SA98181116B1 - HIV protease inhibitors - Google Patents

Abstract

Abstract: The present invention relates to HIV protease inhibitors that can be obtained by chemical synthesis to inhibit or block the biological activity of the HIV protease enzyme, causing remission of HIV to terminate said activity. These compounds, as well as pharmaceutical formulations containing these compounds and experimentally other antiretroviral agents as active substances, are suitable for the treatment of diseases or hosts infected with HIV, which is known to cause disease.

Description

Y —_ — protease inhibitors HIV HIV Full Description BACKGROUND The present invention relates to a new series of chemical compounds useful as HIV inhibitors and using Ja of these compounds as agents Antivirus. Acquired Immunodeficiency Syndrome (AIDS) is a disease or disease that has been recognized relatively recently + AIDS causes a gradual breakdown of the body's immune system in addition to the progressive deterioration of the central and peripheral nervous systems. Since the initial recognition In the early 1980s AIDS spread rapidly and has now reached epidemic proportions within a relatively small segment of the population Extensive research has led to the discovery of the responsible agent Human T-lymphotropic retrovirus IT (HTL 7-1190 0) now more commonly referred to HIV or 1117. HIV is part of a class of viruses known to be retroviruses.The retroviral genetic group consists of RNA that is transformed into DNA by retroviral tissue and then this retroviral DNA is fused in a form Persistent within the chromosome \o the host cell and the use of repeated processes of cells and incubation of new retroviral particles and infection of other cells.It seems that HIV virus has a specific affinity for the human T-4 lymphocyte cell that plays a vital role in The body's immune system. HIV infection that affects these white blood cells depletes the multiplication of these white cells and eventually becomes the immune system

Creamy - Unaffected and ineffective against various utilitarian ailments such as; of between it ; Pneumocystic carini, Kaposi's sarcoma, and lymphatic system cancer. Although the mechanism of HIV formation and action is not understood, the identification of the virus has led to some progress in controlling the disease.

° For example, it was found that the drug (AZT) azidothymidine is effective in inhibiting the reverse transcription (GL) gall of a retroviral virus such as HIV ¢ and then giving a control measure; thought to be inaccurate; for patients with AIDS. The search continues for drugs that can cure the deadly HIV virus, or at least provide an improved way to control it.

Retroviral replication frequently depicts post-transcriptional processing of proteins

0 multiple. This treatment is accomplished by the HIV protease enzyme encoded by a virus.

This results in fully developed polypeptides that will assist Lad after formation and functioning.

contagious virus If this molecular processing is hindered; The normal production of HIV is taking place

turn it off. Therefore, HIV protease inhibitors may act as anti-HIV agents.

\o The HIV protease is a product woven from the recombinant protein Pol gene

HIV acts on retroviral proteases, particularly on cleavage multiples

Polypeptides are another combination of unique sites for editing these proteins and enzymes

newly activated synthetic; In this way a component of virion replication that itself might prevent is introduced

Inhibition of the HIV protease by proviral integrating active compounds for T lymphocytes

© infected during the microbial phase of the 1117-1 life cycle; In addition to inhibiting the Jad preparation of the protein

viral during its late stage; Moreover ; Protease inhibitors may feature

With the advantages of being more readily available, longer inactivation of the virus and less toxicity than available drugs, Ulla is likely to be due to its specific specialization of retroviral proteases. A general description of the invention according to this invention; A new class of chemical compounds that can inhibit and/or block the activity of the HIV protease is provided; Which stops the multiplication of the HIV virus and pharmaceutical formulations that contain these compounds and the use of the compounds as HIV protease inhibitors. The present invention relates to compounds falling within formula (9) below, salts, inert drugs, and pharmaceutically acceptable solubility thereof; that inhibit the protease encoded by HIV-1 (HIV-1) virus type 1 or Type? Antibiotics and vaccines. It is also possible to use the ve compounds of the present invention in the form of inactive drugs. Methods of treating AIDS, methods of treating HIV infection, and methods of inhibiting HIV protease have been discovered. The compounds of the present invention have the formula (9): R nC, bc e ° SPh 1 = bis tar OH | 0

love QO —_— where: RR over a unit to be chosen from 11; 1101-0181 is “substituted or not” or a cycloalkyl group is substituted by an alkyl group (and 0-0) or a (Cy -Cg)alkyl-OH 0 heterocyclic group is substituted by a group alkyl (CC) 0 or (C-Cealkyl-OH + or RSRoN- alkyl ic gana “ or Ry(Y)(X) S- alkyl ¢ Ry group is H « 0 alkyl groups substituted or unsubstituted; or acyl de gana ¢ JS of Ry and y separately chosen from H; alkyl groups either substituted or unsubstituted; and cycloalkyl − and aryl 5 « aryl 5 » heterocyclic groups 0 heterocyclic; and sulfonyl acyl groups; Ry is JH alkyl group substituted or unsubstituted + or cycloalkyl he where H Rs + or lo alkyl substituted or ambiguously substituted + or cycloalkyl ¢ or heterocyclic group or acyl or sulfonyl group.It is preferred in a compound of formula 4; © is an H ; More preferably »© are 11 and 2 are cycloalkyl de sane selected from: frie

51 _ — CH,0H, 77 and > 2 CH,OH etc. It is preferred in compounds of formula 4 when at least one of the RUS R is a salkyl -OR group; 1 is a 11; In particular, when at least one of © ; Ry is an alkyl group -OR," and then the alkyl 0167- is selected from: -C(CH3), CH,0H, -CH(CH;)CH,0H, -CH,CH,0H, -0) 01( (CH;PH),, -C(CH3), ~O- ° -C(CHj), CH,- O- CH,- O-CHs, and ~C(CHs3), CH ;- O- acly 0112-0-05 or a drug in a pharmaceutically acceptable inert form 'Prodrug' or salt or a solute thereof. Preferably when at least one of the SR 8 is a cyclic alkyl Ae seme substituted by a (C1-Ce) alkyl group or an alkyl group (and 0-)- 0 > then choose a cycloalkyl group from:

oY - CH, 7 > yber CH,;0H CH,OH CH,OH and 7 Preferably at least one of 18 and 8 is a heterocyclic de gene replaced by a group (Ci-Co) alkyl or OH -)0,-00 alkyl group A heterocyclic ring group is chosen from: Hj Hj Hj 0,5 CH, H, CH, 0, S, 0, 11-6 N—R3, and HC, mala ° where with a substituted H or an alkyl ic sana or not a dade or a cycloalkyl ic gana or a cyclic group heterocyclic or aryl group ' or acyl ic jana or sulfonyl de gana . There is a preferred form of formula (9) which is:

A —_ — [3[2(2S*,3S*),3 alpha,4a beta,8abeta]]-N-(1,]-dimethyl-2- hydroxyethyl) decahydro-2- [2 -hydroxy-3- [(3-hydroxy-2- methylbenzoyl)amino]-4-(phenylthio)butyl]-3- isoquinolinecarboxamide Sph 0 N e Nd or LA : WS HO . 0 N N H H OH oS© and its pharmaceutically acceptable salts ¢ and inert drug analogues; It is possible to obtain the preferred inactive drugs by substituting hydrogen in one of the alcohol groups with a cacyl group and, more preferably, an amino acid acyl group. The present invention provides; in the form of; Additional 0 “Pharmaceutical formulations included” an effective amount of a compound of Formula (3) or a pharmaceutically acceptable salt thereof; in combination with a pharmaceutically acceptable carrier; such as a diluent or an excipient. Administration to a host or patient such as one of the primates an effective amount of the compound of the present invention The present invention additionally provides a method of inhibiting HIV replication including administration of an HIV-infected or susceptible cell or a host or patient such as one primates; an effective amount of the compound of the present invention.

DETAILED DESCRIPTION: The present invention provides new compounds falling within Formula (9); as described Alay that are useful for the treatment of HIV infection and/or AIDS. The applicants of the present invention combine with reference to US Patent Application No. SEALANT U.S. Patent Applications Nos. (VAT Vo AG Vo AEN) [0A and Japanese Patent Applications 1478177 / 905 and geo 5 [YEAVAE] Clarify that the definitions of reference numbers, terms, variables, illustrations, or the like used in each publication are applicable to the corresponding discovery only from that request. specifically; As long as each of the known Adley prints combined by the 0 - sign is set up separately; It is possible that in some examples the original literature used the same term, illustration, or variant to mean something different. For example ; The variable 7" is used in every publication; but each publication has its own distinct meaning of the substituent or notch represented by this variable 0 It will be obvious to those skilled in this art that the terms, explanations, and variables in each publication incorporated by sign are limited only to 1 On the discovery from that publication, and it is possible to replace it by means of terms, clarifications, and other appropriate variables, or the like, representing certain alternatives and cracks. Of course, those skilled in this field will realize that it is possible to use any appropriate set of terms, clarifications, and variables in practice or to a greater degree. Specifically the topic of discussion disclosed in the present publication; including terms, explanations, variables, etc. © universally applicable to the combined discovery of applications identified above and the following discovery.

- 1.

Compounds of formula (9) may be inactive drugs ¢ that may help improve pharmacological properties

for vehicles; such as pharmacokinetic properties; For example, improved bioavailability or ALE solubility. from

Preparation of inert drugs can be performed by standard methods known to those of skill

In this area . An inactive drug can be obtained by acylation or acylation of the initiating alcohol

© where and 8 is CH(CH;),CH,OH .

All temperatures shown are in degree count: E0 (©) and all units of measurement used in the same

Context Units of weight, except for liquids, which are units of volume.

The term alkyl' as used denotes groups with straight or branched chain; preferably

with a number of from one to eight carbon atoms; more preferably by a number of one to six SIS 0 carbons; Most preferably from one to four carbon atoms. Represent

The term alkyl'-0,0' is a straight or branched chain with one to six carbon atoms

¢ The alkyl groups -m0:0 ¢ on Jaa include for example ¢ methyl , ethyl , n- propyl , pentyl 5 butyl —t , and sec-butyl 5 isobutyl 5 butyl 5 isobutyl 5 butyl 5 isopropyl

and isohexyl 5 hexyls neo-pentyl « and the like; The term C1Cq- alkyl includes within its definition the term CiCi- alkyl mono- or poly-carbocylic mono- § poly- carbocycle “cycloalkyl” ring represents the term

ring is saturated or partially saturated ; Preferably with a number of © to VE cyclic carbon atoms. Includes

Cyclopentyl, cyclobutyl, and cyclopropyl carbon atoms. with cycloalkyl

Jad on a torrent » cycloalkyl and the like. The cycloheptyl and cyclohexyl are saturated containing the hydrocarbon ring number which is of the composition ¢ Cs-Cy cycloalkyl 0

Five to seven carbon atoms.

11- The term alkyl = O - alkoxyl . An example alkoxyl is Ci-Cs alkoxyl ; Jas is a straight or branched alkyl chain with one to six carbon atoms bonded to a . The alkoxyl groups include -,.© ¢ for example: methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, sec-butoxyl, t-butoxyl, pentoxyl,

hexoxyl © and the like. The CiCq- alkoxyl “includes within the C1C4 alkoxyl translocation. The term “aryl” as used herein refers to a carbocyclic ring, heterocyclic, aromatic, monocyclic with a number of © to VE, or polycyclic

: eg caryls includes . polycyclic ring phenyl, naphthyl, anthryl, phenanthryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, ye pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2 ,3 -b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydr oquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl , phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, \o isothiazolyl, phenothiazinyl, and phenoxazinyl. aryl -0- represents “aryloxyl” the term is a Laie bond and the term “hydrolysable group” is a group; which; which can be hydrolyzed in vivo to obtain ester; forms an ester of oxygen B hydrolysable groups include for example; that be. hydroxyl group 0, ll and sulfate function; For example; Such as the optionally substituted acyl groups include ; job

117 - - With water, an amino acid part in the form of blocks or not in Ad blocks, a hemisuccinate part, and a nicotinate part. The term chlorine "halogen" or bromine 4 fluorine or iodine is represented. The term chlorine is "halo", bromo fluoro or iodo. had "8000716 " represents an aromatic, saturated or partially saturated monocyclic or polycyclic Ala at 8-15 parts; such as a monocyclic ring with parts from © to 7 or a bicyclic ring with parts from 7 to 01 ; As all parts of the ring are carbon atoms. The term “heterocycle” represents an aromatic, saturated or partially saturated ring with the number of parts from © to 04 monocyclic or polycyclic; as a monocyclic ring with parts © to 7 and dicyclic 0 by parts 7 to 01 ; It is characterized by the presence of a number of one to three selected hetero-atoms of oxygen s nitrogen and sulfur Whereas any hetero-atoms of sulfur s nitrogen are possible; voluntarily oxidized; It is optionally possible to divide any heterocyclic nitrogen atom into four parts. Any heterocyclic ring can be bonded to any suitable heterocyclic atom or carbon atom. ve Examples of these heterocycles include: decahydroisoquinolinyl, octahydro-thieno[3,2-c]pyridinyl, piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, isobenzofuranyl, furazanyl, imidazolinyl , imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thianthrenyl, triazinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolin yl, Y. groupenyl, xanthenyl , 1soquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, |

1x benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, benzo[b]thienyl,naphtho[2,3-b] thienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolin yl, tetrahydrisoquinolinyl, phenoxathienyl, indolizinyl, isoindolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, °quinzolinyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazin yl, isothiazolyl, phenothiazinyl, and phenoxazinyl. where heterocycle and 5-naphthylthio as and ¢ aryl -5 "thioether" the term includes as ¢ alkyl -5 and cycloalkyl —=(Cs-C7) saturated or partially saturated and 5- heterocycle is 0 s—aryl = possible ; voluntarily The substitution of eo thioether in ¢ Ci-Ce alkylthio -02- alkylthio is a thioether and an atole. An example — cycloalkyl s — is a straight or branched heterocycle with from one to six carbon atoms bonded to an alkyl that represents a chain: ; For example, ©,-©, alkylthio is a carbon atom. Groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, secbutylthio, t-butylthio, 1

. and similar pentylthio, hexylthio

—SH “mercapto” the term Jia and what is preferable to be chosen as Lp that Cus NLL, amino’ represents the term or “hydrogen and sulfonyls and carbocycle heterocycle y carbocycle and independent oxygen ¢ sen or hydrogen or alkoxyl or alkyl is Ly Preferably Cua “Cu 10(01)31 00 and one alkoxyl alkylsaryl Al . on Optionally, it is possible to replace groups

- 1 straight or unibranched alkyl b©-; Which represents the alkylamine chain is amino Akl with alkylamino groups that include . amino group to four carbon atoms bonded to, isopropylamino, propylamino, ethylamino and methylamino for example; And the like. secbutylamino and butylamino are straight or alkyl is synthesized in (0-,21)0 ¢ which represents two amino chains for al and there is an example of a branched amino; Each of them is characterized by the presence of a number of one to four carbon atoms linked to: in a representative way «di (01- C4) alkylamino in common. The groups include group dimethy lamino, ethylmethylamino, methylpropylamino, ethylisopropylamino, . and the like « butylmethylamino, sec-butylethylamino straight or alkyl which is characterized by the presence of a chain C-C4 alkylsulfonylamino is amino and an example of 0 includes . sulfonylamino branched with one to four carbon atoms bonded to a moiety: J©-,© ; Analogously alkylsulfonylaminocile see methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, secbutylsulfonylamino, t- butylsulfonylamino Vo . and the like NS -0 is a single bond or Lg Cua LeC(O)Ls " acyl' or alkoxyl ar hydroxyl or amino or alkyl ¢ additional in ma is preferably acyl N. alkoxyly alkyl Optionally it is possible to substitute straight or branched hydrogen groups alkoxyl which is representatively the ¢ alkoxyl chain ; is b©-, © © (C1-Ca) containing . carbonyl groups with a number of from one to four carbon atoms bonded to the 0 moiety: representatively: a carbonyl alkoxyl º

o — \ — methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like and Jal acyl; Representatively: carboxy where Lg is a single bond and A is hydrogen § alkoxyl or acyl . additional hydroxyl; Representatively ¢ is (Lg) (Ci-C4) alkylcarbamoyl -N m single bond and a (amino) ; which is a straight or branched alkyl chain with one to four carbon atoms attached to a nitrogen atom of the carbamoyl moiety. , and N-t-butylcarbamoyl 01 and the like. In addition to that, the mother is another; representatively;” is: Al-Amsdda: 1171 AH (2,21-01)01-04 ¢, which is characterized by the presence of two chains of alkyl, straight or branched + each has from one to four carbon atoms bonded to a carbamoyl moiety — nitrogen atom Ve. Include groups; representatively: N,N-di (C1-C4) alkylcarbamoyl groups includeN,N-dimethylcarbamoyl, N,N- ethylmethylcarbamoyl, N,Nmethylpropylcarbamoyl, N,N-ethylisopropylcarbamoyl, N,Nbutylmethylcarbamoyl, N,N-sec-butylethylcarbamoyl and the like.

11 - - Jia term sulfinyl' 'compound M80-1' where Ls ¢ is preferably ¢ for an alkyl or aryl and heterocycle cycloalkyl . The term “sulfinyl” represents “compound =SO-Ls” where Ls is “preferably” be 3 than the alkyl heterocycle of cycloalkyl J aryl 4 or amino. Optionally it is possible Substituting o all heterocycle 5 cycloalkyl y aryls alkyl An example of a sulfonyl is an alkyl sulfonyl , which is a straight or branched alkyl chain with one to four carbon atoms bonded to moiety 9010071 . The sulfonyl alkyl groups include. In fact, if not specifically noted, groups defined by terms defined in this application may or may not be substituted for. For example, Lexie is used as the term "null"; it should be understood to include both substituted and unsubstituted alkyl if not One is specifically excluded or the other is conclusively indicated.Examples of aryl s alkyl substituents include thioether s mercapto 0 and cho(0h)hydroxyl s halogens aryloxyls amino acyls alkoxyl ; Furthermore cycloalkyl 5 aryl and heterocyles are saturated and partially saturated. The abil substituents for cycloalkyl 5 heterocyle include those compounds noted above for alkyl and sole garyl on alkyl saryl. aryls include substituted ; representatively a naphthyl phenyl ring substituted with one or more © _ substituents ; preferably one to three alternatives; independently selected from halo or : hydroxy or carbonyl alkoxyl (C;-C4) morpholino or alkoxyl pyridyl (C1-Cy) carbonyl alkyl (C;-Cs) halo OR (Ci-Cs) alkoxyl d (C1-Cs) alkyl or carboxy or carbamoyl of (Cy-C4) carbonyl alkoxyl or 1 Es amino 0 carbamoyl alkyl (C;-C4) —N

11 - — (J-0)amino alkyl or deselected 1 for aldr-0)1l or group —(CH,),-Ry dasa ll where a is 1 or 7 or JY ; These are hydroxy, alkoxyl (C;-Cs), carboxy, (J-0) carbonyl alkoxyl, amino, carbamoyl, alkylamino (N-0), . di(C;-Cy)alkylamino

alkyl © is another substituted ke 3 for alkyl (C-Ca) halo ; Which represents a straight or branched alkyl chain with number from one to four carbon atoms number of halogen atoms from 1 to ? associated with it. Jeo alkyl groups (C1-Cs) halo analogues include: chloromethyl, 2- bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3- chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.

alkyl; The alkyl (Ci-Cq) hydroxy chain of 3 be Lal substituted alkyl is 0 . straight or branched hydroxy bonded to it by a number of one to four carbon atoms of a group: each of the alkyl (0-0-) hydroxy ¢ groups includes; representatively

Hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2hydroxy isopropyl, 4-hydroxybutyl . and the like

1 Furthermore the substituted alkyl is a (C1-Ca)(from-0)contact “alkyl” which is a straight or branched (C1-Cy) alkyl group with an alkylthio group (Ci-Cs) associated with it. groups include; Representatively: Ci-Caalkylthio (C;-C4) alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl and the like.

(C1-C4) substituted heterocycle; representatively An alkyl furthermore is a straight or branched one to four carbon alkyl that forms an alkyl chain in analogy; a Jeo alkyl (Ci-Cy) heterocycle attached to it. The heterocycle 1916 also includes: Z

VA = - pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, limidazolylisopropyl, 4-thiazolylbutyl and the like. Furthermore the alkyl substituted for LAT is (CoC); which is a straight or © branched chain of one to four carbon atoms with an aryl group attached to it; Representatively « the (and ©-,©0) alkyl aryl groups include: phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl, l-naphthylisopropyl, 4-phenylbutyl and the like. It is possible to replace the heterocycle with quot; by 1 or ? or? from independently chosen 0 substituents of halo, alkyl (C,-C4) halo, (y-0) alkyl, alkoxyl (C;-Cy), carboxy, or (n-t)) carbonyl alkoxyl or carbamoyl or alkyl (C;-Cy)-N amino 0 carbamoyl or alkylamino (n-n) or di(C,-Cy)alkylamino or a group with the composition CHR, where a is 1, ?, ¥, or 4 and b is hydroxy ar (C1-Cs) carboxy 0 alkoxyl or carbonyl alkoxyl (C; -Cy), carbamoyl 0 amino, (Ci-Cy) amino alkyl 0, or di(Cy-Cs)alkylamino .substituted heterocycle examples include: 3-N-t-butyl carboxamide decahydroisoquinolinyl , 6-N-t-butyl carboxamideoctahydro- thieno([3,2-c]pyridinyl, 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4- aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl , 6- methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl,6, 8-dibromoquinolinyl, Y. 2-methyl,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl,2-t -butoxycarbonyl- 1,2,3,4-isoquinolin-7, etc. 6

1 - - includes heterogeneous ring systems; Representatively represented by A or (1) B five-part monocyclic groups such as: thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like (Y) monocyclic groups with five parts such as: pyridyl, pyrazinyl, pyrimidinyl, pyridazinly, triazinyl ° and the like; 5 (¥) heterocyclic groups ¢ decahydroisoquinolinyl, octahydro-thieno [3,2-c] pyridinyl , : J— fe benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl and isotopes thereof that are fully or partially saturated. of independently selected substituents 0 of halo or halo (©-n©) alkoxyl )©-©( § alkyl )©-© sl alkyl or carboxy or carbonyl alkoxyl (C ;-Cy) or carbonyl alkyl (C,-C4)-Ns carbamoyl i.e. amino or (©-t©) amino alkyl or its conjugate (H:0-:0) or a group with the composition -.( 032) Ry where a is 1 or ? or ¥ or ? These are hydroxy, alkoxyl (C1-Cs), carboxy, amino of carbonyl alkoxyl (C;-Cy), carbamoyl, alkyl (C-Cy) amino eo, or di(Ch-Cy)alkylamino ; The cyclo-substituted alkyl groups include ; In the form of 3-methylcyclopentyl, 4-ethoxycyclohexyl, 5-carboxycyclo-heptyl, 6-chlorocyclohexyl and the like. Hydrolyzed ALE sets include substituted ; Representatively: N-benzyl glycyl, N-Cbz-L-valyl, and N-methyl nicotinate ~~ ¥ - The compounds of the present invention are characterized by the presence of at least five asymmetric centers denoted by an asterisk in formula (3) below .

Cy. a

SH on 8 as a result of these asymmetric centres; The compounds of the present invention may exist in any one of the stereoisomeric forms; It can be used in mixtures of stereoisomers that may be optically functional racemic o or it can be used 0 alone as essentially pure stereoisomers; That is, with a purity of at least 790. All these non-identical forms, independent stereoisomers, and unions thereof fall within the scope of the present invention. It is possible to prepare independent stereoisomers from five analogues from which another sale is formed by the methods described above; By substitution of racemic mixtures 0 « or by separation of diastereomers it is possible to carry out the substitution in the presence of a substituting agent » by chromatographic separation or by repeat crystallization or by a combination of these techniques which are described in this field; Additional details regarding Pla types can be found in Cajoose et al. enantiomers, racemes, and substitution species; John Willie 8 Sons 1981 . Preferably, the compounds of the present invention are pure; Any greater than the To purity ratio. vo is more preferable; The compounds are considered to have a purity of at least 775. Even on a more favorable level; The compounds are of purity greater than 748; Even on a more favorable level; The compounds shall be of a purity of at least 740; more preferably; At least 7997 purity and most preferably at least 4 purity. As mentioned above; The invention includes pharmaceutically acceptable salts of compounds defined by © formula (3). A compound of this invention may be characterized by the presence of a sufficiently acidic or basic group

71 - - To a sufficient degree or sufficiently basic or both functional groups; thus interacting with any number of inorganic and organic bases; inorganic acids and organic acids; To form a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to what 0 is used in this context; To the salts of the above formula compounds which are essentially non-toxic to living organisms. Pharmaceutically acceptable representative salts include these salts prepared by reaction of compounds of the present invention with a mineral or organic acid or an inorganic base. Generally the reactants (substances involved in the reactions) are combined in an exchange solvent such as ether ethyl SL or benzene; To salts add an acid » or ele or alcohols to salts add a base . It is usual that the salts precipitate from the solution within about an hour to about ten days, and it is possible to isolate these salts by filtration or other traditional methods. Such salts are known as acid addition salts or base addition salts. The acids that can be used to form salts by adding acid are inorganic acids such as: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like; And organic acids: p-toluenesulfonic, 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, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, 0 dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate , isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- \

- Lal 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g - Hydroxybutyrate, glycollate, tartrate, methane-sulfonate, propanesulfonate, naphthalene- 1-sulfonate, napththalene-2-sulfonate, mandelate ° and the like. The salts of acid addition that are acceptable to a pharmacy and preferred are those formed by mineral acids such as hydrochloric acid and those salts formed by organic acids such as maleic acid methanesulfonic acid. 0 Base addition salts include those salts that are derived from inorganic bases and organic bases; Such as ammonium and alkali alkaline earth metal hydroxides or carbonates and bicarbonates and the like. Thus, such useful bases 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 hydroxide, calcium carbonate Vo and the like. The purpose of a “pharmaceutically acceptable inert drug” is to mean a compound that can be converted under physiological conditions or hydrolyzed by a solvent into a compound of Formula 4. The purpose of a “pharmaceutically acceptable solubility” is a solubility that retains the potency and biological properties of the biologically active components of the Formula 4 compounds © Examples of pharmaceutically acceptable solubility include, but are not limited to, Formula 9 compounds in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethano Lamine ethanolamine D 1916

YY — - It shall be acknowledged that a specific Counterion forming part of any salt of this invention is not of a decisive nature; As long as all of the salt is considered pharmacologically acceptable and Counterion does not contribute undesirable amounts to the salt as a whole. A preferred compound is the compound TY Me © 5 Ny >on : º "lb OH H [3S-[2(2S*,3S%*),3 alpha,4a beta,8abeta]] -N-(1,1-dimethyl-2- hydroxyethyl)decahydro-2- [2-hydroxy-3- [(3-hydroxy-2- methylbenzoyl)amino]-4-(phenylthio)butyl]-3- 1soquinolinecarboxamide 5 Provides a process for making compound 71 below Compound 1?0 is also obtained as a metabolite from the plasma of administered patients.(3R,4aR* 8aR* 2'S* 3'S*) ]-2-[2'-hydroxy-3'-phenylthiomethyl- 4'-aza-5-0x0-5'-(2' '- 3[ methyl-3' '-hydroxyphenyl)pentyl] decahydroisoquinoline-3- N-t-butylcarboxamide methanesulfonic acid salt, disclosed in US Patent No. 04844975. GaVo compounds of formula 9 can be prepared according to the following reaction system 1.z 1"

— Y$_

I The interaction system and its dues 9b System 1: The general synthesis path of production

CONH-t-Bu

H~

Naqueous

Hydrolysis——

Step I

H la

COOH

H v ~

N

H Amine Protection. ee re en teres

Step Ib

H

2a and B H

Rp 8 R_ ~~ R' 0

H H

Amid coupling

H Step 2 2b Ry, = amine protecting group

R a ~~ ~ R'

Rr:

Pa~N

H Amine

Deprotection

H Step 3 3 0 SPh oN N.Rr i. z CbzHN cl ~

N on °°

H chloroalcohol epoxide

H close-open sequence

Step 4 4

Y o — — SPh oN NL 2 CbzHN N Cbz removal 8 Step 5 08 H 6 Me NG 8 The SPh AcO.

COQ 3 H,N N H 8 amide coupling 08 H Step 6a 7 Me ° SPh ~~ N 2 AcO. : acetate NH N removal OH 8 Step 6b H 9a SPh 0 N Me 0 ~N RY Nr 1 NH N H OH os 9b Compound 1a perhydroisoquinoline 0 “commercially available from 1156 Technologies (Chicago; Illinois) or Process LLC (Milan 0 0 Italy) undergoes extended acid hydrolysis in step 1a to obtain compound IY. A variety of inorganic acids may be used either in an aqueous/organic solvent mixture or in water only at a temperature greater than 00°C. Examples of this inorganic acid are hydrochloric acid thioestersic ab and estersib 1) standard. Substitutes for Compound 1 at Sle concentration include: D1 AgO 40 Other 002

NY:

H

H

1c

COSZ

HO 8 11

H

1d

CONZ, Z,

Hy:

H

H

then “heterocycle or cycloalkyl or alkyl ¢; 2:22 may be; Independently Z where . Amine to obtain compound "B" in the Ab step nitrogen in IY compound 0 is protected as a conjugate group appropriately to avoid degradation of non-Re protecting group is defined; activator of compound "B" in step? . Desirable carbocycle groups of derivatives can be: 11 in the parent; with the general composition of the carbamate formula «this protection; Typically 11 0 to 01 “6 aryl or alkyl or alkyl 11 8” identities in the formula would include 1 . which can be easily removed in step Deprotection in the heterocycle step: Unlimited SIR" AL methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl or higher branched or unbranched alkyl, 2,2,2-trichloroethyl, 2trimethylsilylethyl, allyl , phenyl, substituted ° phenyl, benzyl, substituted benzyl, 9-fluorenylmethyl, 9anthrylmethyl is possible. higher polycyclic aromatic ring system

Sigma (Aldrich Chemical Co.) Obtain the following materials, as defined below, from Aldrich Fluka 7 2,2,2-trichloroethyl = Te

Cl \ 2-trimethylsilylethyl = —— CH, Tr

HCH; allyl= ——CH,—CH==CH, benzyl = —ad ( 9-fluorenylmethyl = nr 9-anthrylmethyl = "9+6

It is possible 'typically » Alaa) to Alas groups such as this by means of the acylation reaction of the corresponding haloformate ester Y 11 or dicarbonate 11b : 12a 0 R"O X X = halogen 125 0 R"O Y Y = OCOR"© in the presence of an appropriate base in organic solvents ideal for these types of reaction such as 5 halogenated solvents and hydrocarbons (Jie). Typically inorganic bases; metal hydroxides fia, bicarbonates, carbonates or organic bases Je: amines like triethylamine, diethylamine, diethyl isopropylamine, 1,8diazabicyclo[2,2,2]octane (DABCO) or related di- or trialkyl-amines 0 as well as amidine bases amidine bases such as: 1,8diazabicyclo[5.4.0] undec-7-ene (DBU) and 1,8diazabicyclo[4.3.0 [non-5-ene(DBN). The following materials ¢ as described above ¢ can be obtained from Aldrich Chemical Co (Sigma Aldrich Fluka):

DABCO = N,N,

ln

Nx

N

Nx

N

Typically, these reactions take place anywhere from below room temperature up to . Degree approximately 0 Is it possible to achieve a step compared to a step? By any number of methods depending on how ab carboxylic acid is activated by reaction 1 group j is carried out in step . carbocycle group o : "c" ve aa zy

Step Y Step 2 COOH R 5 PX N a H activation of the carboxyl group —_— H 2b amine protecting group = mk J 0 7 i R R y ~ R A AN N N 8 base H 2c J = leaving group N. 0 delete NX R : PNG N H H 3 rng

_71_ The (j) group can be any number of a variety of leaving groups such as, cyanide, and azide (including pseudohalogen or halogen § hydroxy or alkoxyl and arenesulfonate or an alkyl or isothiocyanate isocyanate (including the ¢ N-hydroxyheterocycle) and aromatic heterocycle definitions apply to the terms hydroxybenzotriazole ester or hydroxysuccinimide ° above: azide —N— N=N cyanide —C=N isocyanate —N=—/C=0 isothiocyanate —N—C=—=S i alkylsulfonate oT 0 i arenesulfonate I i 0

N-hydroxyheterocyclic Ho—~_) where ? ( = nitrogen heterocyle 0

N-hydroxysuccinimide ~) 0 a” hydrobenzotriazole 5 N /

Oh

1+4

Fat - It is possible to prepare acyl halides (7 g (halogen = J) using inorganic halogenating agents such as: thionyl chloride or bromide, phosphorous trichloride or bromide, phosphorous sipentachloride or bromide organic agents such as: M trichlorisocyanuric acid oxalyl chloride Then R" ) OR" =J « —aY)Esters (defined above) can be prepared in a variety of ways starting with Cua —aYacid chloride that [ is CI by combining with an alcohol Desirable is the presence of an organic or inorganic base mentioned by a particular — acylation of compound fy or compound 11b . alternatively An ester may be produced by acid-enhanced esterification in the presence of a desired alcohol; Typically Vo sulfonates ( "J + = J = 0502177 ; where W, is an alkyl or aryl ) can be made by reacting carboxylic acid Ab with an alkyl or sulfonyl aryl in the presence of an amine base organic triethylamine Jie in a non-polar solvent at temperatures below zero degrees C. The alkyl and arylsulfonyl are defined as follows: 0 amyl = alkylsulfonylchloride 0 ah = arenesulfonyl chloride I 10 Typically, its derivatives J =J pseudohalogen ( from =J)—=Y acid halides halogen ) are synthesized by reaction with an inorganic pseudohalide in the presence of a base include such

vy — - bases ¢ but not limited to metal hydroxides, bicarbonates, carbonates or organic bases Jw amines Jie : amines like triethylamine, diethylamine, diethyl isopropylamine,1,8-diazabicyclo [2.2. 2] octane (DABCO) or related di- or trialkylamines, as well as amidine bases likel,8-diazabicyclo[5.4.0Jundec-7-ene (DBU) and 1,8diazabicyclo[4.3.0]non-5 -ene (DBN). °. Triethylamine 320 is particularly preferred. In addition, heterogeneous aromatic derivatives are synthesized from (halogen = J) C1 acid halides using a specific heterogeneous aromatic compound in the presence of an amine base in a non-polar solvent. It is possible to manufacture 17-hydroxy heterocyclic derivatives of 7g of acid halides as 0 is above and it is also possible to generate using: (alkyl) alkyl carbodiimides - «alkyl 77 -© =N where alkyl groups could be the same or different) or aryl =C =aryl 2)carbodiimides a<- 0 aryl where aryl groups could be the same 0 different) amine base y as thickening agents. A primary or secondary amine (shown above arrow in step ? of yo System 1) used in the conjugation process may incorporate appropriate protecting groups; Depending on the current function in the amine and the coupling method used. Conjugation of 1c with a primary or secondary amine can be carried out in a variety of ways depending on the identity of J when using a free acid (HC) (OH = J) The conjugation can be carried out using carbodiimide-based methods using any Common reactants of this class ¢ include dicyclohexylcarbodiimide or related dialkylcarbodiimides .¥ or EDC (1-(dimethylaminopropyl)-3-ethylcarbodiimide salts) or water-soluble reactants; having dla; plus to an organic amine base in an organic solvent

DOS-polar DMF 5 dioxane J—”a, 1111, and acetonitrile in the presence of an N-hydroxyheterocyclic compound such as N-hydroxysuccinimide or 3-hydroxybenzotriazole” alternatively; It is possible to use haloformate esters « such as 12d to activate the acid Ja all on mixed anhydrides of the general formula 2d : 2d OR” 0 J Rp : Ny : : 12d 5 A X = halogen 80 * o Typically these haloformate esters are as shown in 12d above and include methyl butyl =n s— isobutyl s - isopropyl s - ethyl 5 - - and the related alkyls - phenyl and aryl chloroformates ¢ defined above. 0 alkyl chloroformate = re 0 to = aryl chloroformate 0 Formula 20 is a possible intermediate in the step from formula 20 to formula 3 Formula 0 is an intermediate; But the process described here originates in Formula 3; without isolating the 2d formula

dos -

Typically, these reactions are accomplished with a variety of non-polar organic solvents such as diisopropyl ether, methyl t-butylether, diethyl ether, ethers s hydrocarbons amine base and 1117 at temperatures below zero degrees Celsius accompanied by dioxane or DABCO diethyl isopropylamine and organic diethylamine triethylamine (fia .0311 DBU (Ji amidine bases) related plus trialkylamines ee

when [a in compound 2c is an alkyl or arenesulfonate ([-050 or (0SO, Ar)

Conjugation can be accomplished with a variety of non-polar organic solvents such as halocarbons dioxane 5 « diisopropyl ether and » methyl t-butylether ¢ diethyl ether s » ethers

THF at temperatures below 0°C ¢ accompanied by an organic amine base such as diethylamine » triethylamine 0 » and DABCO diethyl isopropylamine or

,. DBN 3 DBU as related amidine bases « plus di- or trialkylamines

if [ in a 2¢ compound is a halogen or a pseudohalogen; Comparison is possible

methyl - ar dioxane § diethyl ether § THF Jw le pa in most organic solvents

butyl ether or other ethers and acetone and cyclohexanone and methyl isobutylketone and m ketones « 5 yal ketones such as methyl s ethyl and isopropyl acetate and halogenated solvents

,. ethanes and halogenated methanes are halogenated methanes such as halogenated solvents

And chlorobenzene and other halogenated benzenes + muffled nitriles

t-butanol, isopropanol, and ethanol as lower alcohols “propionitrile” and “acetonitrile”

and related alcohols; and polar organic solvents, dimethylformamide J—3e +, dimethylsulfoxide 00, “N-methyl-2pyrrollidone,” and related amide-containing solvents

A rule is used frequently and can be any number of inorganic rules such as

name -

Metal hydroxides and carbonates s bicarbonates or organic bases such as amines

triethylamine or diethylamine or 1sopropylamine or DABCO or

,. DBN and DBU (fie maidino bases related ¢ plus dior trialkylamines

One skilled in this art will be able to perform amide conjugation by Y-step from [other] possible combinations.

At the ¥ step it is possible to perform the removal of the protection group using any one of the standard methods

To remove the protection of a specific class from the protection group. It is possible to remove alkyl carbamates

simple and substituted by aqueous solutions of base at temperatures up to about 100 degrees

Jie hydroxides (Jie inorganic common metal hydroxides using any one of ¢ A gia . other metals in stoichiometric quantities barium hydroxide i.e. potassium lithium sodium 0

It is possible to remove carbamate protecting groups that contain benzyl groups attached to L

platinum palladium from catalyst with catalyst hydrogen — by decomposition oxygen

Alternatively, hydrolysis of an aqueous base can be used at temperatures up to

about 001 degrees cde using any one of the common inorganic metal hydroxides Vo such as hydrolysis sodium or lithium and potassium or other 0 barium metal hydroxides

in equal quantities at least. A variety of non-aqueous acids can also be used

,. HI 3 HBr 5 NCI including “benzyl base” carbamates for removal protection

Moreover, Lewis acids are prepared for both boron and aluminum, such as BCl feed;

in non-polar active solvents. Certain ©-substituted benzyl, aryl or alkyl groups are also used in which a particular substituent form is chosen for its ability to be removed under certain conditions

. For example + trimethylsilylethylcarbonyl group (Teoc) 2 is a designed protecting group

Als to achieve a specific efficacy advantage of the 2-trimethylsilylethyl group in the process of removing protection. It is possible to use amine nitrogen (Ales) 2-Trimethylsilylethylcarbonyl chloride and it is possible to remove tetraalkylammonium fluoride salts i.e. NF as the last fluoride ion using sources in step 4; The perhydroisoquinoline portion of formula ¢ is conjugated to the alcohol chlorine chloroalcahol© (compound ©; system I) via an intermediate epoxide (VY) generated by base-induced closure of an adjacent chlorine hedrin function 13

SPh

A

0 Composite © is produced by Kaneka Industries « Japan; It is possible to use several closing-opening methods in the connection from ©-component to VW-component and 1-component. 1” epoxide 0 can be isolated or reacted with ; by adding one of them in succession to form a compound 1” or there may be a compound ; from the beginning of the sequence. It is possible to generate 1” epoxide using inorganic bases such as metal methanol ethanol Jie alcohols Jie in solvents of bicarbonates and carbonates 5 hydroxides or ethers s isopropyl alcohol such as dioxane 3 THF or mixtures of the two. It is also possible to produce epoxide! in a two-phase solvent system consisting of water and a halocarbon solvent such as dichloromethane \o =& base. It is possible to use a phase-converting catalyst such as tetraalkylammonium salt to facilitate the process. The process of detecting the VY epoxide is accomplished by a compound of 4 ammonium to facilitate the process. Adee 11 epoxide detection is accomplished by a compound; In alcohol solvents or mixtures of alcohol and another solvent which may be ether or a bipolar aprotic solvent dimethylformamide Jia or dimethylsulfoxide. on about

Ideally, detection of 11” epoxide is performed by a compound; To obtain compound 1 during a period of 1-7 hours at 0 to 1°C. in step©; The carbobenzyloxy group can be removed to give a free amine 17 . This removal can be done using HBr in acetic acid using auxiliary solvents such as halocarbons © . It is also possible to do this using J boron halides #88 and BCl; or boron lla substituted with an alkyl such as dimethylboron bromide in halocarbon solvents such as dichloromethane 5 chloroform at temperatures from zero Celsius to ambient temperature. alternatively It is possible to remove the carbobenzyloxy group by hydrolysis using aqueous/alcoholic solutions of metal hydroxides such as barium, sodium, lithium, or potassium at temperatures greater than ambient for periods of hours. The + step is the conjugation of the benzoic acid derivatives of formula A to yield + . In the formulation A © could be an outgroup and © could be any one of the above inscribed departures of set J . Formula A compounds are; where OH = Q 10 or Cl ; Available on a mandatory basis from EMS Dottikon, Lenzburg, Switzerland and Sugai Chemical Industries, Ltd. In Japan the comparison can be done in a variety of ways; Based on © . When using a free acid (Q = OH) the conjugation is accomplished using carbodiimide based methods using any one of the common reactants of this class including dicyclohexylcarbodiimide (i.e. the related dialkylcarbodiimides) or salts of 1 -(dimethylaminopropyl) -3-ethylcarbodiimide)EDC Y. or related water soluble reactants with organic amine base in polar organic solvents DMF 5 dioxane ie 9+6"

m, NMP and acetonitrile in the presence of a hydroxy = N heterocyclic including N- pseudohalogen sf halogen = Q 13 .3-hydroxybenzotriazole shydroxyheterocyclic ¢ Conjugation can be performed in most common organic solvents such as THF or diethyl ether or dioxane or methyl t-butyl ether or other ethers methyl 5 cyclohexanone s acetone g ketones sisobutylketone ° other “ethers such as ethyl and” isopropyl acetate methyl methanes Jie halogenated solvents and halogenated ethanes 5 chlorobenzene and other types of halogenated benzenes “nitriles such as acetonitrile and propionitrile” lower alcohols such as ethanol and propionitrile and related alcohols 5 t-butanol and rod organic solvents such as dimethylsulfoxide 3 dimethylformamide N-methyl-2pyrrollidone 0 and related amide containing solvents; Frequently a base is used and may be any number of inorganic bases bicarbonates metal hydroxides Jie or organic bases such as amines eg diethyl isopropylamine J triethylamine i.e. dior 5 DABCO trialkylamines related; In addition to amidine bases such as DBN ys DBU . Removal of acetate in step B is accomplished by aqueous or alcohol solutions of non-Vo organic bases such as metal hydroxides, carbonates and bicarbonates at ambient temperatures of up to 0 °C if There is a protected function on the carboxamide group attached to the 0 perhydroisoquinoline ring system that is best removed at this point (during or via step 1<). The nature of this stage depends on the exact identity of the protecting group. A preferred method for accomplishing the whole process is shown in System 1 In the TT system the protected yo amino acid — Cbz — is conjugated by YYamine to yield amide 11. Group 72 is removed by hydrogenation of Schemel1. ‏

A. Scheme IL Synthesis of Amide 21 CONH-t-Bu H 8 N > H 1 6Nag HCl A#E_MBSSMS CbzCl 2 q STEP A Perhydroisoquinoline COOH z Me, Me Cbz : #8 H Bg go HN 22 Za - EDC, HOBt-H,0 STEP B 11

N. 0 Chz 1 Me Me N H, H 5% Pd/C PEP EtOH q STEP © 16 SPh N ~~ H : Md Me CbzHN Cl N > OH 8 Chloroalcohol i od NaOH, IPA H STEP D 17 71+46

— \ $ — -continued hi SPh ~N OX on Me Me : ChzHN N ut 50% aq.

NaOH rrr 011 PA ° : H STEP IE 18 N Me 0 m hd en AC coc i ME Me HAN N H 20 THE, FLOH: or then 5096 aq.

NaOH 181 STEP F 19 MeO NK on Me KID 1 HO N 5 i 8 OH u 21 This is coupled with alcohol chlorine via epoxide using methods 0” in the site to obtain an embedding compound. Removal of the conventional protection by a base and conjugation of the free primary amine with 01 acid chloride © causes an increase in the production level of amide 1? . The details of this process are given below in Examples (1a) through (1f). The letters (a) through (f) correspond to System 17 Examples (1a) through (1f) below. The following examples explain aspects of the invention. These examples are for illustrative purposes and are not intended to limit the scope of the invention.

The abbreviations for melting point, nuclear magnetic resonance spectra, AES field atom ejection spectra, ALS desorption spectra, electron collision mass spectra, fast spectra, infrared spectra, ultraviolet spectra, chemical elemental analysis and separation High performance liquid centrifuge and thin film centrifugal separation are on the . TLC 5 HPLC « UV analysis, IR 5 MS (FAB), MS (FD) and EIMS s NMR s mp respectively © Absorption noted for infrared spectra is ad plus that ; If maximum. Of interest, however, not all extreme values are observed; The following tests are used: single-coherence of electrons NMR related to Lag spectra, double-coherence of electrons, co-correlation (d), co-coherence of even-electronics (5), triple co-correlation of electrons (0), co-coherence (dd) even and multiple bonding of electronics 0, even and multiple bonding (m), covalent multiple bonding of electronics (q), quadruple for electronics, even covalent broad (brs), covalent bonding of electronics wide (dm) for electronics, covalent bonding Wide multiple (br. 1) Broad covalent coherence for electronics (br. d) for electronics if not otherwise stated (HZ) data indicates a constant compared to Hertz T and (br.m) indicates electronics To the free base of the compound under discussion NMR 10 ¢ General Electric QE-300 300MHz is expressed on the NMR device spectra are obtained and spectra (ppm) are obtained for the chemical changes in values Delta in ppm states « Scripps Research Institute, La Jolla, VG ZAB-3 has a mass spectrometer

Midac California, USA; The infrared spectra are recorded on a spectrometer. Varian, Cary 3E Ultraviolet spectra were obtained on a Corporation 30 apparatus available at EMERCK conducting thin-layer chromatography using silica plates. Incorrect Mettler 17026 Melting points measured on a device

EXAMPLE 1 Methods for the manufacture of formula YY alpha,4a beta,8abeta]]-N-(1,I-dimethyl-2- hydroxyethyl) decahydro-2- 2(25%*,35*), 3[-35[ [2-hydroxy-3- [(3-hydroxy-2- methylbenzoyl)amino]-4-(phenylthio)butyl]-3- isoquinolinecarboxamide ° 21 Sph © N Me © 7 OH LA : = HO : N N H H OH H { suspension Y1,£) Perhydroisoquinoline g 110 mmol Commercially available from: NSC Technologies (Chicago) , IL) or Procos SpA (Milan, Italy) in water (Yoo ml) and concentrated aqueous hydrochloric acid (Ja Yo). The mixture is heated to evaporation and stirring for 0–1 days during which time it turns into a solution. solvents were removed under reduced pressure to obtain a light yellow solid sale; The solid is transformed into a thin slurry in (Ja Y + +) 2-propanol and then filtered. The filtrate is evaporated under reduced pressure to obtain oil. Add EtOac 01 (ml) and water 001 (ml) to make the pH reach + A, by adding aqueous chlorine formate KOH benzyl at a concentration of ? Standard 111 de VOM (mol) in the form of 1 droplets during Ye min. Pug Maintaining the pH 11°C to be between 7 Ag by adding KOH. Aqueous Y OS standard Stir the mixture at 1°C room temperature for YA hours. Ve added

With — (Je 001) EtOAc and the organic layer was washed by Al hydrochloric acid at a concentration of 1 Standard 001 (ml) and brine 001 (ml). The organic layer 04880 was dried, filtered and evaporated under low pressure to obtain Product purified by silica gel chromatography and rinsed with 1:1 petroleum ether 0-50 EtOAc/m followed by rinsing with EtOAc 7001; product-containing fractions combined and evaporated under reduced pressure to obtain On compound (AVY Marg 11,©(Vo) in the form of colorless oil: (m, 5 H), 5.17 (br s, 2H), 476 (m, 1H), 3.79 7.43-7.28H (mod. b) Add ¥V,€ ¢ ol ya £,Y) I-Hydroxybenzotriazole mmol) 5 ol =) EDC; ¥Y, Ey. mmol) to a solution of acid AF) V0 g ¢ 77.7 mmol ) in DMF (YYA) ml) at ambient temperature The mixture is heated at 800 °C for 10 minutes Add 7104 al pn 6,1 (1,1-Dimethyl-2trimethylsilyloxyethylamine mmol) prepared -1 1, (Aldrich Chemical Co) dimethyl-2-hydroxyethylamine and hexamethyldisilazane (Aldrich Chemical Co) by heating a clean mixture under recession for several hours followed by vo evaporation of the volatile components and heating the solution at Ay degree Lda for 117 hours. It takes 17 hours. The yellow solution is poured into hydrochloric acids (Je Yo +) EtOAc with a standard concentration (Je 701) (after stirring for 10 minutes, 06:2 Vor ml) is added and the mixture is washed with water (1 volume by volume). 500 ml) and brine (1 volume » Yor ml). flash (EtOAc) hexanes at a ratio of 0 50/5) to obtain compound 11 as a colorless oil (7.5 g; (AVA: ºC)

o — $ _ 'H NMR (300 MHz, CD; OD) & 7.36 (m, 5 H), 5.20 (d, J= 8.1 Hz, 1H), 5.10 (m, 1H), (m , 1H), 3.78 (dd, J = 13.2, 4.4 Hz, 1H), 3.60 (m, 2H), 3.48 (d, J = 10.7 Hz, 1H), 4.53 (m, 12H), 1.31(s, 3H) 1.29 (s, 3H) 2.15-1.25 . c) A mixture of carbamate (11 V,9 g ¢ 01.4 mmol) and palladium is hydrogenated over carbon 759 (Pde)© (1,1 g) in 50 Jha per square inch of hydrogen in absolute (011) EtOH (Je) at ambient temperature for YA hours. The mixture was filtered through silite and evaporated in vacuum to obtain amine 117 in the form of a white solid, crystalline color: 'H' NMR (300 MHz, CD; OD) 83.63 (q, J = 7.0 Hz, 2H), 3.34 (m, 1H), 3.27 (dd, J = Hz, 1H) 2.91 (m, 1 H), -2.02 1.15 (m 12H), 1.32 (s, 3H), 1.31 (s, 3H) 3.3 11.8 , 11.8 d NaOH added at t-stc (, mL + Yeo mmol) to a warm suspension (7 L residual degree) of alcohol chlorine (obtained from Kaneka Industries, Japan) 016 (g ¢ YAN mmol) in (Je 01;(IPA) isopropanol) with mechanical stirring. After passing 1 hour add hydrochloric acid at a concentration of 1 standard in IPA (prepared by adding 1 ml of concentrated aqueous hydrochloric acid to VY ml of IPA approximately (about 1 ml) for neutralization ve (pH (V = pH). Amine (0,Y) VY g + 00.54 mmol) is added as a solution in TPA (00 ml) and the thin suspension is heated at 01 degrees Celsius for 1 hour. 1 remains in the void. The remainder was diluted with EtOAc (Yor) ml) and washing with water (7 001 volume X ml) 5 saturated aqueous NaHCO (1 volume (do 50#) and 1 volume (door X ml) brine. The aqueous aggregates are extracted by 11086 (1 YO volume x ml) 2. The organic aggregates (010750,01) are dried by flash chromatography [EtOAC] ARE:

- Ye/Vo hexanes then (EtOAc) to obtain the compound VA in the form of a white solid (AV AAA)

White solid (8.98 g, 76%) : 'H NMR (300 MHz, COs0D) & 7.33 (m, 10H), 5.08 (AB,

Jap = 12.2 Hz, A Uap = 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), 5 . 1.28 (s, 6H) mL + 7.1 mmol) to a suspension of VA + g (YY) 78 0 aqueous NaOH (e) added mL) at room temperature; VE) TPA mmol ) in 11.6 1 (2 liter VA carbamate g) h. After cooling to ambient temperature; dilute VY the mixture is heated under refrigeration for

X and washing with water (¥ volume (Jo 001) (MTBE) butyl ether — methyl t) mixture with 0. The aqueous strata are extracted using 1 volume (Je YYO X) and brine (Ja©). mL) The combined organic layers (E048:50 and vacuum evaporation 10501 X aaa V) MTBE were dried to yield a mixture of benzyl alcohols 19 as an oily white solid sale b 7.20' H NMR (300 MHz, CD; 0D) & 7.53 (d, J = 7.3 Hz, 2H), 7.32 (t, J= 7.0 Hz, 2H), J=7.3Hz), 7.06 (t, J = 8.1 Hz, 1H), 6.92 (d . mmol) to a solution of a mixture of Cal 4 g 01.4 mmol theoretical of benzyl alcohols (VA in YY HIOH mL) at ambient temperature. A solution of (01) 3-acetoxy-2-methylbenzoyl chloride (© Obtained Ey for the methods and methods described in series is added to US Patent Application No. 7411/04; Registered © Sept. 11995; incorporated specifically by reference mentioned in this

sy — - context) (;,7 11.59 «ala mmol) in THF (; ml). After 7 hours NaOH (,; 0 g 7.8 ml; 7.7© mmol) was added and the mixture was heated under recession for 1 hour; after cooling to ambient temperature; The mixture is neutralized to pH -No by HCL with a concentration of ¥ standard (77 (Jo). This mixture is diluted with EtOAc (+©mL)© and washed with water (1 volume) Jo YOu X saturated aqueous NaHCO (7 volume X 75960 ml), water 1 (volume Jo YOu X) and brine (1 volume) Jo YY0 X. The organic layer (N2, 804) and purification by flash chromatography (Vo [Yo hexanes [EtOAC) to yield amide 1 as a white foam (STA) -1173 + 1.79 g 6 777). hydrogen indicates the presence of 701 EtOAc by weight that may not be removed in vacuum 0. 1H), 4.08 (m, 17H), 3.61 (dd, J = 13.6, 4.0 Hz, 1H), 3.45 (ABJap = 11.0 Hz, AUp = Hz, 2H), 3.29 (dd, J = 13.6, 10.3 Hz 1H), 3.10 (m, 1H), 2.66 (m, 2H), 2.28 (s, 3H), 18.0 ( m, 2H), 2.04 (m, 1H), 1.86- 1.20 (m, 11H), 1.19 (s, 3H), 1.18 (s, 3H). 2.22 NMR (75.5 MHz, CD;0D) 8 175.7 , 172.5, 155.9, 138.8, 136.7, 129.8, 128.9, 126.3, here \o , 31.1 , 34.1 , 34.2 , 36.5 , 53.0 , 54.9 , 58.8 , 59.3 , 68.2 , 69.9 , 70. 3, 115.9, 118.4, 122.4, 126.0 12.1, 20.8, 23.0, 23.1, 26.0, 26.4, 30.7. Example Y HIV protease inhibition activity and anti-HIV activity in cell culture for compound 71 A tight correlation pharmacokinetic analysis is used to quantify the Ki values for compound 71. Where Ki = v, 00 + 4 , + tanumil

ways

Genetic modification of HIV protease 1

The 1117-1 protease gene isolates from viral spot 1118 (Ratner, L); (aly we spread;

77 T (11858). Journal of Biological Chemistry ¢ YAT ¢ 11474- 11459 (1397).

glutamine fragment at (Q7) site 1 to 5) p«v»_by Pla) segment YY base pair between

NDEL and [35021] for a protease gene sequence with encoded synthetic oligonucleotides.

to transform 075 . The modified gene sequence is inserted into the vector (Menge, K.L.) PGZ plasmid «

and others; Biochemistry ; ;?: ((Y490) 15947 —Y108YE under control of phage promoter (phage) 0 27 . The resulting construct 1907589 transforms PGZ/HP- into E. coli strain 3121

Novagen, Inc. Purchased from (DE3)

Genetic modification of HIV-1 RR

Cultures are grown in media (Trypticase Pepton) 71,1 2Yt » Yeast Extract NaCl 71

5 at an initial pH (V,0 pH) containing Yoo μg of ampicillin Ve in a 100 liter fermenter (Biolafitte SA) at TV°C for © hours Willy that

Induction by adding (Isopropyl-ss-D-thiogalactopyranoside). 1 mM IPTG raises the temperature

farm during induction to 7; C to increase the accumulations of recombinant HIV-1 protease as two

insoluble inclusion bodies.

after passing? h at ¢y settling point, collect cells by cross-flow filtration using (Millipore) 0.1 um +7170000005810 and store and freeze the cell slurry at -Ve°C.

Purification of Protease 1171-1 Recombinant protease All steps are performed; If it is not mentioned otherwise; in ; Celsius degrees. Protein concentrations were determined using BioRad protein titrant with bovine serum albumin (BioRad, Richmond, CA) as a standard. Chromatographic separation steps and HIV RR purity were analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS). - PAGE). The final purity is LSTHIV- RR 7948. A typical end product from each 0 liter culture is about 171 mg. The cell paste from the 100 liter culture is resuspended in 00" ml of 50 mM Tris-©! buffer analyte at YO ¢ A, pH mmol of 01 “NaCl” mmol of 0 (2mercaptoethanol) and trituration (grinding to several microns) in a microfluidized liquefaction unit in 05 1 at a pressure level of 770.001 psi. The results of crude cell lysis were purified by centrifugation at 14,0060 rpm for 70 minutes; RR 1117 was predominantly found in the granule in the form of inclusion bodies. Thereafter Inclusions were washed several times in assay buffer containing additional JS 100 Trition-X 0.196 and 1 mol of urea 1 and after each washing procedure; inclusions were formed into granules by centrifugation at 0000 rpm per minute for Yo minutes. Make the selected inclusion bodies dissolved in buffer containing 50 mM Tris-Cl; At a pH Yo 5 8.00 pH mmol of NaCl and 10 mmol of -mercaptoethanol 2 and a mole of urea. The solution is purified by centrifugation at 14,000 rpm and placed at room temperature; on Y. (Piscataway, NJ Pharmacia, ) Fast Flow Q-Sepharose column and equilibrate with the same buffer solution. Under these conditions RR 1117 does not bind to the column and the enzyme is substantially pure in the portions through which the mixture flows. to return the protein to the normal state; is being spread

Shake-membrane portions from a Fast Flow Q-Sepharose column against three charges of buffer solution containing 25mM NaHPO, pH 0.0 pH, 11801 Yo, 5 mmol DTT 10 and Glycerin 701 » after refolding; Small amounts of the precipitate are removed by centrifugation and the resulting enzyme preparation is concentrated and diffused e vs NaCl 1.5 moM MES 50 mM pH 9.3 pH 10 7 with stoichiometric parts at about ¥ mg/mL and storage in Vem °C. Tight binding pharmacokinetic assay and analysis The protein current activity of the purified HIV-1 protease was measured using a modified chromogenic assay developed by Richards, A.D. (Richards, A.D.) ¢0 et al » Journal of Biological Chemistry «I.

Biol.

Chem 65 “Al-Hala (1494) uses the plant’s peptide: His- Lys- Ala- Arg- Val- Leu- Phe- (para NO2)- Glu- Ala- Nle- Ser- NH, ) Co. American Peptide (where the abbreviation Nle stands for norleucine) as an affected substance. The titration is carried out in NaCl at a concentration of 1.5 mo » 50 mM MES at pH 7,© and 04 5024 and DMSO 216 at VV C. 1 Cleavage titration of the cleavable bond between leucine and phenyl - paranitro phenylalanine (Phe- para, NO,) is performed by La yl Spectrophotometric of the decrease in absorbance at the level of 05 nm. The initial velocity La lies the rate of decrease of the absorbance during the first 100 seconds of the enzymatic reaction. Under these conditions, using a 1117-1 075 protease, they are The Michaelis constant 0 in this affected equation is 117 04 micromoles.

1 — 0 is for YY compound inhibition; The saturation concentration of Sal all affected is used as 100 µmol between the concentrations and or 1 for the inhibitors. The evaluation is carried out, and the reaction rate is measured at each concentration as described above. The explicit ki (Ki app) shown above is determined by matching the computer-aided nonlinear quadratic data HY to the Morrison tight correlation equation 0 (Morrison ¢ JF alas ¢ Biochem.

Biophys.

Acta 4 vol. YTA 179). Example ? Antiviral activity of YY complex against HIV in cell culture cell and virus stains CEM-SS and human T cell lines RFs MT-2 and IIB for 1111-1 stains obtained from 0program AIDS Research and References; aud AIDS © NIAID and NIH . Assay of cell production The inhibitory effects of each agent on the 1117-1 repeat are measured by the MTT dye-reduction method (© Alley, 1. et al. » Cancer Research Canar Res.; 48:4 (YAAA) 11). Dissolve the compounds in DMSO at a concentration of 560 mg/mL and then dilute 1:000 in 10 (RPMI) culture medium; Added to it a genetic bovine serum (701). 100 µl of each stock dilution was added to a slide containing 976 wells and dilutions were prepared by means of the HMRP. serial in separate tubes; ~MT-2 cells and CEM-SS cells are co-infected with either HIV-1 8 or peg 1117-1 at a multiplicity of infection (mo.07 at a concentration of 101 and 07; respectively; after an adsorption period for four hours; 100 μl of empty infected or uninfected cells were added to the slide containing the drug to obtain a final concentration of 01 xy cells/

to the bowl. After six days (CEM-SS cells) or seven days (MT-2 cells; MTT (0 mg/mL) was added to the test slides and the amount of formazan produced was estimated spectrophotometrically. At a scale of 070 nm, the data are expressed as the percentage Ay she of formazan produced in drug-treated cells compared to the formazan produced in vessels of uninfected, drug-free 0 cells. EDsp is calculated as the concentration of drug causing Increasing the percentage of formazan production in infected and drug-treated cells to 750 of the concentration by drug-free uninfected cells The therapeutic index (TT) is calculated by dividing the toxicity (TC) by the antiviral activity (EDs) ) Table 1 Evaluation levels of antiviral activity and toxicity of compound 71 in acute infection of CEM- SS cells B 1117-1 Name of compound Dose | effective dose | toxicity ratio | effective therapeutic index ratio 795 (uM) 0 (nM) (nM) 8

YAY o 41,1 yo, TR 71 compound OEY) ov, v azidophymidine (AZT) >m L > blu aA 17,4a EAE dideoxycytidine (ddc) (EDsg) antiviral activity + (TCsp) therapeutic index = toxicity 0

or - - table? Evaluation of Antiviral Activity and Toxicity of Compound 71 in Alla Acute Infection of HIV-1 22c Cells [Ib Name of Compound Dose Toxic Dose Effective Index Ratio | effective ratio | 750 @M) Therapeutic (nM) 70 | (mM) 708 compound Ao, YY undefined 71 ta ¢v.y | azidophymidine (AZT) unspecified fot yo dideoxycytidine (ddc) 74 unspecified ara v. therapeutic index = toxicity (TCs) + antiviral activity (EDso) . As noted above; The compounds of the present invention are useful for inhibiting the HIV protease ¢, which is an enzyme associated with the production and assembly of the viral component. The embodiment of the present invention is a method of treating HIV infection that includes administration to host or patient; like one of the chiefs; An effective amount of the compound of Formula (3) or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a method of treating AIDS involving giving a host or patient an effective amount of the compound of Formula (3) or a pharmaceutically acceptable salt thereof. Another embodiment of the invention Jal is HIV protease inhibition method including administration of an HIV-infected cell, host, or HIV-infected patient; eg an infected primate 0b1117; an effective LS of a compound of formula (1) or an acceptable salt The term “effective amount Jlad Ans!” means the amount of a compound of formula (4) or a pharmaceutically acceptable salt thereof that is effective for inhibiting the production and assembly of an HIV viral intermediate component. In fact, the effective amount of a given compound will be determined according to the invention to obtain on jide effects ',

Y - inhibition by the relevant surroundings of the condition. Including; For example, the compound given, the method of administration, the condition being treated, and the host or individual patient being treated. potion contains; For example (given in single or divided doses; a dosing level of about 00 mg/kg to about 050 mg/kg body weight of the compound of this invention). In general, the preferred daily doses are from about 0 mg/kg to about £0 mg/kg and more preferably 0 from about 0 mg/kg to about Te mg/kg. The compounds of the invention can be administered by a variety of Gohl's routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal routes. . It is preferable to formulate the compounds of the present invention before use. Therefore, another embodiment of the present invention is a pharmaceutical composition or pharmaceutical formulation that includes an effective amount of the compound of formula (4) or a pharmaceutically acceptable salt thereof and an acceptable carrier (Wasa), such as a dilute or an excipient thereof. It is preferable that The active substance includes from 01.1 7 to 799.9 by weight of the formula. Harm to host or patient Pharmaceutical formulations may be prepared from the compounds of the invention by known methods using known and readily available active substances In the manufacture of compositions of the present invention it is usual that the active substance will be mixed with a carrier or diluted with a carrier or included within a carrier;

Which may be in the form of a capsule, a sachet, a paper bag, or another suitable container. when the stand acts as an attenuator; It may be a liquid solid or semi-solid that acts as a carrier, excipient or medium for the substance in the form of tablets, granules, powders, fudge tablets ¢, sachets, granules, suspensions, emulsions, solutions, syrups, aerosols 0 (in the form of solid medium or in Ada liquid medium) Most important bitters (containing, for example, up to 1/0 by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile solutions for injection, powders packaged with sterilization, and the like. The following example wordings are illustrative only and are not intended to limit the scope of the invention. The term 'active substance' represents the compound of Formula (3) or a pharmaceutically acceptable salt thereof. ye Formulation 1 Hard gelatin capsules are prepared using the following active ingredients in quantity (mg/capsule) Active ingredient Yo. Dried Starch Yoo 1 Magnesium stearate VY |

hy _ 0 m syntax ? A tablet is prepared using the materials below: Quantity (mg/capsule) Active ingredient Yo. Cellulose, microcrystalline F [Silicon dioxide vaporized 1 Stearic acid ° Ingredients are mixed and compressed to form tablets To weigh each one of them 165 milligrams. or wording? An aerosol solution is prepared containing the following components: Basically, we oe the active substance Yo Yo, Vo Methanol propellant (Chlorodifluoromethanc) YY 0

The active compound is mixed with ethanol and the mixture is added to a part of the propellant YY and cooled to -31 °C and transported to a filling device. Then the required amount is fed into a stainless steel bowl and diluted with the remaining amount of propellant. Then install the valve units in the container. editing ; 0 discs are made; Each contains 60 milligrams of the active ingredient; As follows: Amount (mg/opportunities) Active ingredient Te to Lis Crystalline cellulose 383 Molecules Yo Microcrystalline cellulose Polyvinylpyrrolidone (as a solution of 701 in water) ¢ Sodium carboxymethyl starch M Magnesium stearate - 0” Talc powder! American sieve with mesh number VE The produced granules are dried at 50 degrees Celsius and passed through an American yo sieve mesh No. 18. After that, sodium methyl carboxy Li, magnesium stearate and tale powder are added ¢ which were previously passed through an American sieve, Sad No. 20; to the granules which, after mixing them, are pressed on a tableting machine to produce tablets, each weighing 1,5 m.

op - - formulation 6 capsules are made; Each contains 80 milligrams of the active ingredient; As follows: HQ (mg/capsule) Active ingredient 0 mg Starch 4 mg Microcrystalline cellulose 04 mg Magnesium stearate 0 mg M Mix the active substance, cellulose, and starch Magnesium stearate s and pass through a sieve American Reticle No. fo and packed in gelatin capsules in quantities of 0010 milligrams Formulation > Each suppository contains YYO milligrams of the active substance as follows: or the active substance 8 milligrams of saturated fatty acid glycerides Yo een Saturated fatty acid glycerides 16 milligrams

a — The active substance is passed through an American mesh sieve No. 01 and suspended in saturated fatty acid glycerides previously melted using the minimum necessary heat. Then the mixture is poured into a suppository mold with a nominal capacity. grams and let it cool. formulation 7 0 suppositories are made; Each contains 50 mg of active ingredient per dose * ml ¢ as follows: Active ingredient 0 mg 0 Sodium carboxymethyl cellulose mg = | . Yo Syrup ml Benzoic acid solution vy i 0 ml

Flavor

Color as desired

To taste pure water to make the total volume

© Do not pass the active substance through a US mesh sieve No. ©*; Mixing with carboxy sodium methyl cellulose and syrup to form a smooth textured dough. Benzoic acid solution and flavor 010 color are diluted with a part of water and added with stirring. Then enough water is added to produce the required volume. 1" 46

= 1. Formula A An intravenous formulation is prepared as follows: Active substance 0 mg isotonic saline solution 000 ml Isotonic saline at a rate of 1 ml every minute.

Formulate 9 tablet preparations using the active ingredients below

Quantity

(mg/capsule) Active ingredient 7 mg ilicat 10 calcium silicate £7 1 mg crospovidone magnestumn stearate © mg

Claims (1)

- +1 Claims_element: (9) Compounds of the present invention having formula 1-1 and NS: and where substituent or not alkyl-OR1 and 8 over a unit are chosen from 11; (and©-0) alkyl dc sane substituted by a cycloalkyl having a ¢ substitution or © group or group 191-011ld0m0-,©); or a heterocyclic group with inference 1 (071-0117adam0-0); or dc sana and ©-©0) or alkyl group by VY ¢ Ry(Y)(X) S- alkyl group or » RsRoN- alkyl A acyl substituent or non-substituted ; or an alkyl group or a cH aR group; 9 has a substitution or an alkyl W separately to be selected from 11 ; and Ry groups each from the 0 ¢ heterocycle; cycloalkyl 5 ¢ heterocyclic groups with no substitution 11; heterocyclic sulfonyl s acyl ¢ and arylgc aryl 0” cycloalkyl of lapetsa groups with or without an alkyl substitution or with a “H” group VY heterocyclic aryl or aryl or heterocyclic group OR 4 : 5 and 57 are selected separately from -0 or none yo OR a pharmaceutically acceptable prodrug OR salt ; or soluble thereof 0 Ty - - =v 1 compound according to element ¢ where R is H or an inert drug or salt or 1 0 compound according to element +1 where when at least one of the +1 R's is combination -,08 then Ry is 17 or an inert drug or salt or solute thereof is acceptable 1 ¢- compound according to element 2 wherein at least one of both +1 fondness is OR; The mentioned alkyl ic gana Y is chosen from: _C(CHy), CH,OH, -CH(CH:)CH;OH, -CH,CH,OH, -C(CH3) (CH;PH),, - C(CHa3): —O-CH;-O-CHj, -C(CHs)2 CH;- O- CH;- O-CHs, and —C(CHj3)2 ¢ and —~C (CHz); CH,-S-acyl© ,ethane -5 CH;- O- acly- C(CHs); CH,-O- CH;- . 0 or an inert drug or a salt or a pharmaceutically acceptable solubility thereof. 1#- compound according to element 1 ; Where, when at least one of the 18 and 8 expressions Y is of an Aafiu «cycloalkyl group with a (C1-Co) alkyl group or an OH- (C1-Co) alkyl group 3, then the said cycloalkyl group is Selected from: M10 CH,OH, 112011, o MY — - 1 or an inert drug or a pharmaceutically acceptable salt or dissolved thereof. 1-1 01 compound according to element 1 ; Where, when at least one of the RR is a heterocycle group substituted by a (C1-Ce) alkyl group or a V (Ci-Cs) alkyl group -011 then a heterocycle group is chosen Stated from: ‎CHa neda nd-nam ¢ ? oO 5 , 7 5 1 HaC and 8 HaC C Hi HaC Rs N \ | 5( and N—R, © with Lim, :0 : 2 where Rs is an H or an alata alkyl ic jana or unsubstituted or an i_c group of a cycloalkyl or a cyclic group Heterocycle, aryl group, acyl Ac sana A, sulfonyl ic sana, inert drug, salt, or acceptable solubility 1 7- A compound according to element 1, where the said compound is characterized by the formula 71 : N © .Nm58 ol Lo Ny > Sou 0 HO . ; N N H H Or 1 H ? . Or an inert drug of salt or a pharmaceutically acceptable cycloalkyl dissolved thereof when 18 is a Cua group compounded according to the element? ; CH, OH CHLOH ¢ WO). Or an inert drug, or a salt, or a pharmaceutically acceptable solubility thereof: 2: It is distinguished by having the formula (4b) 1 salt according to the element 4-1 sph O_N Me © POYNR cso or hob : 3303 v OH 1 y H 9b : Pharmaceutical composition including 1-01 effective amount of a compound according to any of Claims (1-1); Pharmaceutical for that purpose dds 2 (2 * includes giving the host HIV virus protease a way to inhibit the protease enzyme 1-11 or its salt or soluble thereof (1-1) of a compound according to any of the protection elements Ald Amount of Y. Pharmaceutical Acceptable YF qe - 10-1 method of inhibiting the HIV protease, including giving the host an effective amount of (S50 element 7) or Jala drug or salt or a mixture thereof that is pharmaceutically acceptable. 14-1 compound According to which of the claims (1-1) has a purity greater than 90. -1#1 is a compound according to which of the claims (1-1) has a purity of at least 740. -11-1 is a compound according to Any of the claims (1-1) has a purity of at least 749. 1-17 is a compound according to which any of the claims (1-1) has a purity of at least 7949. VA) is a compound according to element 7 which It has a purity of at least 74906. 1 4- A compound according to element 7, which is characterized by a purity of at least 780. -71-1 A compound according to element V which is characterized by a purity of at least TAY . 1 1 ?- compound according to element 7; Which is characterized by a purity of at least 799. 1 77- Pharmaceutical composition according to item 01; Where the compound is characterized by a purity greater than 790. YY) a pharmaceutical formula according to element 0; The compound is characterized by a purity of at least 798. a 1; 7- A pharmaceutical composition according to item 01; The compound is characterized by a purity of at least 747. 1 ©?- a pharmaceutical composition according to item 01; Where the compound is characterized by a purity of 744 at least “|-11-1. Pharmaceutical formula according to element VY, where the compound is characterized by a purity of 7985 greater than “1.00 1 7”- a pharmaceutical composition according to element 11, where the compound is characterized by a purity of at least 790. —YA 1 Pharmaceutical formula, Ga, for element 11, where the compound is characterized by a purity of at least 7997. 1 19- A pharmaceutical composition according to item 11; Where the compound is characterized by a purity of 754 at least. ,. 7960, where the compound is characterized by greater purity than the VY method according to the element Fy . ; Where the compound is characterized by a purity of at least 790 17 of the element Gp 1-*1 method The compound is characterized by a purity of at least 791 Yi Cum; 11 method according to the element 1-*”7 . ; Where the compound is characterized by a purity of at least 7449 (VY method according to element TY) . ; Where the compound is characterized by a purity of at least 7938 17;*- method according to element 1 . ; Where the compound is characterized by a strength of at least 790, 17 methods according to the element -*© 1 . ; Where the compound is characterized by a purity of at least 799 VY method according to the element oY . ; Where the compound is characterized by a purity of at least 7949 1 “method according to element #7 1 1 - compounds of formula (9) ¢ and processes for its preparation 'and pharmaceutical formulations containing X on them or methods for inhibiting the enzyme of a virus protease HIV by using them, mainly * - as mentioned in this application by reference to the examples.