows:

Active ingredient 225 mg

Saturated fatty acid glycerides ______________2 000 mg

Total 2 225 mg

The active ingredient was digested through a N 60 US mesh sieve and suspended in saturated fatty acid glycerides pre-melted using the minimum amount of heat required. The mixture is then poured into a suppository matrix with a nominal capacity of 2 g and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are

prepared as follows: Active ingredient 50 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 ml Benzoic acid, solution 0.10 ml Flavor q.v. Coloring q.v. Purified water to 5 ml

The active ingredient ^- is passed through a N 45 US mesh sieve and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, flavoring agent and colorant are diluted with some of the water and added with stirring. Then sufficient water is added to obtain the required volume.

Formulation 8

The intravenous formulation is prepared as follows:

^p S'G '

Active ingredient 100 mg

Isotonic saline solution 1 000 mL

The solution of the above ingredients is generally administered intravenously to a subject at a rate of 1 ml per minute.

Formulation 9

A tablet is prepared using the ingredients below:

Active ingredient

Calcium silicate Crospovidone

Magnesium stearate

Total

Amount (mg / tablet)

292 mg

146 mg

146 me mg

589 me.

Claims (23)

1, Compound of Formula (9): in which: R and R 'are independently selected from H, substituted or unsubstituted alkyl-OR! 5 group, a cycloalkyl group substituted with a (C ₁ -C ₆₎ alkyl group or (u STsalkil-OH group, a heterocyclic group substituted with (C _<6) alkyl group or (u STsalkil-OH group, an alkyl A N, 3 group, yl / alk / 1-8 (X) (Y) P ₄ group in which: 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, heterocycle and aryl groups, and acyl or sulfonyl groups; R ₄ is H, substituted or -substituted alkyl, cycloalkyl, heterocyclic or aryl; and X and Y are each independently / summed by = 0 and nothing; 15 or a pharmaceutically acceptable prodrug, salt or solvate thereof. 2. A compound according to claim 1 wherein R, is H, or a pharmaceutically acceptable prodrug soeds ^- st, salt or solvate thereof. A compound according to claim 1, wherein when at least one of R and R 'is alkylOR. a group, Rt is H, or a pharmaceutically acceptable prodrug, salt or solvate thereof. The compound of claim 1, wherein when at least one of R and R 'is alkyl- OR! the group mentioned alkyl-OR! the group is selected from: -C (CH ₃ ) ₂ CH ₂ OH, CH (CH ₃ ) CH ₂ OH, -CH ₂ CH ₂ OH, -C (CH ₃ ) (CH ₂ OH) ₂ , -C (CH ₃ ) ₂ -O-CH ₂ -O-CH ₃ , 5 -C (CH ₃ ) ₂ CH ₂ -O-CH ₂ -O-CH ₃ , -C (CH ₃ ) ₂ CH ₂ -O-acyl, -C (CH ₃ ) ₂ -S-CH ₂ -O- CH ₃₁ -C (CH ₃ ) ₂ CH ₂ -S-CH ₂ -O-CH ₃ , -C (CH ₃ ) ₂ -O-CH ₂ -S-CH ₃ , -C (CH ₃ ) ₂ CH ₂ -O- CH ₂ -S-CH ₃ and -C (CH ₃ ) ₂ CH ₂ -8-acyl and its pharmaceutically acceptable prodrug, salt or solvate. A compound according to claim 1, wherein when at least one of R and R 'is a cycloalkyl group _; substituted with (C _<6) alkyl group or a _(C.-C) alkyl-OH group, said cycloalkyl group is selected from: or a pharmaceutically acceptable prodrug, salt or solvate thereof. A compound according to claim 1, wherein when at least one of R and R 'is a het- 15 a cyclic group substituted with a (C 1 -C 6 alkyl group or (C 1 -C _e ) alkyl-OH group, said heterocyclic group being selected from: wherein R ₃ is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocyclic or aryl group, or an acyl or sulfonyl group, or a pharmaceutically acceptable salt thereof; BG is a salable prodrug, salt or solvate. The compound of claim 1, wherein said compound has the formula 21: 5 or a pharmaceutically acceptable prodrug, salt or solvate thereof. The compound of claim 2, wherein when R 'is a cycloalkyl group substituted with a (C 1 -C ₆ ) alkyl group or a (C 1 -C ₆ ) alkyl-OH group, this cycloalkyl group is selected from: or a pharmaceutically acceptable prodrug, salt or solvate thereof. A salt according to claim 1 having the formula (9b): • CHjSOjH 10. A pharmaceutical composition comprising: (A) an effective amount of a compound of claim 1; and (b) a pharmaceutically acceptable carrier therefor. 11. pharmaceutical composition comprising: (a) an effective amount of a compound of claim 7; and 5 (b) a pharmaceutically acceptable carrier therefor. A method of inhibiting HIV protease comprising administering to the host an effective amount of a compound of formula 1 or a pharmaceutically acceptable prodrug, salt or solvate thereof. A method for inhibiting HIV protease, comprising administering to the host an effective amount of a compound of claim 7 or a pharmaceutically acceptable prodrug, salt or solvate thereof. A compound according to claim 1 having a purity of more than 90%. A compound according to claim 1 having a purity of at least 95%. A compound according to claim 1 having a purity of at least 97%. 15 A compound according to claim 1 having a purity of at least 99%. A compound according to claim 7 having a purity of more than 90%. A compound of claim 7 having a purity of at least 95%. A compound of claim 7 having a purity of at least 97%. The compound of claim 7 having a purity of at least 99%. 20 The pharmaceutical composition of claim 10, wherein the compound has a purity of more than 90%. The pharmaceutical composition of claim 10, at least 95%. which compound has a number24. The pharmaceutical composition of claim 10 is at least 97%. which compound has a number25. The pharmaceutical composition of claim 10, at least 99%. which compound has a number26. The pharmaceutical composition according to claim is more than 90%. which compound has a number27. A pharmaceutical composition of at least 95%. claim 11 which compound has the number 28. Pharmaceutical composition according to the at least 97%. claim 11 which compound has the number29. pharmaceutical composition according to the ratio of at least 99%. claim 11, which has the compound 30. The method of claim 12, wherein the compound has a purity of more than 90% The method of claim 12, wherein the compound has a purity of at least 95%. The method of claim 12, wherein the compound has a purity of at least 97%. The method of claim 12, wherein the compound has a purity of at least 99%. The method of claim 13, wherein the compound has a purity of more than 90% The method of claim 13, wherein the compound has a purity of at least 95%. The method of claim 13, wherein the compound has a purity of at least 97%. The method of claim 13, wherein the compound has a purity of at least 99%.