SK283636B6 - Decahydroisoquinolinecarboxamide derivatives, pharmaceutical preparations containing them and their use - Google Patents

Abstract

Decahydroisoquinolinecarboxamide derivatives of general formula (I); pharmaceutical preparations suitable for treating patients infected with the HIV virus, which contain said composition as an effective substance, and the medical use thereof.

Description

Technical field

The present invention relates to novel series of chemical compounds useful as HIV protease inhibitors and to the use of these compounds as antiviral agents.

BACKGROUND OF THE INVENTION

Acquired immune deficiency syndrome (AIDS) is a relatively recently recognized disease or condition of health. AIDS causes a gradual breakdown of the body's immune system as well as progressive disruption of the central and peripheral nervous systems. Since its initial recognition in the early 1980s, AIDS has spread rapidly and has now reached epidemic proportions in a relatively limited section of the population. Intensive research has led to the discovery of a responsible agent - human T-lymphotropic retrovirus III (HTLV III), now more commonly referred to as the human immunodeficiency virus or HIV.

HIV is a member of a class of viruses known as retroviruses. The genome of the retrovirus is composed of RNA which is transcribed into DNA by reverse transcription. This retroviral DNA is then stably integrated into the chromosomes of the host cells and, using the replication processes of the host cells, produces new retroviral particles, thereby spreading the infection to other cells. HIV appears to have a particular affinity for human T-4 lymphocyte cells, which play a vital role in the body's immune system. HIV infection of these white blood cells reduces the population of these white blood cells. Alternatively, the immune system becomes inoperative and ineffective against a variety of occasional diseases, including but not limited to pneumocystic carcinoma pneumonia, Karposi's sarcoma and lymphatic cancer.

Although we still do not fully understand the exact mechanism of HIV production and action, the identification of the virus has led to some progress in disease control. For example, azidothymidine (AZT) has been shown to be effective in inhibiting the reverse transcription of the retroviral genome of HIV, which allows some regulation, but not cure, of AIDS-affected patients. There continues to be a search for drugs that will cure or at least provide an increased level of regulation of the fatal HIV virus.

Retrovirus replication is typically characterized by post-translational processing of polyproteins. These modifications are associated with the HIV-protease - enzyme encoded by the virus. Thus, mature polypeptides are formed, which in turn will assist in the production and operation of the infectious virus. If these molecular treatments are suppressed, normal HIV production is stopped. Thus, HIV protease inhibitors can act as agents against HIV.

The HIV protease is one of the translation products of the pol gene encoding the structural proteins of HIV. This retroviral protease specifically cleaves other structural polypeptides at certain sites, releasing new activated structural proteins and enzymes, thereby rendering the virion eligible for replication. Inhibition of HIV protease by itself active compounds can prevent proviral integration of infected T lymphocytes during the early phase of the HIV-1 life cycle, as well as inhibit proteolytic modifications of the virus at a later stage. In addition, protease inhibitors may have advantages in easier availability and longer life in the virus and lower toxicity compared to currently available drugs, possibly due to their specificity against retroviral protease.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a new class of chemical compounds that can inhibit and / or block HIV protease activity that halts HIV proliferation, pharmaceutical compositions containing these compounds, and the use of these compounds as HIV protease inhibitors.

The present invention relates to compounds given by the formula (9) below and their pharmaceutically acceptable salts, prodrugs and solutions that inhibit the protease encoded by the human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 ( HIV-2). These compounds are useful in the treatment of HIV infection and the treatment of acquired immune deficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions of the present invention can be used alone or in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. The compounds of the present invention can also be used as prodrugs. Methods of treating AIDS, methods of treating HIV infection, and methods of inhibiting HIV protease are disclosed.

The compounds of the present invention

in which:

R and R 'are independently selected from H, substituted or unsubstituted alkyl, -OR _b -cycloalkyl substituted (C _{r C6)} -alkyl or (C _r C _H) -alkyl-OH, a substituted heterocyclic group ( C 1 -C ₆ -alkyl or (C 1 -C ₆ ) -alkyl-OH, alkyl-NR ₂ R ₃ or alkyl-S (X) (Y) R ₄ , wherein:

R 1 is H, substituted or unsubstituted alkyl, or acyl;

R ₂ and R ₃ are each independently selected from: H, substituted or unsubstituted alkyl, cycloalkyl, heterocyclic and aryl groups, and acyl and sulfonyl groups;

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

X and Y are each independently selected from: = O and no substituent;

or a pharmaceutically acceptable prodrug, salt or solvate thereof.

In compounds of formula (9), R is preferably H. Even more preferably, R is H and R 'is a cycloalkyl group selected from:

Preferably in compounds of formula (9), if at least one of the radicals R and R 'is an alkyl-OR _{1 group;} tak R! is H. In particular, if at least one of the radicals R and R 'is an alkyl-OR _b group, then an alkyl-OR _b group is selected from the group: -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 , -C (CH ₃ ) ₂ CH ₂ -O-CH ₂ -O-CH ₃ and -C (CH ₃ ) ₂ CH ₂ -O-acyl or a pharmaceutical thereof an acceptable prodrug, salt or solvate thereof.

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

Preferably, if at least one of R and R is a substituted heterocyclic group (CrQj-alkyl or a (C _{r C6)} -alkyl-OH and the heterocyclic group is selected from the group:

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

Preferred compounds of formula (9) are [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

and pharmaceutically acceptable salts and prodrug analogues thereof. Preferred prodrugs are obtained by replacing hydrogen in one of the alcohol groups with an acyl group, and more preferably an amino acid acyl group.

The present invention further provides 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, for example, a diluent or vehicle.

The present invention further provides a method of treating AIDS comprising administering an effective amount of a compound of the present invention to a host or patient such as a primate.

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

The present invention provides novel compounds corresponding to formula (9) above, which are useful in the treatment of HIV infection and / or AIDS.

Applicants include U.S. Pat. U.S. Pat. U.S. Patent No. 5,484,926; U.S. Pat. 08/708411 and 08/708607 and Japanese Patent Application Nos. JP 95-248183 and JP 95-248184 with the notion that definitions of benefits, terms, variable items, brands, and the like. used in each application are only applicable to the relevant clarification of the application.

In particular, since each of the aforementioned references appended was prepared separately, the original applications may in some cases use the same term, brand or variable item which means something different. For example, the variable "X" is used in each request, but each request has its own separate definition of a substituent or residue represented by that variable. The skilled artisan will appreciate that the terms, tags and variable items in each of the references appended hereto are limited solely to the clarification of that application and may be replaced by other suitable terms, tags and variable items and the like. representing different substituents and residues. Of course, those skilled in the art will appreciate that any suitable set of terms, tags, and variable items may be used generally or more specifically to represent the nature of the subject matter set forth in the present invention, including terms, tags, variable items and the like. universally applicable in the attached clarifications of the above-mentioned applications and the following clarifications.

The compounds of formula (9) may be prodrugs which may serve to improve the pharmaceutical properties of the compounds, such as pharmacokinetic properties, e.g. improved bioavailability or solubility. The preparation of prodrugs can be accomplished by standard procedures known to those skilled in the art. A preferred prodrug can be obtained by acylation or alkylation of the parent alcohol when R or R 'is CH (CH ₃ ) ₂ CH ₂ OH.

All temperatures reported herein are in degrees Celsius (° C). All units of measure used herein are units by weight except for liquids where the units are by volume.

The term "alkyl" as used herein refers to linear or branched carbon chains, preferably those having one to eight, more preferably one to six, most preferably one to four carbon atoms. The term "C ₁ -C ₆ -alkyl" represents a linear or branched alkyl chain of one to six carbon atoms. Examples of C _r C ₆ -alkyl radicals are: methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 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" represents saturated or partially saturated, monocyclic or polycyclic hydrocarbon systems having preferably 5-14 carbon atoms per cycle. Examples of cycloalkyl are monocyclic systems having 3-7, more preferably 3-6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. An example of cycloalkyl is C ₅ -C ₇ -cycloalkyl, which is a saturated hydrocarbon cyclic skeleton containing five to seven carbon atoms.

The term "alkoxy" represents -O-alkyl. An example of an alkoxy is C 1 -C 4 -alkoxy, which represents a linear or branched alkyl chain of one to six carbon atoms attached to an oxygen atom. Examples of C 1 -C ₆ -alkoxy groups are: methoxy, ethoxy, propoxyl, isopropoxyl, butoxyl, sec-butoxyl, tert-butoxyl, pentoxyl, hexoxyl and the like. C _{r C6} alkoxyl includes within its definition the art C _r C ₄ -alkoxy.

The term "aryl" as used herein means carbocyclic or heterocyclic aromatic, 5-14 membered monocyclic or polycyclic systems. Examples of aryls are: 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] thiantrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathien], indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, quinolinyl, naphthyridinyl, quinoxyalinyl, quinolinyl, benzothiazolyl, benzimidazolol, carbimidazolol, cinimidazolyl, cinimidolyl, cinimidolyl, cinimidolyl, cinimidol -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl and phenoxazinyl.

The term "aryloxy" represents a -O-aryl group.

The term "hydrolyzable group" is a group that, when attached to oxygen, forms an ester that can be hydrolyzed to a hydroxyl group in vivo. Examples of hydrolyzable groups which may be optionally substituted are acyl, sulfonate and phosphate functional groups. Examples of these hydrolyzable groups are: blocked or non-blocked amino acid residue, hemisuccinate or nicotinate residue.

The term "halogen" represents chlorine, fluorine, bromine or iodine.

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

The term "heterocycle" means an aromatic or saturated, or partially saturated 5-14-membered monocyclic or polycyclic system, such as a 5-7 membered monocyclic or 7-10 membered bicyclic system having one to three heteroatoms selected from: nitrogen , oxygen and sulfur, and in which any nitrogen or sulfur heteroatom may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. The heterocyclic system may be attached via any suitable heteroatom or carbon atom. Examples of such heterocycles are decahydroisoquinolinyl, octahydrothieno [3,2-c] pyridinyl, piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, isobenzofuranyl, furazanyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl. oxazolidinyl, isoxazolyl, thiantrenyl, triazinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, chromenyl, xantenyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl, benzothienyl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenoxathienyl, indolizinyl, isoindolyl, indazolyl, quinolinyl, purinyl, choline, purinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl quinzolinyl, tetrahydroquinolinyl, cinolinyl, pteridinyl, carb azolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl and phenoxazinyl.

The term "thioether" represents S-aryl groups such as phenylthio and naphthylthio, S-heterocycle wherein the heterocycle is saturated or partially saturated, S- (C ₅ -C ₇ ) -cycloalkyl and S-alkyl such as C 1 -C _6- alkylthio. In the thioether, the aryl, heterocyclic, cycloalkyl and alkyl groups may be optionally substituted. An example of a thioether is "C _r C ₆ -alkylthio", which represents a straight or branched chain alkyl of one to six carbon atoms, bound to the sulfur atom. Examples of C | -C ₆ alkylthio are: methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and the like hexyltio-.

The term "mercapto" represents -SH.

The term " amino " and L ₂ are preferably independently selected from: oxygen, carbocycle, heterocycle, alkyl, sulfonyl and hydrogen, or NC (O) L ₃ , wherein L ₃ is preferably alkyl, alkoxy, hydrogen or -NL ₁₁ . The aryl, alkyl and alkoxy groups may be optionally substituted. An example of an amino group is a C 1 -C ₄ -alkylamino group which represents a linear or branched alkyl chain of one to four carbon atoms attached to the amino group. Examples of C 1 -C ₄ -alkylamino are: methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like. Another example of an amino is di (C _r C ₄₎ alkylamino, which comprises two straight or branched alkyl chains, each having from one to four carbon atoms attached to the same amine. Examples of di (C ₁ -C ₄ ) -alkylamino are: dimethylamino-, ethylmethylamino-, methylpropylamino-, ethylisopropylamino-, butylmethylamino-, sec-butylmethylamino and the like. An example of an amino is C _r C ₄ alkylsulfonylamino group having a linear or branched chain alkyl of one to four carbon atoms attached to a sulfonylamino moiety. Examples of the C 1 -C 4 alkylsulfonylamino group are: methylsulfonylamino-, ethylsulfonylamino-, propylsulfonylamino-, isopropylsulfonylamino-, butylsulfonylamino-, sec-butylsulfonylamino-, tert-butylsulfonylamino and the like.

The term "acyl" represents L ₆ C (O) L ₄ , wherein L ₆ is a single bond, -O or -N, and wherein L ₄ is preferably alkyl, amino, hydroxyl, alkoxy or hydrogen. The alkyl and alkoxy groups may be optionally substituted. Examples of the acyl group is a C _r C ₄ -alkoxycarbonyl, wherein the linear or branched alkoxy chain having from one to four carbon atoms attached to a carbonyl moiety. Examples of C 1 -C ₄ -alkoxycarbonyl groups are: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like. Another example of acyl is a carboxyl group wherein L ₆ is a single bond and L ₄ is alkoxy, hydrogen or hydroxyl. Another example is N-acyl (C _r C ₄₎ alkylcarbamoyl (L _D is a single bond and _L4 is an amino), which is a straight or branched chain alkyl of one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Examples of N- (C 1 -C ₄ ) -alkylcarbamoyl are: N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-tert-butylcarbamoyl and the like. Yet another example of acyl is N, N-di (C 1 -C ₄ ) -alkylcarbamoyl having two linear 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 (C 1 -C ₄ ) -alkylcarbamoyl groups are: Ν, Ν-dimethylcarbamoyl, N, N-ethylmethylcarbamoyl, Ν, Ν-methylpropylcarbamoyl, N, N-ethylisopropylcarbamoyl, Ν, Ν-butylmethyl, carbamoyl, N, N-ethylmethylcarbamoyl N-sec-butylethylcarbamoyl and the like.

The term "sulfinyl" represents -SO-L ₅ , wherein L ₅ is preferably alkyl, amino, aryl, cycloalkyl or heterocycle. Alkyl, aryl, cycloalkyl and heterocycle may all be optionally substituted.

The term "sulfonyl" represents -SO ₂ -L ₅ , wherein L ₅ is preferably an alkyl, aryl, cycloalkyl heterocycle or amino group. Alkyl, aryl, cycloalkyl and heterocycle may all be optionally substituted. An example of a sulfonyl is C _r

-C ₄ -alkylsulfonyl in which a linear or branched alkyl chain of one to four carbon atoms is attached to the sulfonyl radical. Examples of C _r C ₄ alkylsulphonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.

As indicated, a variety of groups may be optionally substituted. Indeed, unless specifically indicated, all 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 to include both substituted and unsubstituted alkyl, unless the exception of one or the other is explicitly mentioned. Examples of substituents of alkyl and aryl groups are: mercapto, thioether, nitro (NO ₂ ), amino, aryloxy, halogen, hydroxyl, alkoxy and acyl, as well as aryl, cycloalkyl and saturated or partially saturated heterocycles. Examples of heterocycle and cycloalkyl substituents are those mentioned above for alkyl and aryl as well as aryl and alkyl.

Examples of substituted aryls include phenyl and naphthyl substituted by one or more substituents independently selected from: halo, hydroxy, morpholino (-C ₄₎ alkoxycarbonyl, pyridyl (C _r C ₄₎ -alkoxycarbonyl, halo (C | -C ₄₎ -alkyl, C -C ₄ alkyl, C _C4 alkoxy, carboxy, C _r C ₄ -alkoxycarbonyl, carbamoyl, N- _(Ci-C4) alkylcarbamoyl, amino, C ₄ alkylamino, di (C ₄ ) -alkylamino or a group of the formula - (CH ₂ ) _and -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 ₄ alkylamino or di (C _r C ₄₎ alkylamino.

Another substituted alkyl is halogen (C ₁ -C ₄ ) -alkyl, which represents a linear or branched alkyl chain of one to four carbon atoms to which 1-3 halogen atoms are attached. Examples of halo (C _r C ₄₎ -alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloro-isobutyl, jódterc-butyl, trifluoromethyl and the like.

Another substituted alkyl is hydroxy (C _r C ₄₎ -alkyl, which is straight or branched chain alkyl of one to four carbon atoms, which is bound to the hydroxyl group. Examples of hydroxy (C _r C ₄₎ -alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-, 4-hydroxybutyl and the like.

Yet another substituted alkyl is C 1 -C ₄ -alkylthio (C 1 -C ₄ ) -alkyl, which represents a linear or branched C 1 -C ₄ -alkyl group to which C ₁ -C ₄ -alkylthio is attached. Examples of C ₁ -C ₄ -alkylthio (C ₁ -C ₄ ) -alkyl groups are: methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl and the like.

Another example of a substituted alkyl heteroĽyklus | C _r C ₄₎ alkyl. which represents a linear or branched alkyl chain of one to four carbon atoms to which the heterocycle is attached. Examples of heterocyclic (C _r C ₄₎ alkyl are: pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3- (2-thienyl) propyl, 1 -imidazolylizopropyl, 4-tiazolylbutyl and the like.

Yet another substituted alkyl is aryl (C _{r C4)} alkyl, a straight or branched chain alkyl of one to four carbon atoms, to which is attached an aryl group. Examples of aryl (C 1 -C ₄ ) -alkyl groups are phenylmethyl, 2-phenylethyl, 3-naphthylpropyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.

For example, the heterocycle may be substituted with 1, 2 or 3 substituents independently selected from:

halo, halo (C | -C ₄₎ alkyl, C | -C ₄ -alkyl, C _r C ₄ alkoxy, carboxy, C _r C ₄ -alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl-iCrCj, amino, C _r C _4- alkylamino, di (C ₁ -C ₄ ) -alkylamino or a group having the structure - (CH ₂ ) _and -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 are: 3-N-tert-butylcarboxamide decahydroisoquinolinyl, 6-N-tert-butylcarboxamidoctahydrothieno [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-methylquinolin-2-yl, 2-tert butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.

Examples of heterocyclic systems represented by A or B are:

(1) 5-membered monocyclic systems such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like; (2) 6-membered monocyclic systems such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and triazinyl; similarly, (3) heteropolycyclic systems such as decahydroisoquinolinyl, octahydrothieno [3,2-c] pyridinyl, benzo [b] thienyl, naphtho [2,3-b] thiantrenyl, isobenzofuranyl, chromenyl, xanthenyl, and fully or partially saturated analogs thereof.

The cycloalkyl may be optionally substituted with 1, 2 or 3 substituents independently selected from: halo, halo (C _r C ₄₎ alkyl, C, -C ₄ alkyl, C | -C ₄ -alkoxy, carboxy, C | -C ₄ -alkoxycarbonyl, carbamoyl, N- (C _{r C4)} alkylcarbamoyl, amino, C, -C4-alkylamino, C ^ dijCj-alkylamino or a group having the structure - (CH _{2) a} -R ⁷ where a is 1 , 2, 3 or 4 and ^R7 is hydroxy, C | -C ₄ -alkoxy, carboxy, C _r C ₄ -alkoxycarbonyl, amino, carbamoyl, C _r C ₄ alkylamino or di (C _r C ₄₎ alkylamino. Examples of substituted cycloalkyl groups are: 3-methylcyclopentyl, 4-ethoxycyclohexyl, 5-carboxycycloheptyl, 6-chlorocyclohexyl and the like.

Examples of substituted hydrolyzable groups are: N-benzylglycyl, N-Cbz-L-valyl and N-methylnicotinate.

The compounds of the present invention have at least five asymmetric centers, indicated by an asterisk in formula (9):

(9)

As a consequence of the existence of these asymmetric centers, the compounds of the present invention may exist in any possible stereoisomeric form and may be used as mixtures of stereoisomers, which may be optically active or racemic, or may be used alone as substantially pure stereoisomers, e.g. . j. at least 95% pure. All asymmetric forms, separate stereoisomers and combinations thereof are within the scope of the present invention.

Separate stereoisomers may be prepared from their corresponding precursors by the procedures described above, by resolution of the racemic mixtures into enantiomers or by separation of diastereoisomers. Resolution to enantiomers may be carried out in the presence of an agent capable of causing resolution, chromatography or recrystallization, or any combination of these techniques, as is known in the art. Further details on resolution to enantiomers can be found in: Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley & Sons, 1981.

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

As noted, the invention includes pharmaceutically acceptable salts of the compounds of formula (9). The compounds of the present invention may have sufficiently acidic, sufficiently basic, or both, and react accordingly with each of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

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. Examples of pharmaceutically acceptable salts are those prepared by reacting the compounds of the present invention with mineral or organic acids or inorganic bases. The reactants are generally mixed in a common solvent such as diethyl ether or benzene for acid addition salts, or water or alcohols for base addition salts. Salts normally precipitate out of solution within about one to ten days and may be isolated by filtration or other conventional methods. These salts are known as acid addition salts and base addition salts.

Acids that can be used to form acid addition salts are inorganic acids such as e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as e.g. p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.

Examples of pharmaceutically acceptable salts are: sulfate, disulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, hemiobutate, hemiobutate, hemiobutate propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, sulfonate, sulfonate, sulfonate, xylate phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, mandelate and the like.

Preferred pharmaceutically acceptable acid addition salts are formed with mineral acids such as e.g. with hydrochloric acid and hydrobromic acid, and with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts are salts derived from inorganic and organic bases such as hydroxides, carbonates, ammonium or alkali or alkaline earth metal hydroxides, and the like. Thus, the bases useful for preparing the salts of the present invention are sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. The potassium and sodium salt forms are particularly preferred.

By "pharmaceutically acceptable prodrug" is meant a compound that can be converted into a compound of formula (9) under physiological conditions or by solvolysis.

By "pharmaceutically acceptable solution" is meant a solution that retains the biological activity and properties of the biologically active components of the compounds of formula (9).

Examples of pharmaceutically acceptable solutions include, but are not limited to, compounds of formula (9) in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethylamine.

It should be noted that the concomitant counterion which forms part of any salt of the present invention is not critical as long as the salt as a whole is pharmaceutically acceptable and the concomitant counterion does not impose undesirable properties of the salt as a whole.

A preferred compound is compound (21)

[3S- [2 (2S *, 3S *), 3 alpha, 4abeta, 8abeta]] - N- (1,1-dimethyl-2-hydroxyethyl) decahydro-2- [2-hydroxy-3 - [(3- hydroxy-2-methylbenzoyl) amino] -4- (phenylthio) butyl] -3-isoquinolinecarboxamide.

The procedure for the preparation of compound (21) is described. Compound 21 was also obtained as a plasma metabolite from patients receiving [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-tert-butylcarboxamide methanesulfonic acid salt as disclosed in U.S. Pat. U.S. Pat. 5,484,926th

Compounds of formula (9) may be prepared according to the following Reaction Scheme I

Reaction Scheme I

Scheme I. General Synthetic Route for the Production of 9b and Derivatives

Compound 1a, perhydroisoquinoline, commercially available from NSC Technologies (Chicago, Illinois) or Procos SpA (Milan, Italy), is subjected to long-term acid hydrolysis in step 1a to give compound 2a. Multiple inorganic acids may be used in a mixture of an aqueous and an organic solvent or in water alone at a temperature above 50 ° C. An example of such an inorganic acid is 6 N HCl in water. Compound 1a can be replaced by the corresponding esters 1b, thioesters 1c or other amides 1d:

COOZ

conz, of ₂

benzyl =

9-fluorenylmelyl

wherein Z, Z ₁ and Z ₂ can each independently be alkyl, cycloalkyl, heterocycle or aryl.

Compound 2a is then protected on the amino nitrogen atom to give compound 2b in step 1b. The protecting group _Rp is defined as a suitable conjugating group to prevent unwanted decomposition of the activated carboxylate derivatives of compound 2b in step 2. Such protecting groups generally have the general structure according to formula (11), i.e. they are carbamates:

Such protecting groups can usually be introduced by the acylation reaction of the corresponding haloformic acid ester 12a or dicarbonate 12b:

ABOUT

(12a)

The radical R 'in formula (11) can be any alkyl, cycloalkyl, aryl or heterocycle which can be easily removed after step 2. Examples of R 'are, inter alia, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or higher branched or unbranched alkyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, phenyl, substituted phenyl], benzyl, substituted benzyl, 9-fluoromethyl, 9-anthylmethyl and higher polycyclic aromatic systems. The following substances, as mentioned, can be obtained from Aldrich Chemical Co. (Sigma Aldrich Fluka)

X = halogen

ABOUT

Y-OCOR (12b), in the presence of a suitable base in the organic solvents customary for these types of reactions, such as halogenated solvents, ethers or hydrocarbons. These bases are usually inorganic substances, for example metal hydroxides, bicarbonates and carbonates, or organic substances, for example amines such as triethylamine, diethylamine, diethylisopropylamine, 1,8-diazabicyclo [2.2.2] octane (DABCO) or similar dialkylamines or trialkylamines, as well as amidirium bases. such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) α1,8-diazabicyclo [4.3.0] non-5-ene (DBN). The following substances, as described, can be obtained from Aldrich Chemical Co. (Sigma Aldrich Fluka)

DABCO =

DBN = CQ

These reactions are usually carried out anywhere in the temperature range from temperatures below room temperature to about 100 ° C.

The amide coupling in step 2 can be performed in a number of ways depending on how the carboxyl group is activated. The group J is introduced in step 2 by reacting the carboxylic acid 2b to form the activated derivative 2c.

KrM 2

H \ - mktm <kim aniiw _{2 <} | . «ÄtTÄp.aU,

The group J may be any of a number of substituted groups such as alkoxy, hydroxy, halogen, pseudohalogen (including azide, cyanide, isocyanate and isothiocyanate), alkylsulfonate or arenesulfonate, aromatic heterocycle (linked via hydroxyheterocycles) or N-hydroxybenzyl, . The following definitions apply to the terms mentioned above:

azide --N - N = N cyanide C = N isocyanate N-C "H izcKiokyanát -N-C-S sulfonate 0 II --0-S-efcyl (1 0 0 II -0-S-aryl, II 0 arenesulfonate N-hydroxyheterocyklus "-0 where ⁼ nitrogen heterocycle N-hydroxysukelnimid ^H0 'V r - [i hydroxy benztriazole n I 1 OH

Acyl halides (2c, J = halogen) can be prepared using inorganic halogenating agents such as thionyl chloride or thionyl 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 as defined above) can be prepared by a number of methods starting from acid chloride 2c, where J is Cl, by coupling with the desired alcohol in the presence of the organic or inorganic base mentioned in the acylation of 12a or 12b . Alternatively, the ester can also be prepared by acid catalyzed esterification in the presence of the desired alcohol. The sulfonates (2c, J = OSO ₂ W _b where W? Is alkyl or aryl) are typically made by reaction of the carboxylic acid 2b, alkylsulfonyl or arylsulfonyl chlorides in the presence of an organic amine base such as triethylamine, in a non-polar solvent at temperatures below 0 ° C. Alkylsulfonyl and arylsulfonyl are defined as follows:

arylsulfonyl chloride = alkylsulfonyl chloride =

ABOUT

Cl-S-aryl i

ABOUT

Pseudohalogen derivatives 2c (J = pseudohalogen) are usually made from 2c acid halides (J = halogen) by reaction with an inorganic pseudohalogenide 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, diethylaminomethylisopropylamine, 1,8-diazabicyclo [2.2.2] octane (DABCO), or similar dialkylamines and trialkylamines, as well as amidine bases such as 1. 8-diazabicyclo [5.4.0] undec-7-ene (DBU) α1,8-diazabicyclo [4.3.0] non-5-ene (DBN). A particularly preferred base is triethylamine. Heteroaromatic derivatives 2c are also produced from acid halides 2c (J = halogen) using a specific heteroaromatic compound in the presence of an amine base in a non-polar solvent. The N-hydroxy heterocyclic derivatives 2c can be made from acid halides as described above and can also be prepared using alkylcarbodiimides (alkyl-N = C = N-alkyl, wherein the alkyl groups can be the same or different) or arylcarbodiimides (aryl-N = C = N-aryl, wherein the aryl groups may be the same or different) and amine bases as coupling reagents.

The primary or secondary amine (indicated above the arrow in step 2 of Scheme 1) used in the coupling process may incorporate suitable protecting groups depending on the functional groups present in the amine and the coupling method to be used. The coupling method of 2c with a primary or secondary amine can be accomplished in a number of ways depending on what J. is used. When the free acid (2c, J = OH) is used, coupling can be accomplished using carbodiimide-based methods using any reagent of conventional reagents of this category including dicyclohexylcarbodiimide or similar dialkylcarbodiimides, EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide salts) or similar water-soluble reagents together with an organic amine base in polar organic solvents such as dioxane, DMF, NMP and acetonitrile An N-hydroxy heterocyclic compound such as N-hydroxysuccinimide or 3-hydroxybenzotriazole.

Otherwise, formic acid esters such as 12d can be used to simultaneously activate the acid to form the mixed anhydrides of formula 2d.

(2d)

(12d)

X - halogen

Such halo formate esters are generally those as shown in 12d above and are, for example, methyl, ethyl, isopropyl, isobutyl, η-butyl, phenyl, and the like alkyl and aryl chloroformates as defined later.

alkyl chloroformate = aryl chloroformate »

C1 alkyl-O

Compound 2d is a possible intermediate in converting compound 2b to compound 3. Compound 2d is an intermediate, but the process described herein results in compound 3 without isolating compound 2d.

These reactions are generally carried out in many non-polar organic solvents such as halohydrocarbons and ethers, such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, dioxane and THF, at temperatures below 0 ° C in conjunction with an organic amine base such as triethylamine, diethylamine, diethylisopropylamine. , DABCO or similar dialkylamines or trialkylamines, as well as amidine bases such as DBU and DBN.

When group J in compound 2c is an alkylsulfonate or arenesulfonate (J = OSO ₂ R or OSO ₂ Ar), the coupling can be performed in many non-polar organic solvents such as halocarbons and ethers, for example diethyl ether, methyl tert-butyl ether, diisopropyl ether, dioxane and THF , at temperatures below 0 ° C in conjunction with an organic amine base such as triethylamine, diethylamine, dictylisopropylamine, DABCO or similar dialkylamines and trialkylamines, as well as amidine bases such as DBU and DBN.

When group J in 2c is halogen or pseudohalogen, the coupling may be carried out in the most common organic solvents such as THF, diethyl ether, dioxane, methyl tert-butyl ether or other ethers, acetone, cyclohexanone, methylisobutyl ketone and other ketones, ester, e.g. methyl acetate and isopropyl acetate, halogenated solvents such as halogenated methane and ethanes, chlorobenzene and other halogenated benzenes, nitriles such as acetonitrile and propionitrile, lower alcohols such as ethanol, isopropanol, tert-butanol and similar alcohols, and polar organic solvents such as dimethyl amide dimethylsulfoxide, N-methyl-2-pyrrolidone and similar amide solvents. Often, a base can be used, which can be any of a number of inorganic bases such as metal hydroxides, bicarbonates and carbonates, or organic bases such as amines such as triethylamine, diethylamine, diethylisopropylamine, DABCO or similar dialkylamines or trialkylamines, as well as amide bases. , such as DBU and DBN.

The person skilled in the art is able to effect the amide coupling in step 2 with other possible J groups.

In step 3, the deprotection may be performed using any standard procedure to remove individual protecting group categories. Unsubstituted and substituted alkyl carbamates can be removed in aqueous base solutions at temperatures up to about 100 ° C using any conventional inorganic metal hydroxide, for example sodium, lithium, potassium or barium hydroxide, or other metal hydroxides in at least a stoichiometric amount. Protective carbamate groups which contain oxygen-linked benzyl groups can be removed by hydrogenolysis using palladium or platinum as a catalyst. Alternatively, aqueous base hydrolysis can be used at temperatures up to about 100 ° C using any conventional inorganic metal hydroxide such as sodium, lithium, potassium or barium hydroxide, or other metal hydroxides in at least a stoichiometric amount. A number of anhydrous acids, including HCl, HBr, and H1, can also be used to remove the protecting group of the benzylated carbamates. Lewis acids of boron and aluminum, such as AlCl ₃ , BBr ₃ , BCl ₃ , are also effective in non-polar solvents. Certain substituted benzyl, aryl or alkyl groups, specific substitutions, may also be used, which are chosen to exploit their removability under specific conditions. For example, 2-trimethylsilylethylcarbonyl (Teoc) is a protecting group designed to exploit the specific reactivity of a 2-trimethylsilyl group in the deprotection process. 2-Trimethylsilylethylcarbonyl chloride can be used to protect the amine nitrogen and later can be removed using a source of fluoride anions such as HF or tetraalkylammonium fluoride salts.

In step 4, the perhydroisoquinoline moiety of molecule 4 is coupled to a chloro alcohol (Compound 5, Scheme I) via an epoxy intermediate (13) formed by a base-induced closure of the vicinal chlorohydrin moiety.

Compound 5 is manufactured by Kaneka Industries, Japan. Several closure and subsequent ring opening procedures may be used in the following steps: compound 5 - compound 13 - compound 6. The epoxide 13 may be isolated or reacted with compound 4 added either following formation of compound 13, or compound 4 may be present from the beginning succession. The epoxide 13 can be formed using inorganic bases such as metal hydroxides, carbonates and bicarbonates in the following solvents: alcohols, e.g. methanol, ethanol or isopropyl alcohol; ethers, e.g. THF and dioxane, or mixtures of alcohols with ethers. The epoxide may also be formed in a 2-phase solvent system consisting of water and a halogenated hydrocarbon solvent such as dichloromethane together with a base. A biphasic catalyst, such as a tetraalkylammonium salt, can be used to facilitate inter-phase transfer. The process of opening epoxide 13 with compound 4 is performed in alcoholic solvents or mixtures of alcohol with another solvent, which may be an ether or a dipolar aprotic solvent, such as dimethylformamide or dimethylsulfoxide. The opening of epoxide 13 by compound 4 to form compound 6 is optimally performed within 2-7 hours at 50-60 ° C.

In step 5, the benzyloxycarbonyl group can be removed to give the free amine 7. This can be accomplished using HBr in acetic acid using cosolvents such as halocarbons. This may also be performed using halides of boron, such as BBr ₃ and BC1 ₃ or boron halides substituted alkyl, e.g. dimetylbromidom tribromide in halocarbon solvents like chloroform and dichloromethane at temperatures ranging from 0 ° C to room temperature. Alternatively, the benzyloxycarbonyl group may be removed by hyphrolysis using aqueous / alcoholic metal hydroxide solutions such as barium, sodium, lithium or potassium hydroxides at temperatures above room temperature for hours.

Step 6a is coupling of benzoic acid derivatives of formula 8 to form 9a. In formula 8, Q may be a substituted group. Q may be any substitution group as previously mentioned for group J. Compounds of formula 8 wherein Q = OH or C1 are commercially available from EMS Dottikon, Lenzburg, Switzerland and from Sugai Chemical Industries, Ltd. in Japan. Coupling can be accomplished in a number of ways depending on what Q is. When the free acid (Q = OH) is used, coupling can be accomplished using carbodiimide-based procedures using any conventional reagents of this category including dicyclohexylcarbodiimide or similar dialkylcarbodiimides, EDC (salts) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) or similar water-soluble reagents together with organic amine bases in polar organic solvents such as dioxane, DMF, NMP and acetonitrile, in the presence of N-hydroxyheterocycle including N-hydroxysuccinimide or 3- hydroxybenzotriazole. When Q = halogen or pseudohalogen, coupling may be carried out in the most common organic solvents such as THF, diethyl ether, dioxane, methyl tert-butyl ether or other ethers, acetone, cyclohexanone, methyl isobutyl ketone and other ketones, esters such as ethyl acetate, methyl acetate and isopropyl acetate. halogenated solvents such as halogenated methane and halogenated ethanes, chlorobenzene and other halogenated benzenes, nitriles such as acetonitrile and propionitrile, lower alcohols such as ethanol, isopropanol, tert-butanol and similar alcohols and in polar organic solvents such as dimethylformamide, dimethylsulfide methyl-2-pyrrolidone and similar amide solvents. Often a base is used, which can be any of a number of inorganic bases, such as metal hydroxides, bicarbonates and carbonates, or organic bases such as amines, e.g. triethylamine, diethylamine, diethylisopropylamine, DABCO or similar dialkylamines or trialkylamines, as well as amidine bases, e.g. DBU and DBN.

The removal of the acetate is carried out in step 6b in aqueous or alcoholic solutions of inorganic bases such as metal hydroxides, carbonates and bicarbonates at temperatures from room temperature to 100 ° C. If there is a protecting group on the peroxyisoquinoline-linked carboxamide group, it is best to remove it at this stage (during or after step 6b). The nature of this step is dependent on the exact composition of the protecting group.

A preferred method for carrying out the entire process shown in Scheme I is shown in Scheme II.

Scheme II. Amide synthesis 21

The Cbz-protected amino acid 15 was coupled with amine 22 to form amide 16. The Cbz residue was removed by hydrogenation to give amine 17. This was coupled to the chloro alcohol via an epoxide using an in situ procedure to adduct 18. Conventional deprotection with base and coupling of free primary of the amine with acid chloride 20 gave amide 21. The details of the procedure are described below in Examples 1Λ to F. The designation A to F in Scheme II corresponds to Examples 1A to F below.

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

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations for melting point, nuclear magnetic resonance spectra, electron impact mass spectra, feld field desorption mass spectra desorption mass spectra), fast atom bombardment mass spectra mass spectra, infrared spectra, ultraviolet spectra, elemental analysis, high performance liquid chromatography and thin layer chromatography are respectively t. m.p., NMR, EIMS, MS (FD), MS (FAB), IR, UV, Analysis, HPLC and TLC. In addition, the reported absorption maxima for IR spectra are selected, not all observed maxima are listed.

The following abbreviations are used in conjunction with NMR spectra: singlet (s), doublet (d), doublet of 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 gives coupling constants in Hertz (Hz). Unless otherwise indicated, NMR data is based on the free base of the test compound.

NMR spectra were obtained on a 300 MHz General Electric QE-300 instrument. Chemical shifts are expressed in δ-values in ppm. Mass spectra were recorded on a VG ZAB-3 spectrometer at the Scripps Research Institute, La Jolla, California. Infrared spectra were recorded on a Midac Corporation spectrometer. UV spectra were obtained on a Varian Line 3E instrument. TLC was performed on E. Merck silica gel plates. Melting points were measured on a Mettler FP62 and are not corrected.

Example 1

Procedures for the synthesis of the amide of Formula 21 [3S- [2 (2S *, 3S *), 3alpha, 4abeta, 8abeta)]] - N- (1,1-dimethyl-2-hydroxyethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-metylbezoyl) amino] -4- (phenylthio) butyl] -3-isoquinolinecarboxamide

A. Perhydroisoquinoline (26.4 g, 111 mmol) (commercially available from NSC Technologics (Chicago, Illinois) or Procos SpA (Milan, Italy)) was suspended in water (200 mL) and concentrated HCl in water (200 mL). The mixture was heated to reflux with stirring for 3 days, during which time it was dissolved. Solvents were removed under reduced pressure to give a light yellow solid. The solid was slurried 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 pH 8.0 by addition of 2 N KOH in water. Benzyl chloroformate (15.8 mL, 111 mmol) was added dropwise over 30 min, maintaining the pH between pH 7 and 8 by adding 2 N KOH in water. The mixture was stirred at room temperature for 18 hours. EtOAc (200 mL) was added and the organic layer was washed with 1 N HCl in water (100 mL) and saturated aqueous sodium chloride solution (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 petroleum ether 40-60 with EtOAc 1: 1 and then 100% EtOAc. Product containing fractions were collected and evaporated under reduced pressure to give compound 15 (11.3 g, 32%) as a colorless oil: 1 H NMR (300 MHz, CDCl 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); 1.88-1.15 (m, 10H).

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 room 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.) by heating the undiluted mixture was added. under reflux for several hours followed by evaporation of the volatiles - and the solution was heated at 80 ° C for 17 hours. The yellow solution was poured into a mixture of EtOAc (250 mL) with 2 N HCl in water (250 mL). After stirring for 10 minutes, EtOAc (750 mL) was added and the mixture was washed with H ₂ O (3 x 500 mL) and saturated aqueous sodium chloride solution (1 x 250 mL). The combined aqueous layers were extracted with EtOAc (1 x 250 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and purified by flash chromatography with EtOAc / hexanes 50:50 to give compound 16 as a colorless oil (7.9 g, 78%): 1 H NMR (300 MHz, CD ₃ OD) δ 7.36 (m, 5 H), 5.20 (d, J = 8.1 Hz, 1H), 5.10 (m, 1H), 4.53 (m, 1 H 1.78 (dd, J = 13.2, 4.4 Hz, 1H), 3.60 (m, 2H), 3.48 (d, J = 10.7 Hz, 1H), 2.15 1.25 (m, 12H), 1.31 (s, 3H), 1.29 (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 (50 psi H ₎ square inch) in absolute EtOH (110 mL) at room temperature for 18 hours. The mixture was filtered through Celite and evaporated in vacuo to give amine 17 as a white, crystalline solid: 1 H NMR (300 MHz, CD ₃ OD) δ 3.63 (q, J = 7.0 Hz, 2H), 34 (m, 1H), 3.27 (dd, J = 11.8, 3.3 Hz, 1H), 2.91 (m, 1H), 2.02-1.15 (m, 12H), 1 32 (s, 3H), 1.31 (s, 3H).

D. To a warm (27 ° C) suspension of chloro alcohol (obtained from Kaneka Industries in Japan) (10.4 g, 28.6 mmol) in isopropanol (IPA) (104 mL) was added 10.2 N NaOH in water (2 mL). (4 mL, 24.5 mmol) with mechanical stirring. After 1 hour, approximately (ca.) 1 mL of 1 N aqueous HCl in IPA (prepared by adding 1 mL concentrated aqueous HCl to 12 mL 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 slurry was heated at 60 ° C for 10 h. IPA was removed by vacuum. The residue was diluted with EtOAc (150 mL) and washed with H ₂ O (2 x 50 mL), saturated aqueous NaHCO ₃ (1 x 50 mL) and saturated aqueous sodium chloride (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 (EtOAc / bexanes 75:25, then EtOAc) to give compound 18 as a white solid (8.98 g, 76%): 1 H NMR ( 300 MHz, CD ₃ OD) δ 7.33 (m, 10 H), 5.08 (AB, J _AB = 12.2 Hz, AU = _AB = 12.1 Hz, 2H), 3.96 (m, 2H 3.56 (q, J = 7.3 Hz, 2H), 3.50 (m, 1H), 3.20 (dd, J = 13.6, 9.2 Hz, 1H), 3.03 (m, 1H), 2.64 (m, 2H), 2.20-1.20 (m, 14H), 1.28 (s, 6H).

E. 50% NaOH in water (2.7 g, 1.8 mL, 33.6 mmol) was added to a suspension of carbamate 18 (6.75 mg, 11.6 mmol) in IPA (34 mL) at room temperature. The mixture was heated at reflux for 12 hours. After cooling to room temperature, the mixture was diluted with methyl tert-butyl ether (MTBE) (600 mL) and washed with H ₂ O (2 x 250 mL) and saturated aqueous sodium chloride solution (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 (300 MHz, CD 3 OD) δ 7.34 (m, 10H), 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. 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 theoretically based on 18) and benzyl alcohol in EtOH (23 mL) at room temperature. A solution of 3-acetoxy-2-methylbenzoyl chloride (20) (obtained according to the procedures described in U.S. Patent Application Serial No. 08/708411 filed September 5, 1996, which is incorporated herein by reference) (2.4 g, 11, 5 mmol) in THF (4 mL). After 2 hours, 50% NaOH in water (4.1 g, 2.8 mL, 52.2 mmol) was added and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the mixture was neutralized to pH = 7 with 2 N HCl in water (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 saturated aqueous sodium chloride (1 x 250 mL). x 125 ml). The organic layer was dried (Na ₂ SO ₄ ) and purified by flash chromatography (EtOAc / hexanes 75:25) to give amide 21 as a white foam (1173-57A, 1.39 g, 23%). 1 H NMR indicated the presence of 11 wt% EtOAc, which could not be removed by vacuum.

analysis:

Ή NMR (300 MHz, CD, OD) 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, J _and B = 11.0 Hz, AU _{and ab} = 18.0 Hz, 2H), 3.29 (dd, J = 13.6, 10.3 Hz, 1H), 3.10 (m, 1H 1.66 (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).

¹³ C NMR (75.5 MHz, CD ₃ OD) 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.

Example 2

Inhibition of HIV protease activity and anti-HIV activity in cell cultures by compound 21

Kinetic analysis of binding strength was used to determine the magnitude of the K i values of compound 21. It was found that K; = 5.6 ± 0.91 nM.

techniques

HIV-1 protease expression

The gene encoding HIV-1 protease was isolated from a strain of virus 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 the serine residue (S) by replacing a 33-pair region. a base between the sites recognized by NdeI and BstEII in the protease gene sequence by a synthetic oligonucleotide encoding a Q7S mutation. The modified gene sequence was inserted into the plasmid vector pGZ (Menge, K. L. et al., Biochemistry, 34: 15934-15942 (1995)) under the control of the T7 phage promoter. The resulting vector containing the modified -pGZ / HP-19Q7S # 9 gene sequence was introduced into E. coli strain BL21 (DE3) supplied by Novagen, Inc.

HIV-1 PR Expression: Cultures were grown on 2YT media (1.6% trypticase peptone, 1% yeast extract, 0.5% NaCl at an initial pH of 7.5) containing 200 µg / L ampicillin in a 100-1 fermentor (Biolafitte SA ) at 37 ° C for 5 hours and then induced by the addition of 1 mM 1PTG (isopropyl-β-D-thiogalactopyranoside). During induction, the temperature of the culture 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 harvested by cross-flow filtration using 0.1 µm Pellicon WPP000C5 Cassette # 1. 10 (Millipore) and cell paste was stored frozen at -70 ° C.

Recombinant HIV-1 Protease Purification: All steps were performed at 4 ° C unless otherwise noted. Protein concentration was determined using a BioRad protein determination solution using bovine serum albumin (BioRad, Richmond, California) as a standard. Chromatographic steps and purity of HIV PR were analyzed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE). The final purity of HIV PR was> 98%. The usual final yield from each 100-1 culture was -120 mg.

Cell paste from 100-1 culture was resuspended in 300 ml of lyric solution (50 mM Tris-Cl pH 8.0, 25 mM NaCl, 20 mM 2-mercaptoethanol) and liquefied on a small scale on a Microfluidics Corporation liquefier at 151.7MPa ( 22,000 psi). The crude cell hydrolyzate was clarified by centrifugation at 14,000 rpm for 20 minutes ("revolution per minute"). HIV PR was predominantly in the pellet in the form of inclusion bodies. The inclusion bodies were subsequently washed several times with a lysis solution containing 0.1% Triton-X100 and 1 M urea. After each wash, the inclusion bodies were centrifuged at 5000 rpm for 20 minutes. The purified inclusion bodies were solubilized with a solution 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 onto a 300 ml Q-Sepharose Fast Flow column (Pharmacia, Piscataway, New Jersey) equilibrated in the same solution at room temperature. Under these conditions, HIV PR did not bind to the column and the substantially pure enzyme was found in the run-off fractions. For protein renaturation, fractions from the Q-Sepharose Fast Flow column were dialyzed against a solution containing 25 mM pH 7.0, 25 mM NaCl, 10 mM DTT and 10% glycerol, which was changed three times. After renaturation, small amounts of precipitated material were removed by centrifugation and the resulting enzyme preparation was concentrated, dialysed against a solution composed of 0.5 M NaCl, 50 mM MES pH 5.6, 10 mM DTT, frozen in small amounts (-2 mg / ml). and stored at -70

Determination of kinetics and bond strength analysis

Proteolytic activity of purified HIV-1 protease was measured by a modified chromogenic assay developed by Richards et al. (Richards, AD et al. J. Biol. Chem., 256, 7733-7736 (1990)). The synthetic peptide His-Lys-Ala-Arg-Val-Leu-Phe (paraNO ₂ ) -Glu-Ala-Nle-SerNH ₂ (American Peptide Company) (Nlc is norleucine) was used as substrate. The assay was performed in a solution containing 0.5 M NaCl, 50 mM MES pH 5.6, 5 mM DDT, and 2% DMSO at 37 ° C. The cleavage of the binding between leucine and paranitrophenylalanine (Phe para-NO ₂ ) was determined spectrophotometrically by monitoring the decrease in absorbance at 305 nm. The initial rate was determined as the rate of decrease in absorbance during the first 100 seconds of the enzyme reaction. Under these conditions and using the protease Q7S HIV-1, the Michaelis constant (K _m ) for this substrate is 59 ± 17 μΜ.

A saturated substrate concentration of 200 μΜ was used to determine inhibition by Compound 21. 13 to 20 inhibitor concentrations were evaluated and the reaction rate at each concentration was measured as described previously. The apparent Ki (K, app) described above was determined by computer nonlinear regression - least squares - data for the Morrison bond strength equation (Morrison, J.F., Biochem. Biophys. Acta, 185, 269-286 (1963)).

Example 3

Antiviral activity of compound 21 against HIV-1 in cell cultures

Virus cells and strains

CEM-SS and MT-2 human T cell lines and RF and IIIB strains were obtained 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 dye reduction method (Alley, MC et al., Cancer Res. 48: 589-501 (1988)). Compounds were dissolved in DMSO at a concentration of 40 mg / ml and then diluted 1: 200 with culture medium (RPMI supplemented with 10% bovine serum). 100 µl of each control stock was removed into a 96-well microplate and series of dilutions were prepared in which the logarithm of the concentrations was halved. In separate tubes, MT-2 and CEM-SS cells were infected with HIV-1 IIIB and C-1B, respectively. HIV-1 RF with a multiplicity of infection (moi) of 0.01 and 1, respectively. 0.03. After a 4-hour adsorption period, 100 μΐ of infected and uninfected cells were added to the drug-containing microplate wells to give a final cell concentration of 1 x 10 ⁴ per well. After 6 (CEM-SS cells) or 7 (MT-2 cells) days, MTT (5 mg / ml) was added to the test microplates and the amount of formazan formed was quantified spectrophotometrically at 570 nm. Data were expressed as a percentage of formazan produced by cells to which drug was added compared to formazan produced in wells with uninfected cells to which drug was not added. ED ₅₀ was calculated as the concentration of drug that increased the percentage of formazan produced in infected cells to which drug was added to 50% of the amount produced by uninfected cells to which no drug was added. Cytotoxicity (TC ₅₀ ) was calculated as the concentration of drug that reduced the percentage of formazan produced by uninfected cells to which drug was added to 50% of the amount produced by uninfected cells to which no drug was added. The therapeutic index (TI) was calculated by dividing the cytotoxicity (TC ₅₀ ) by antiviral activity

Table 1

Evaluation of antiviral activity and cytotoxicity of compound 21 for CEM-SS cells in their acute HIV-1 RF infection

compound ED50 (nM) ED «(11M) TC _W Therapeutic index * 21 34.2 154.1 96.6 2825 azidothymidine (AZT) 52.3 543.1 > 374.5 > 7161 dideoxycytidine (ddC) 94.70 142.0 37.69 398

"Therapeutic index - cytotoxicity (TC ₅ a) + antiviral activity (ED ₅₀

Table 2

Evaluation of antiviral activity and cytotoxicity of compound 21 for MT-2 cells in their acute HIV-1 IIIB infection

compound EDjo (M? ED95 (nM) TC _{! O} (μΜ) Therapeutic index * 21 85.6 ND 92.6 1082 AZT 430.7 ND 109.4 254 ddC 5924 ND 176.3 30

• Therapeutic index = cytotoxicity (TC 50) - antiviral activity (ED _SO )

As mentioned above, the compounds of the present invention are useful for inhibiting HIV protease, an enzyme associated with the formation and arrangement of viral particles. The present invention includes a method of treating an 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 further comprises a method of treating AIDS comprising administering an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof to a host or patient. Further, the present invention provides a method of inhibiting HIV protease comprising administering an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof to HIV-infected cells or a host, or a patient such as a primate, infected with HIV.

The term "effective amount" means an amount of a compound of formula (9), or a pharmaceutically acceptable salt thereof, that is effective to inhibit HIV-protease-mediated formation and alignment of virus components. Of course, to achieve therapeutic or inhibitory effects, the specific dose of a compound administered according to the invention will be determined by the particular circumstances of the case, including e.g. the compound administered, the route of administration, the condition of treatment and the host or patient being treated. Exemplary daily doses (administered as a single dose or divided into multiple doses) achieve dosage levels of from about 0.01 mg to about 50 mg of the compound of this invention per kg body weight. Preferred daily dosages are generally from about 0.05 mg / kg to about 40 mg / kg, and more preferably from about 1.0 mg / kg to about 30 mg / kg.

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 the present invention are preferably formulated prior to administration. Therefore, the present invention further comprises pharmaceutical compositions or formulations comprising an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, such as a diluent or vehicle thereof.

The active ingredients preferably comprise from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" is meant that the carrier, such as a diluent or vehicle, is compatible with the other ingredients of the formulation and is not deleterious to the host or patient.

Pharmaceutical compositions may be prepared from the compounds of this invention by known procedures using known and readily available ingredients. In preparing the compositions of the present invention, the active ingredient is usually admixed with the carrier or diluted by the carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other suitable container. When the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a carrier, vehicle, or environment for the active ingredient. Thus, the compositions may take the form of tablets, pills, powders, crayons, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid compositions), 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 formulation examples are illustrative 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.

Preparation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mgfkapsula)

Active ingredient 250 Dried starch 200 Magnesium stearate 10 Together 460 mg

Preparation 2

The following ingredients are used to prepare the tablets:

Quantity (ing / tablet)

Active ingredient 250 Cellulose microcrystalline 400 Silicon dioxide airgel 10 Stearic acid 5 Together 665

The ingredients are mixed and compressed into tablets, each weighing 665 mg.

Preparation 3

Preparation of an aerosol solution containing the following components:

mass Active ingredient 0.25 methanol 25.75 Propelant 22 (chlorodifluoromethane) 74,00 Together 100.00

The active ingredient is mixed with ethanol, and the mixture is added to a portion of propellant 22 cooled to -30 ° C and transferred to a filler. The required amount is then dispensed into a stainless steel container and diluted with the remainder of the propellant. The reservoir is then provided with a valve unit.

Preparation 4

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

Active ingredient

starch

Cellulose microcrystalline

Polyvinylpyrrolidone (as a 10% solution in water) Carboxymethylated Starch, sodium magnesium stearate

talc

Together

Quantity (mg / table (a)

4.5

0.5

150

The active ingredient, starch and cellulose are passed through a 45 mesh U.S. sieve and mixed thoroughly. An aqueous solution containing polyvinylpyrrolidone is mixed with the resulting powder and passed through a 14 mesh U.S. sieve. The resulting granules are dried at 50 ° C and passed through an 18 mesh U.S. sieve. The sodium salt of carboxymethylated starch, magnesium stearate and talc, previously sieved through a 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed into a tablet machine, each having a weight of 150 mg.

Preparation 5

Capsules, each containing 80 mg of the active ingredient, are prepared as follows:

Quantity (mg / capsule)

Active ingredient 80 mg starch 59 mg Cellulose microcrystalline 59 mg Magnesium stearate 2 mg Together 200 mg

The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a 45 mesh U.S. sieve and filled into hard gelatin capsules in an amount of 200 mg.

Preparation 6

Lace, each containing 225 mg of active ingredient, is prepared as follows:

Active Ingredient 225 mg

Saturated fatty acid glycerides 2000 mg

Total 2,225 mg

The active ingredient is passed through a 60 mesh U.S. sieve and suspended in saturated fatty acid glycerides pre-melted using the minimum heat required. The mixture is then poured into a suppository mold with a nominal loading capacity of 2 g and allowed to cool.

Preparation 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are prepared as follows:

SK 283636 Β6

Active ingredient 50 ing Carboxymethylcellulose, sodium salt 50 mg syrup 1.25 ml Benzoic acid solution 0,10 ml Fragrances q. in. colorants ad q.v. Clean water to total volume 5 ml

The active ingredient is passed through a 45 mesh U.S. sieve and blended with carboxymethylcellulose sodium and syrup to form a fine paste. The benzoic acid solution, fragrances and colorants are diluted with some of the water and added with stirring. The required amount of water is then added to the desired volume.

Preparation 8

The intravenous preparation is prepared as follows:

Active ingredient 100 mg

Isotonic saline 1000 ml

The solution of said components is generally administered intravenously at a rate of 1 ml per minute.

Preparation 9

The tablet is prepared from the following ingredients:

number

(Mg / tablet) Active ingredient 292 mg Calcium silicate 146 mg crospovidone 146 mg Magnesium stearate 5 mg Together 589 mg

PATENT CLAIMS

Claims (34)

A decahydroisoquinolinecarboxamide derivative of the general formula (9) wherein: R and R 'are independently selected from the group consisting of hydrogen, radicals -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; -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 ₃ , -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 a -C (CH ₃ ) ₂ CH ₂ -S-acyl, groups a an alkyl-NR ₂ R ₃ group or an alkyl-S (X) (Y) R 4 group wherein: R ₂ and R ₃ are independently selected from the group consisting of H, optionally substituted alkyl, cycloalkyl, heterocyclic and aryl groups and acyl and sulfonyl groups, R ₄ is H, an optionally substituted alkyl, cycloalkyl, heterocyclic or aryl group and X and Y are independently selected from the group consisting of = O no substituent, or a pharmaceutically acceptable salt, or solvate thereof. A derivative according to claim 1 of the general formula (9), wherein R 1 is H, or a pharmaceutically acceptable salt or solvate thereof. A compound according to claim 1 of the general formula (9), wherein at least one of R and R '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 , or a pharmaceutically acceptable salt or solvate thereof. The derivative according to claim 1 which is a compound of the formula or a pharmaceutically acceptable salt or solvate thereof. A derivative according to claim 2 of the general formula (9), wherein R 1 is selected from groups or a pharmaceutically acceptable salt or solvate thereof. The salt of claim 1, which is a compound of formula (9b) (9b). ú c i 7. A pharmaceutical composition comprising an effective amount of a compound of claim 1; and b) a pharmaceutically acceptable carrier. 8. A pharmaceutical composition comprising (a) an effective amount of a compound of claim 4; and b) a pharmaceutically acceptable carrier. Use of a derivative according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a pharmaceutical composition for inhibiting HIV protease. The use of a derivative according to claim 4 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a pharmaceutical composition for inhibiting HIV protease. The derivative according to claim 1 having a purity of more than 90%. The derivative according to claim 1 having a purity of more than 95%. The derivative according to claim 1 having a purity of more than 97%. The derivative according to claim 1 having a purity of more than 99%. The derivative according to claim 4, having a purity of more than 90%. A derivative according to claim 4 having a purity of more than 95%. The derivative according to claim 4 having a purity of more than 97%. A derivative according to claim 4 having a purity of more than 99%. 19. A pharmaceutical composition according to claim 7, comprising as component a) a derivative according to claim 11. 20. A pharmaceutical preparation according to claim 7, characterized in that it comprises as component a) a derivative according to claim 12. 21. A pharmaceutical composition according to claim 7, characterized in that it comprises as component a) a derivative according to claim 13. 22. A pharmaceutical composition according to claim 7, comprising as component a) a derivative according to claim 14. Pharmaceutical preparation according to claim 8, characterized in that it comprises as component a) a derivative according to claim 15. 24. A pharmaceutical composition according to claim 8, comprising as component a) a derivative according to claim 16. Pharmaceutical preparation according to claim 8, characterized in that it comprises as component a) a derivative according to claim 17. 26. A pharmaceutical preparation according to claim 8, characterized in that it comprises as component a) a derivative according to claim 18. The use according to claim 9, wherein the derivative according to claim 11 is used to manufacture the pharmaceutical composition. Use according to claim 9, wherein a derivative according to claim 12 is used for the manufacture of the pharmaceutical composition. The use according to claim 9, wherein the derivative according to claim 13 is used to manufacture the pharmaceutical composition. The use according to claim 9, wherein a derivative according to claim 14 is used to manufacture the pharmaceutical composition. The use according to claim 10, wherein a derivative according to claim 15 is used to manufacture the pharmaceutical composition. Use according to claim 10, wherein a derivative according to claim 16 is used for the manufacture of the pharmaceutical composition. Use according to claim 10, wherein a derivative according to claim 17 is used for the manufacture of the pharmaceutical composition. Use according to claim 10, wherein a derivative according to claim 18 is used to manufacture the pharmaceutical composition.