SK76093A3 - Aminediol protease inhibitors - Google Patents

Abstract

The aminediole compounds, their pharmaceutically acceptable mixtures and the methods for their application in the inhibition of retroviral protease are designed for the treatment and/or prophylaxy against HIV infections (AIDS).

Description

The invention relates to novel amindiol compounds, to pharmaceutical compositions containing them, and to a method of using the compounds to inhibit retrovirus replication. In particular, the invention relates to novel amindiol compounds suitable for the treatment and / or prevention of acquired immune deficiency syndrome (AIDS).

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

A ^a - D ^a - CH - N - CH

(I) where

^And A, N, and ^c is independently a (1) hydrogen, (2) alkyl, especially lower alkyl, (3) ^R3 - C (4) ^R3 - S0 ₂ -,

(5) R ³ - N - I Sat ₂ "/ 1 R ⁴ (6) R ³ - N - c - / 1 II R ⁴ from 0 n (7) R ³ -ε- C- κ ⁶ from 1 II (8) ^R 5 - c - 0 - c - or 1 R ⁷ (9) R ³ - SO ”F

D ^and a are independently selected from the groups of formula

wherein D ^a , respectively. D * ⁵ are bound to group A ^and , respectively. * ⁵ via a group -EN (R ⁸⁾ -, wherein E is a single bond or peptic chain containing from 1 to 4 amino acids, the N-terminus is linked to A ^and, as part of the E ^and D or A to ^b, where E is part of D ^b ,

R ¹ and R ² independently represent (1) hydrogen, (2) alkyl, especially lower alkyl, (3) alkenyl, especially lower alkenyl, (4) aryl, (5) heterocyclo or (6) carbocyclo, such as cycloalkyl,

R ³ and R ⁴ independently represent (a) hydrogen, (b) alkyl, especially lower alkyl, (c) aryl, (d) heterocyclo, (e) carbocyclo, such as cycloalkyl, (f) when R ³ and R ^{4 are} attached to a common nitrogen atom, this may be via a nitrogen atom linked to the heterocycle, for example a 5 to 7 membered heterocycle, or (g) when E is a single bond and R ³ is part of the a or a ^{and b} may, together with R ³ R ⁸ to form an alkylene group, for example one to five atoms, such as a cyclic group, formed by R ³ and R ⁸ together with the atoms to which they are attached, of the formula

II

R ⁵ , R ⁶ and R ⁷ independently represent (a) hydrogen, (b) alkyl, especially lower alkyl, (c) aryl, (d) carbocyclo, such as cycloalkyl, (e) fluorenyl, (f) heterocyclo, (g) R ⁵ , R ⁶ and R ⁷ can be independently attached to the carbon atom to which they are attached to form a mono-, bi- or tricyclic carbocyclic ring system, especially when each ring contains 3 to 7 carbon atoms or mono-, bi- or a tricyclic heterocyclic ring system, (h) alkynyl, (i) alkenyl, or (j) when E is a single bond and R ⁵ , R ⁶ and R ⁷ are part of A ^and or A ³ , one of R ⁵ , R ⁵ may be ⁶ or R ⁷ together with R ⁸ form an alkylene group, for example having one to three carbon atoms, for example when R ⁵ and R ^{8 are} methyl and R ⁷ and R ⁸ together with the atoms to which they are attached form a cyclic group of the formula

ABOUT

II

ch ₃

R ⁸ is (a) hydrogen, (b) alkyl, especially unsubstituted lower alkyl or aryl-lower alkyl, (c) R ⁸ and R ⁹ may be attached to the atoms to which they are attached to form a heterocyclic ring system, e.g. (d) R ⁸ may be linked to the above-mentioned substituent R ⁵ , r 6 or R ⁷ , (e) R ⁸ may be linked to the above-mentioned substituent R ^8, or (f) R ⁸ and R 7 ¹¹ may be attached to the atoms to which they are attached to form a heterocyclic ring system, for example R ⁸ and R ¹¹ together form an alkylene group,

R ⁹ and R ⁹ 'independently represent (a) hydrogen, (b) alkyl, especially lower alkyl, (c) alkenyl, especially lower alkenyl, (d) alkynyl, (e) aryl, (f) heterocyclo, (g) carbocyclo , for example cycloalkyl, i (h) R ⁹ may be linked to the above R ⁸ , (i) R ⁹ and R ⁹ 'may be linked to the carbon atom to which they are attached to form a carbocyclic group such as 5- or 6 - membered carbocyclic ring.

R ¹⁰ is (a) hydrogen, (b) alkyl, such as unsubstituted lower alkyl or hydroxy-lower alkyl, cycloalkyl-lower alkyl, aryl-lower alkyl or heterocyclo-lower alkyl, (c) alkenyl, especially lower alkenyl, (d) ) alkynyl, (e) carbocyclo, such as cycloalkyl, (f) aryl or (g) R ¹⁰ and R ¹¹ can be taken together to form a keto group (c = O), (a) hydrogen, (b) a hydroxyl protecting group, such as alkyl, (c) R ¹¹ may be linked to the aforementioned substituent R ^8, or (d) R 11 may be taken together with R ^{8 to} form a bond to form the aforementioned keto group,

Z is oxygen or sulfur, and p and q are independently integers from 0 to 4, and salts thereof, preferably pharmaceutically acceptable salts thereof.

The compounds of the invention inhibit retrovirus replication. The invention thus provides methods and pharmaceutical compositions for the treatment and / or prevention of diseases caused by such pathogenic organisms.

The terms alk or alkyl, either alone or as part of other groups, refer to optionally substituted straight and branched chain saturated radicals, for example containing 1 to 12 carbon atoms, most preferably 1 to 8 carbon atoms in the normal chain. Thus, it is understood that the terms alk and alkyl refer to unsubstituted groups such as methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1- methylbutyl, 2,2-dimethylbutyl,

2-methylpentyl, n-hexyl and the like, as well as substituted groups such as phenylmethyl and the like. Examples may include one or more, for example, one, two or three of the following groups:

(1) hydroxy (or protected hydroxy), (2) oxo (ie = 0), with the proviso that the carbon bearing the oxo group is not adjacent to the heteroatom, (3) carboxy, (4) halo (especially forming trihaloalkyl, especially trifluoromethyl), ( 5) alkoxy such as phenyl-lower alkoxy;

R ¹⁶ - [O- (CH ₂ ) _m ) _n -Where m is an integer from 2 to 5, n is an integer from 1 to 5 and R ¹⁶ is (a) (b) hydrogen, alkyl, especially unsubstituted lower alkyl or alkoxy - lower alkyl, aryl or heterocyclo, (c) (d) aryloxy, alkoxycarbonyl, (8) (R ¹² ) (R ¹³ ) N - C

Wherein R ¹² and R ¹³ independently represent hydrogen, alkyl, especially lower aryl, heterocyclo, carbocyclo such as R ¹² and R ¹³ may be attached to, a heterocyclic ring, alkyl, cycloalkyl, linked to a nitrogen atom, to a 5- up to 7-membered (9) (R ¹² ) (R ¹³ ) Ν - such as amino (H ₂ N -), (10) * 1

R ¹⁵ - C where

R ¹⁴ is

R ¹⁵ (a) hydrogen, (b) alkyl, especially lower alkyl, (c) aryl, (d) heterocyclo, (e) carbocyclo, such as cycloalkyl, or (f) R ⁴ · ⁴ _{and m <} 5 may be linked to alkylene a group having 3 to 5 carbon atoms and is (a) hydrogen, (b) alkyl, especially lower alkyl, (c) alkenyl, especially lower alkenyl, (d) aryl, (e) heterocyclo, (f) carbocyclo, for example cycloalkyl, (g) R ⁶

I

R ⁵ - C - O wherein R ⁵ , R ⁶ and R ⁷ independently represent groups (a) to (i), as defined above, R ⁵ , R ⁶ and R ⁷ or (h) R ¹⁵ may be associated with the above by the said group R ¹⁴ , (11) R ¹⁵ - SO ₂ - N -,

I

R ¹⁴ (12) carbocyclo, for example, cycloalkyl (13) heterocyclo, (14) heterocyclooxy, (15) aryl, (16) alkylcarbonyloxy, such as lower alkylcarbonyloxy, (17) arylcarbonyloxy, (18) cyano, (19) mercapto, ( (20) alkenyl, (21) alkynyl such as ethynyl (e.g., forming a propargyl group), (22) alkylthio, (23) arylthio, (24) trialkylsilyl, such as trimethylsilyl, (25) azo (ie R ¹⁶ 0-N = wherein R ¹⁶ is as defined above, preferably hydrogen (to form oxime (HO-N =)) or unsubstituted alkyl (to form unsubstituted alkoxyimino (alkyl-O-N =)) or (26) (R ¹² ) (R ³³ ) NC (O) -O-, wherein R ¹² and R ¹³ are as defined above.

The term alkoxy refers to an alkyl group bonded via an oxygen bridge (-O-), alkylthio refers to an alkyl group bonded via a sulfur bridge (-S-), the term alkoxycarbonyl (also referred to as carboalkoxy) refers to an alkoxy group attached to a carbonyl group to form an ester, the term alkylcarbonyloxy refers to an alkyl group bonded to a carbonyl group which is itself bonded through an oxygen bridge, the term aminocarbonyloxy refers to an amino group bonded through a carbonyl group which is itself bonded via an oxygen bridge, the term alkylaminocarbonyloxy refers to an alkyl group bonded via the above aminocarbonyloxy group, alkylaminocarbonyl refers to an alkyl group bonded via an amino group, which itself is bonded via a carbonyl group, and the term alkylene refers to a divalent alkyl group. With respect to alkyl groups which are substituted, the term alkoxy-alkyl refers to an alkoxy group linked via an alkyl group, the term aryl-alkyl refers to an aryl group linked via an alkyl group, a heterocyclo group, a cycloalkyl-alkyl alkyl group, and a plurality of hydroxyl all mentioned below substituted fluoroenylalkyl refers to the cycloalkyl term of the hydroxyalkyl groups attached to the terms may be or unsubstituted.

heterocycloalkyl refers to via an alkyl group, the term bonded via to one or an alkyl group. In alkyl as above, likewise denotes a fluorenyl group bonded via an alkyl.

The same terms arylalkoxy, alkoxyalkoxy, hydroxyalkoxy, heterocycloalkoxy, aminoalkoxy, aminocarbonyloxyalkoxy, heterocyclocarbonylalkoxy, heterocyclooxyalkoxy, alkoxycarbonylalkoxy, and carboxyalkoxy denote alkoxy, substituted aryloxy, heterocyclo, alkoxy, hydroxy, heterocyclic, alkoxy, hydroxy, heterocycloalkoxy, hydroxy, heterocycloalkoxy; carboxy.

The term lower alkyl, used alone or as part of another group, refers to optionally substituted groups referred to above as having 1 to 6 carbon atoms in the normal chain. Lower alkyl groups are preferred among alkyl groups.

or as part of another optionally substituted radical with or

12, preferably 2 to 8, at least one double directly through that

The term alkenyl, used alone as a group, refers to a branched chain containing, for example, 2 to carbon atoms in the normal chain, containing a carbon-carbon bond and which are attached from the double bond carbons. It is therefore understood that alkenyl refers here not only to unsubstituted ethenyl, propenyl, butenyl, pentenyl, hexenyl substituted groups. Examples of substituents one or more, for example one, two or residues:

groups, and the like, one term, but also may include three of these (1) alkyl, especially lower alkyl, (2) aryl, (3) carbocyclo, for example, cycloalkyl, (4) heterocyclo, (5) carboxy, ( 6) halo, (7) (R ¹²⁾ (R ¹³⁾ N - C

II o

(8) cyano, (9) alkoxycarbonyl, (10) trialkylsilyl or (11) alkynyl.

The term lower alkenyl, used alone or as part of another group, refers to optionally substituted groups mentioned above as alkenyl containing 2 to 6 carbon atoms in the normal chain. Lower alkenyl groups are preferred among alkenyl groups.

The term alkynyl, used alone or as part of another group, refers to optionally substituted straight or branched chain residues, for example containing 2 to 12, preferably 2 to 8 carbons in the normal chain, containing at least one carbon-carbon triple bond and which are bonded directly through one of the triple bond carbons. Thus, it is understood that the term alkynyl herein refers to both unsubstituted groups such as ethynyl, methyl-ethynyl, and the like, as well as substituted groups. Examples of these substituents may include one or more, for example one, two or three of the following:

(1) alkyl, especially lower alkyl, (2) aryl, (3) carbocyclo, for example cycloalkyl, (4) heterocyclo, (5) carboxy, (6) (R ¹² ) (R ¹³ ) N - C -,

II o

(7) cyano, (8) alkoxycarbonyl, (9) alkenyl or (10) trialkylsilyl.

The term carbocyclo, carbocyclic or carbocyclic ring system, used alone or as part of another group, refers to an optionally substituted, saturated or partially unsaturated homocyclic carbon ring system such as a cycloalkenyl ring system that is a partially unsaturated or preferably cycloalkyl ring system that is fully saturated wherein both the cycloalkenyl and cycloalkyl ring systems are optionally substituted as defined above. Such cyclic groups preferably contain 1 to 3 rings and 3 to 12, preferably 3 to 7 carbons on the homocyclic ring. Thus, it is understood that the terms carbocyclo, carbocyclic, and carbocyclic ring system refer to both unsubstituted groups such as monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, bicyclic groups such as octahydropentalenyl, decalin, norborlohltyl, spirocyl [2,4Jheptyl], spirocyclooctyl (e.g., spiro [3,4-octyl), spirocyclononyl (e.g., spiro [4,4] nonyl) and the like. and tricyclic groups such as adamantyl, but also substituted groups. Examples of substituents may include one or more, for example, one, two or three of the following:

(1) alkyl, especially lower alkyl, (2) hydroxy (or protected hydroxy), (3) halo, (4) mercapto, (5) cyano, (6) carboxy, (7) alkoxycarbonyl,

(8) (R ¹² ) (R ¹³ ) N - C -, II 0 (9) (10) (11) (12) (13) alkylcarbonyloxy such as lower alkylcarbonyloxy, arylcarbonyloxy, (R ¹² ) (R ¹³ ) N-, for example amino (H ₂ N-), alkoxy, aryl, for example when the aryl group is bonded by a single bond or fused to said carbocyclic group (e.g. to form a tetrahydronaphthyl, indanyl or indenyl group), in each case the arylcarbocyclo group formed is bonded via a carbocyclo group, (14) (15) (16) (17) (18) (19) heterocyclo, heterocyclooxy, oxo (= O), aryloxy, alkylthio, arylthio, (20) 0 II R ¹⁵ - C - N - 1 R ¹⁴ (21) (22) (23) alkenyl, alkynyl or trialkylsilyl.

The terms ar or aryl, used alone or as part of another group, refer to homocyclic or optionally substituted aromatic groups, preferably monocyclic or bicyclic groups containing 6 to 12 carbons in the ring moiety such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, etc.

Thus, it is understood that the terms ar and aryl refer to unsubstituted and substituted groups herein. Examples of substituents may include one or more, for example, one, two or three of the following:

(1) alkyl, especially lower alkyl, (2) alkoxy, (3) hydroxy (or protected hydroxy), (4) halo, (5) (R ¹² ) (R ¹³ ) N -, for example amino (H ₂ N-) (6) alkylthio, (7) mercapto, (8) nitro, (9) cyano, (10) carboxy, (11) carboalkoxy, (12) carbocyclo, for example, when said carbocyclo group is bonded via a single bond or is fused to said aryl group (e.g., to form tetrahydronaphthyl, indanyl or indenyl), wherein in each case the resulting carbocyclo-aryl group is bonded via an aryl group, (13) (R ¹² ) (R ¹³ ) N - C -,

II o

(14) (R ¹² ) (R ¹³ ) N - SO ₂ -, (15) R ³

wherein R ¹⁷ is (a) hydrogen, (b) alkyl, especially lower alkyl, (c) aryl, (d) heterocyclo, (e) carbocyclo, such as cycloalkyl, (f) R ¹⁷ together with R ³ may form an alkylene group with 3 to 5 carbons, (16) R ³ - SO ₂ - N -,

I

R ¹⁷ (17) phenyl, (18) alkylcarbonyloxy, such as lower alkylcarbonyloxy, (19) arylcarbonyloxy, (20) arylthio, (21) heterocyclooxy, (22) aryloxy, (23) alkylthio or (24) alkenyl.

The terms arylcarbonyloxy or aroyloxy refer to an alkyl group which is bonded via a carbonyl group which is itself bonded via an oxygen bridge, the term aryloxy refers to an aryl group bonded via an oxygen bridge, the term arylcarbonyl refers to an aryl group bonded via a carbonyl group, arylaminocarbonyl refers to aryl linked via an amino group which itself is linked via a carbonyl group and the term arylthio refers to an aryl group linked via a sulfur bridge.

The terms halogen or halo, used alone or as part of another group, refer to chlorine, bromine, fluorine and iodine.

The terms heterocyclo, heterocyclic or heterocyclic ring system, used alone or as part of another group, refer to an optionally substituted, fully saturated or unsaturated aromatic or non-aromatic cyclic group, such as a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic or A 10- to 15-membered tricyclic ring system having at least one ring heteroatom containing at least one carbon atom. Each ring of the heteroatom-containing heterocyclo group may contain one, two or three heteroatoms selected from nitrogen, oxygen or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclo group may be attached at any heteroatom or carbon atom.

Examples of monocyclic heterocyclo groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazoyl, thiazolyl, thiadiazolyl, thiazolidinyl, piperothiazolyl, furyl, thiazolyl, furyl, thiazolyl, furyl, thiazolyl, furyl, thiazolyl, 2-oxo-piperazinyl,

2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl,

4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl and the like.

Examples of bicyclic heterocyclo groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, pyrrolidinyl, quinolinyl, quinoxal, quinolinyl, quinoxal

O-furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4- oxoquinazolinyl) and the like.

Examples of tricyclic heterocyclo groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms heterocyclo, heterocyclic, and heterocyclic ring system include both unsubstituted and substituted groups. Examples of substituents may include one or more, for example one, two or three of the following:

(1) alkyl, especially lower alkyl, (2) hydroxy (or protected hydroxy), (3) halo, (4) oxo (ie = O), (5) (R ¹² ) (R ¹³ ) N-, for example amino (H ₂ N -), (6) alkoxy), (7) carbocyclo, such as cycloalkyl, (8) carboxy, (9) heterocyclooxy, (10) alkoxycarbonyl, for example unsubstituted lower alkoxycarbonyl, (11) (R ¹² ) ( R ¹³ ) N - C -,

U o

(12) mercapto, (13) nitro, (14) cyano, (15) carboalkoxy, (16) (r ¹² ) (r ¹³ ) n - Sat ₂ -, (17) R ³ - C - N -, (18) ) R ³ - SO ₂ - N

I

R ¹⁷ (19) aryl, (20) alkylcarbonyloxy, (21) arylcarbonyloxy, (22) arylthio, (23) aryloxy, (24) alkylthio or (25) formyl.

The term heterocyclooxy refers to a heterocyclo group bonded via an oxygen bridge and the term heterocyclocarbonyl refers to a heterocyclo group bonded via a carbonyl group.

The term hydroxyl protecting group herein refers to any group known or capable of functioning as a hydroxyl protecting group, such as those described in Protective Groups in Organic Synthesis by T. W. Greene, John Wiley and Sons, 1991 or Fieser & Fieser. Examples of such protecting groups include benzyl, trialkylsilyl, acetate and benzoate.

The term carboxy, used alone or as part of another group, refers to the -COOH group of a carbocyclic acid.

The term amino acid, used alone or as part of another group, preferably refers to a group

R ¹⁹ /

- C

II where R ¹⁸ a

R ¹⁹ independently represents (D (2) (3) (4) (5) (6) (7) (8) hydrogen, alkyl, especially alkenyl, especially lower alkenyl, ^aryl , heterocyclo, carbocyclo, such as cycloalkyl,

R ¹⁸ and R ²⁹ may be joined together with the carbon atom to which they are attached to form a carbocyclo group such as a 4- to 7-membered cycloalkyl ring or R ¹⁸ and R ²⁰ may be

R ²⁰ , lower alkyl, linked as defined in the definition

R ²⁰

is a (D hydrogen (2) alkyl, especially lower alkyl, (3) aryl, (4) heterocyclo, (5) carbocyclo such as cycloalkyl or (6) R ¹⁸ and R ²⁰ may be bonded together with atoms; to which they are bound, to a heterocyclic group, <

A 4- to 7-membered saturated monocyclic ring which may be unsubstituted substituted by groups such as heterocyclic or (i) (ii) (iii) hydrogen alkyl, especially lower alkyl, alkenyl, especially lower alkenyl, (iv) (v) (vi) (vii) (vii) (ix) (x) (xi) (xii) (xiii)

The above aryl, for example when the aryl group is bonded by a single bond or is fused to said monocyclic heterocyclic ring to form an unsaturated bicyclic heterocyclic ring system, heterocyclo, mercapto, alkoxy, carbocyclo such as cycloalkyl, for example when the cycloalkyl group is bonded by a single bond or is fused or spiro-fused to said monocyclic heterocyclic ring to form a saturated bicyclic heterocyclic ring system, hydroxyl (or protected hydroxyl), aryloxy, alkylthio, arylthio or oxo.

an amino acid unit includes, for example, those units which may be present in D- and L-alanine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, homoserine, homoserine, homoserine , tryptophan, tyrosine, valine, hydroxyvaline, norleucine, norvaline, phenylglycine, cyclohexylalanine, leucine ethylamide (t-leucine), hydroxy-tert.butylglycine, aminobutyric acid, ornithine, and cycloleucine, and preferably, when R ¹⁸ and R ²⁰ taken together with the atoms to which they are attached, proline, 4-hydroxyproline, pyroglutamic acid, azetidinecarboxylic acid, pipecolinic acid, indoline-2-carboxylic acid, tetrahydro-3-isoquinolinecarboxylic acid,

- 21

The term peptide chain herein refers to two or more of the above amino acids linked by a peptide bond - (C (O) -N-).

I

The term N-terminus refers to the above-mentioned amino group -N (R ²⁰⁾ -.

The term salt herein refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (inner salts), such as quaternary ammonium salts, for example alkylammonium salts, are included in the term salt. Preferred are non-toxic pharmaceutically acceptable salts, but other salts are useful, for example, in the isolation and purification stages of the preparation.

Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glycerophosphate, glucoheptanoate, glucoheptanoate, glucoheptanoate hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate and thiocyanate.

Examples of basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine,

N-methyl-D-glucamine and amino acid salts such as arginine, lysine, etc. The nitrogen-containing basic groups can be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl diamyl sulfate), halides with long chain (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide) and others.

The invention relates to all compounds containing a group

R ¹ R ²

I I

- D ^a - CH - C - CH - ^C D ^B Ia in particular compounds capable of inhibiting retroviral, preferably HIV, protease.

The invention also includes prodrugs and solvates of the compounds of the invention. The term prodrug herein refers to a compound that upon administration to a subject undergoes chemical conversion by metabolic or chemical processes to form a compound of Formula I or a salt and / or solvate thereof. See. H. Bundgaard, Drugs of the Future 16 (5), 443-458 (1991) and H. Bundgaard (Ed), Design of Prodrugs, 1985, Elsevier (Amsterdam).

The solvates of the compounds of formula I are preferably hydrates. Also included are tautomers of the compounds of the invention, such as hydroxyketone hemiketals, ketone enolforms, and the like.

The original definitions of groups and terms given above apply to the above groups and terms throughout the text unless otherwise stated. It goes without saying that the examples given above are merely illustrative and not limiting. It is particularly advantageous to use the groups indicated by the terms in particular, particularly or preferably. Throughout the text, groups and substituents thereof may be selected to form stable units and compounds.

All stereoisomers of the compounds of the invention are also within the scope of the invention. For example, the individual stereoisomers of the compounds of the invention may be devoid of other isomers, or may be in the form of mixtures, for example racemates, or with all or some of the other selected stereoisomers. The chiral centers of the compounds of the invention may have the S or R configuration as defined in IUPAC Recommendation 1974.

The following are some examples of procedures for preparing the compounds of the invention. The reaction conditions of these procedures, such as temperature, reagent quantity, pressure, reaction time, atmosphere used and solvent, can be readily determined by one skilled in the art.

In the above reaction schemes

Q ^x and Q ² independent mean:

(1) ^R3 - C -,

H

Z (2) R ³ - S0 ₂ -, (3) R ³ - N - S0 ₂ -,

IR ⁴ (4) R ³ - N - C -,

IR ⁴ Z

0 II (5) R ³ -ε- c - F (6) κ ⁶ from 1 1! R ⁵ - c - 0 - C - or 1 R ⁷ (7) R ³ - SO ”·

Said groups Q ¹ and Q ² are preferably used in the above cases because they remove the basicity of the nitrogen atoms to which they are attached. If compounds of the invention where A ^{and a} and / or A ^b is one of the abovementioned groups 1 to 7 are desired, they do not need to be removed in the following reaction schemes of groups Q ¹ and Q ² . If compounds of the invention where A ^{and a} and / or A ^b is no, other than the groups 1 to 7 mentioned above, Q ^x and Q may for example be

R ³ - C th

or

(especially tert-butoxycarbonyl (Boe) or carbobenzyloxy (Cbz)) to form an amide and a carbonyl group, respectively. carbamate group. These groups may be removed and replaced by the desired ^group, and ^A and / or ^Ab known methods. The groups Q · ¹ · and Q are chosen to be stable under the conditions used in the following reaction schemes, except for the conditions used for their eventual removal.

Q ³ is (1) hydrogen or (2) alkyl.

Said Q ³ groups are preferably used in the above cases because they cause the basicity of the nitrogen atom to which they are bound. Values of ^J Q are hydrogen, unsubstituted lower alkyl, alkenyl-lower alkyl and aryl-lower alkyl. If compounds of the invention where A ^c is one of (1) or (2) are required, it is not necessary to remove Q ³ in the following reaction schemes Q ³ . If compounds of the invention are desired wherein A ^c is other than said group (1) or (2), Q ^{3 may} be, for example, a benzyl group. The benzyl group can be removed and replaced with the desired group A ^c by known methods. The Q ³ groups are chosen to be stable under the conditions used in the following reaction schemes, except for the conditions used to remove them.

If it is desired in the following reaction schemes to remove the Q ¹ , Q ² and / or Q ³ groups and to condense the resulting amino groups with another of the groups A ^a , A ^b and / or A ^c , methods known in the art may be used (e.g. D

E and F of Reaction Scheme 11). For examples of amino protecting groups and their removal, see, e.g. in Greene, Protective Groups in Organic Synthesis, John Wiley (1991).

Reaction scheme 1

Preparation of intermediates

Method (A)

ABOUT

Cl-C-OR ²¹

Method (B)

R ⁹ R | reduction |

Q ¹ - NH - CH - CO 2 H ---- - Q ¹ - NH - CH - CH 2 OH

IIvn oxidation

j NaCH ₂ SM62

Q ¹ --HN - CHCHO in m

Q ¹ --- HN-CH — CH>

VI

O '- HN - CH - CH = CH ₂ mCPBA |

IX

Intermediates for the preparation of compounds of formula I may be prepared by Method A or B shown in Reaction Scheme 1. Starting compounds II may be readily prepared by one skilled in the art by known methods, for example according to Greene.

In Method A, the N-protected amino acid II is converted to a reactive intermediate (not shown), for example, an acid chloride by reaction with thionyl chloride or oxalyl chloride, or to a mixed anhydride by reaction with chloroformate of formula C1-C (O) -OR ²¹ , where R ²¹ is unsubstituted lower alkyl. and then treated with diazomethane to form a diazoketone

III. Reaction of III with HCl affords α-chloroketone IV, which can be converted to chlorohydrin V by reduction and then reacted with bases according to known methods (see Handa et al., EP-A-346.847, Rich et al., J. Med. Chem. Chem. 34, 1222 (1991) to epoxide VI. For example, α-chloroketone IV can be reduced by a hydride reducing agent such as lithium aluminum hydride, sodium borohydride, lithium and / or potassium selectoride, potassium borohydride, diisobutylaluminum hydride and the like to chlorohydrin V. can be converted to epoxide VI by treatment with a base such as sodium or potassium hydroxide, sodium or potassium hydride or an alkylamine base such as triethylamine. can be prepared or used wherever in the reaction schemes (e.g., for preparation V).

prepares or uses the α-chloroketone of bromohydrin, the corresponding chlorohydrin

It is known to be possible to use methods (cf.

by means of α d and an alternative method B, Desholms et al., EP 356.223). to reduce the protected amino acid of an agent such as lithium aluminum hydride., J. Amer. Chem. Soc. 82, 3866 (1960))

This method

II to or a fairy alcohol borane (Brown or to reduce an intermediate mixed anhydride (formed as described above) with a hydride reducing agent such as sodium borohydride (Corey et al., J. Amer. Chem. Soc. 98,

6417 (1976). Alcohol VII can be oxidized to aldehyde VIII with a hexavalent chromium reagent (Evans et al., J. Ogr. Chem. 47, 3016 (1982)) or by the Moffat procedure (Albright et al., J. Org. Chem. 30 , 1107 (1965)) or Swerna (Swern et al., J. Org. Chem. 43, 2480 (1978)). Aldehyde VIII can be converted directly to epoxide VI by reaction with a sulfonium or arzonium ylide (Corey et al., J. Amer. Chem. Soc. 87, 1353 (1965); Still et al., J. Amer. Chem. Soc. 103, 1283 (1981)) or indirectly by Wittig or Peterson (Peterson, J. Org. Chem. 33, 780 (1968)) by reaction to olefin IX, which is then epoxidized with an agent such as m-chloroperbenzoic acid (mCPBA), peracetic acid and the like.

In Method B, aldehyde VIII can also be prepared from a carboxylic acid ester II (not shown) by reduction with diisobutylaluminum hydride (Ito et al., Chem. Pharm. Bull. 23, 3081 (1975)) or by reduction of methyl hydroxylamine with lithium aluminum hydride (Castro et al.). Synthesis, 676 (1983) and aldehyde VIII were converted to epoxide VI as described above.

Reaction scheme 2

Preparation of compounds I, wherein A ^and A * = ³ and ^D =

Method (A)

s

N-C-C 1

R ²⁰ θ tariaTrare reagents

X 1 b

N “C — C * I · ΝΗ — CH I ¹¹

R20 O ^Jv

ΧΠ

Reaction Scheme 2 (cont.)

Method (B)

CP-N H

VI ------ R ⁹

I vi qi-hn-CH-CH-CH2-NH-NH xm

Method (C)

R ⁹ i

Q 1 -HN — CH — C CH 3 Cl

II IV o

Q ³ Q ^J -HN

R ⁹ i

-CH-C

II o

XIV

R ⁹ i

CH, N - CH, -CH-NH-C ¹ -C reduction

Reaction Scheme 2 (cont.)

Method (D)

R ’I

Q 1 -HN-CH-CH-CH ₂ -NH

1 XIII ^θ Η Q ³ IV R ⁹ R ⁹ 1 CH -CH-- _CH2-N-CH, C - CH

II ¹¹

OH Q ³ 0

XV

I reduction

------------ X

Method (E)

R ⁹ .CH

Q ^{* 1 —} NH-CH-CH3

I ^Jun X '

N ₃ -I ¹ ----- Q ¹ —HN —CH —CH —CH, - N,

I OH xvi reductionI n

Q ¹ —HN —CH —CH —CH, —NH,

I OH XVII

Reaction Scheme 2 (cont.) Or

1) IV

2) reduction

R ⁹ i

CH ₂ - CH - CH - NH - Q ¹ I

OH

XVHI

Method (F)

CH ₂ = CH (M)

Reaction Scheme 2 explains methods A to F that can be used to prepare compounds of Formula I wherein A ^a is identical to A 1 and D ^and is identical to D * ³ (symmetrical compounds).

Method A begins with the reaction of two equivalents of epoxides VI with one equivalent of Q ³ -NH 2, wherein Q ³ is preferably hydrogen, unsubstituted lower alkyl, alkenyl-lower alkyl (for example allyl) or aryl-lower alkyl (for example benzyl), especially benzyl and for this is heated in a solvent such as methanol or dimethylformamide (Parker et al., Chem. Rev. 59, 737 (1959);

for alternative conditions see Posner et al., J. Amer. Chem. Soc. 99, 8208 (1977); Overman, J. Org. Chem. 50, 4154 (1985); Tetrahedron Lett. 27, 2451 (1986)) to give aminediol X.

The end groups Q ¹ amíndiolu X can optionally be removed by methods known by a person skilled (Greene), and of the resulting bis-amine XI coupled to N-protected amino acid or a peptide chain (prepared using standard techniques of solid-or solution-phase, described e.g. Bodanszky and Bodanszky, The Practice of Peptide Chemistry, pp. 89-150,

Springer-Verlag, 1984, where Q ² is as defined above and is compatible with the conditions used in the coupling reaction) using a coupling agent such as dicyclohexylcarbodiimide (DCC), 3-ethyl-3 '- (dimethylamino) propylcarbidiimide (EDCI) , bis- (2-oxo-3-oxazolidinyl) -phosphinic acid chloride (BOP-C1), benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), diphenylphosphoryl azide (DPPA) and the like to form an amidiol XII. (For further methods see Bodanszky, Principles of Peptide Synthesis, pp. 9-58, Springer-Verlag (1984)).

In the N-protected amino acid or peptide chain, v is an integer from 1 to 4. If there is hydrogen in the bis-amine XI Q ³ , the central nitrogen atom to which it is attached, (central amine) can optionally be protected. Here and in the appropriate subsequent reaction schemes, the central amine may be protected by known nitrogen protecting groups, for example an aryl-alkyl group such as benzyl or trityl, an alkenyl-alkyl group such as allyl, as well as groups forming together with the central nitrogen atom a carbamate or amide group.

The methods B to F described below illustrate alternative routes of obtaining compound X, which can be further processed, for example, according to Method A.

The process of Method B may be carried out in a stepwise manner by reacting one equivalent of epoxide VI with one equivalent or excess of primary amine or ammonia (Q ³ -NH ₂ ) to give amino alcohol XIII, which may be further reacted with epoxide VI to compound X.

Method C can be carried out by reacting two equivalents of chloroketone IV (or the corresponding bromoketone) with one equivalent of said primary amine or ammonia (Q ³ -NH _2f wherein Q ³ is preferably benzyl) to form diketoamine XIV, which can be reduced to amindiol X a hydride reducing agent such as lithium aluminum hydride, sodium or potassium borohydride, lithium or potassium selectoride (ie, tris-butyl lithium or potassium borohydride), diisobutylaluminum hydride, and the like.

In Method D, the process can be carried out by condensing said amino alcohol XIII with chloroketone IV (or the corresponding bromoketone) (Gordon et al., Org. Chem. 51, 3073 (1986)) to ketohydroxyamine XV, which can be reduced by the above methods.

In method E, for example, azide can be opened with azide anion, sodium, to azidoalcohol XVI by treatment with azide (Ingham et al., J. Org. Chem. 21, 373 (1956); Rosenberg et al., J. Med. Chem.

32, 1371 (1989); Saito et al., Tetrahedron Lett. 30, 4153 (1989)).

The azido group can be reduced to an amine, for example, by hydrogenation on Pd / C or by treatment with triphenylphosphine (Vaultier et al.

Tetrahedron Lett. 24, 763 (1983)). The resulting amino alcohol XVII can be condensed with epoxide VI or chloroketone IV (or the corresponding bromoketone) followed by reduction to the aminodiol XVIII as described above. The central amine may optionally be protected as described above, optionally cleaved off Q ¹ groups, and the amines obtained may be coupled with amino acids or peptide chains, as described above.

In Method F, the aminoaldehyde VIII can be reacted with a vinyl organometallic reagent of the formula CH ₂ = CH (M) wherein M is a metal containing group such as vinyl lithium, vinyl magnesium bromide and the like to form the allyl alcohol XIX. The olefinic group can be cleaved by oxidation to the aldehyde by ozonolysis or converted to the corresponding diol (not shown) with osmium tetroxide or potassium permanganate followed by cleavage of the diol with sodium periodate (Lemieux et al., J. Org. Chem. 21, 478 (1956)). to form an aldehyde. The aldehyde XX may then be reacted with an amino alcohol XIII under reductive amination conditions (e.g., hydrogenation to Pd / C or reaction with sodium cyanoborohydride, wherein Q ³ is hydrogen or benzyl, see. Hudlicky, Reductions in Organic Chemistry, pp. 134-136, John). Wiley, 1984) to compound X.

Reaction scheme 3

Preparation of compounds I wherein a / D ^a = D ^b

A = ^a AND ^b

Method (A)

R ⁹ *

Q — HN — CH — CH — CIu — NH III

OH ->

_R 9b

Q ^1b —HN —CH

1) -Q ¹ * xm

I

OH or

9b

1) Q ^1b —HN — CH

2) _R 9b reduction

I

-CH, -CH — CH

-C-CH, Cl XXH

II-NH-Q ^1b

_R 19a _R 19a

Q ²⁴ 4- N- 1'-C -4-; L in Jva

Ŕ ²⁰

II o

R &lt; ⁹ &gt; NH-CH

1) —Q ^1b

RlSb _R 19b r2O

kcndenzačné agent _W j | OH; a tensifying agent II

O _R 9a

I

NH - CH - CH

I

OH

XXV

R ^9b

I

R 19b \ ^L8B R ₂ -N-CH-CH, -CH-CH - NH-N-jQ FCC ^2b * II II · | ^{J vb} q3 QH O R2Ob

Reaction Scheme 3 (cont.)

Method (B)

R ⁹ ·

Q '- HN — CH VI reduce

R ·

ABOUT

Q ³ reductive amrATION

1) ΧΧΠ

2) reduction of r9.

I

Q ¹ —HN — CH — CH

NH-Q ^1b

method

CH = CH (M)

9b

I

CH — CH — CH, —NH χχνπ I OH xxm

Scheme 3 depicts methods A-C, useful in the preparation of compounds of formula I wherein A ^and differing from ^B and / or ^{D, and} is different from (asymmetric compound) Using the method of Scheme 2. In reaction scheme 3, and further, the symbols a or b, added to the group (e.g. R), denote groups which ultimately form part of the group A ^and -D ^and - ^and - respectively in compound I; A ^b -D ^b - or in the case of Q ^1a or Q ^2a and Q ^1b or Q ^2X) denote these groups on the corresponding side of the molecule. The units to which a or b are added otherwise have the meanings given above (e.g. R ^9a has the same meaning as R ⁹ ) but can be defined independently of one another (e.g. R ^9a can be defined independently of R ⁹ * ⁵ ).

Method A in Reaction Scheme 3 starts with the condensation of amino alcohol XIII with epoxide XXI (for preparation of epoxide XXI see Method A of Reaction Scheme 1) or with chloroketone XXII (for preparation of chloroketone XXII see Method A of Reaction Scheme 1); also prepare and use the corresponding bromoketone) followed by reduction to the asymmetric amindiol XXIII. Optionally, sequentially cleaved Q a ^and Q ^b and the resulting amine coupled with N-protected amino acids or peptide chains to give the compound XXV. When Q ^{3 is} hydrogen, the central amine to which it is attached may optionally be protected as described above.

Compounds prepared as described above may also be prepared by Method B or C of Reaction Scheme 2. In particular, Scheme 3 may be carried out analogously to Scheme 2, a method analogous to that described in Scheme 2.

B reaction

E reaction perform

Of the asymmetric diols XXVI and as

C of Scheme 3, method F of reaction XXIII may be optionally the method method of Scheme 2. cleavage of the protecting groups and condensation as described above. If Q ³ is hydrogen, the central amino group to which it is attached may in any case be optionally protected as described above.

Reaction scheme 4

Preparation of compounds I wherein R ¹ and / or R ² = hydrogen

Method (A)

R ²

I (to) -H N-CH-CH - _CH2 --NH - Q ^lb

I ^0H xxvm

- (Pro)

R ²

H ₂ N - CH - CH - CH ₂ - NH - Q ^1b

OH

R ⁹ *, I

Q - HN - CH - CH - CH _{2 -} NH 1

OH

XXX

1) protection

2) -Qi>

XXIX

R ^9a

Q ' ^and —NH-CH-CH

VI or

R ^9a

1) Q ^U -HN-CH-C-CH ₂ -C 1; ₂ ) ref

IV ⁰

R ²

I _lh ____

CH-CH-CH ₂ - NH-0-OH

R18 and _R ^ Q ^^ I9a NVC + l · _r R> 8 »R ^19. '• ^{R20' in and} about ³ F ² + n ^ C-C-OH · J where J II in and R ²⁰ 'O kcndenzačré agent

R ^9a R

I *

NH-CH - CH - _CH2 - C - CH - CH - CH ₂ - NH-Q ^{1 lb} OHA

DQ ^{, b} _R 18b Rbb ° ^H XXXI 'f

2) Q ^2b 4 N-C 4 -C 4 OH 1 R 8 Ob q 8 vb

ΧΧΧΠ

39a Reaction Scheme 4 (cont., 1

Method (B)

R ⁹ ·

Q ¹ '—HN — CH - CHO »9a

Ph ₃ P = CH-R '. .

---------- Q ¹¹ —NH —CH - CH = CH-R 'xxxm

R ⁹ * I, R 'CHCH ^1B -HN-CH-CH I XXXV ° pp-thyridium

XXXIV

R ²

I

H ₂ N - CH - CH - CH ₂ - NH - Q ^{, b}

XXKi

------------------ _R 9 _R 1

Q ^1s - HN - CH - CH - CH - NH - CH - CH - CH ₂ - NH OHOH

XXXVI lb

D Chránaiie

2) -Q ¹¹

3) _R 18 _R 19

Q ² * ”! NCC -r OH kcrriaizačré agent ^L and U _ _{n R} 2 *, and H

- _R ) 8a R! '·

Q ^2a fNC-C 4 _R 20a q ^ va

R ⁹ · ^R1 i I

NH-CH-CH-CH-N-CH-CH ₂ -CH-NH-Q ^b and ^c OH XXXVII

R ²

I

OH

1) -Q ^1b

-p 18b pl9b

UVc-cl ^l> - n J

R ^9a

I

NH - CH - CH - CH - N - CH - CH - CH ₂ -NH ¹ Η Ä Ó OH xxxvni Ŕ ^20b _R 18. _R 19a \ /

Q ^ fNcc-fr · · _r . £ iva. θ _Η . a corrosive agent in b

R ¹ i

R ² i

_R 19b, R 18b

4C-C-N-} ^Q2b0

- 39b Reaction Scheme 4 (cont.)

Method (C)

R ⁹ · i

Q ¹ * —HN —CH -CHO xxxm ^X c = ch ₂ /

M

XXXIX

R ^{9 and} R ¹ , I ¹

QU-hn -CH-CH -C = CHn

I

OH

XL

R ⁹ · i

Q ¹ * —HN —CH

XLI

R ¹ i

CH-C = O 1

OH

O3 * - R ²

H ₂ N — CH — CH — CH ₂ —NH — Q ^1b

XXIX

OH

--►

R ⁹¹ R ¹ R ² , ¹ 'Q ¹ · —HN — CH — CH — CH — NH -CH reductive amination

I OH-CH ₂ -NH-CH I OH

qlh

XXXVI xxxvm smell pcsl. 5 stxprv of line B preparation of XXXIX

R ¹ —CSCH ------ ►

XLH

R ¹ = C = CH ₂

br

XXXIX xun

39c

Reaction Scheme 4 (cont.)

method

R ^9a R ¹ l ^{1 1}

Q-NH-CH-CH-C = O

XLI

OH reductive etc

R ”R ¹ , I ·

Q-NH-CH-CH-CH-NH ₃ i

XLIV

OH

R ^9b R ²

Q ^1b - HN-CH-CH -C = O

OH XLV reductive amination

R ⁹ 'R ¹ R ² R ^9b , l'l |

Q - H - CH - CH - CH - NH - CH - CH - CH - NH - Q ^1b I

OH

XLVI see the last 5 stuprcv

------—>

methods B _R 18a RW * R ^9a R *

Q ² * f · N - C - c + NH - CH - CH - CH

I ii I ·

R ²⁰¹ O ^va OH

R ² - N-CH

I

A ^c

R ^9b 1 -CH-CH 2;

OH

XLVII

Reaction Scheme 4 illustrates methods A to D useful for the preparation of compounds of formula I wherein R ¹ and / or R ² is not hydrogen.

As described in Method A above, selective cleavage of the protecting group (Pro) of compound XXVIII (which compound can be prepared by analogous methods to the above preparation of compound XIII) is carried out when (Pro) is independently selected from the groups defined by for Q ¹ and thereafter the amine XXIX formed is condensed with epoxide VI or chloroketone IV (or the corresponding bromoketone) followed by reduction to amindiol XXX. Alternatively, where ^Ac is hydrogen, may be the central amino group to which it is attached, is protected as described above and the N-terminal of Q a ^and / or Q ^Ib may then be sequentially or simultaneously cleaved and the resulting amine methods described above coupled with N -protected amino acids or peptide chains.

Alternatively, method B may be used to convert the aldehyde XXXIII (see Method B of Reaction Scheme 1) by Wittig or Peterson reaction to olefin XXXIV, which is then epoxidized by methods analogous to those described above (see Reaction Scheme 1, Method B). to compound XXXV. The epoxide XXXV can be condensed with an amine XXIX to form an amidiol XXXVI, which can optionally be protected on a central amine if A ^{c is} hydrogen as above and the N-terminal groups Q ^1a and / or Q ^1b can be sequentially or simultaneously cleaved. and condensation with N-protected amino acids or peptide chains can be performed to form the amidiol XXXVIII.

Aminiol XXXVIII can also be prepared according to the method

C by reacting an aldehyde XXXIII with a vinyl organometallic compound XXXIX wherein M is a metal-containing group such as magnesium bromide, lithium,

CeCl ₂ and the like, to allyl alcohol XL. The double bond can then be cleaved by the methods described above to give the ketone XLI, which can then be subjected to the reductive amination methods described above in the presence of amine XXIX to form compound XXXVI. Compound XXXVI can be converted to amindiol XXXVIII by the methods described above in Method B. Compound XXXIX used in Method C can be prepared from the corresponding acetylene XLII via vinyl bromide XLIII (Pollet et al., Syn. Commun. 10, 805 (1980)). Suzuki et al., Tetrahedron Lett., 24, 731 (1983)).

Alternatively, as shown in the method, subjected to reductive methods in the presence of ammonia to

D, ketone XLI can be amination by the above described formation of amino alcohol XLIV, which can then be subjected to reductive amination in the presence of ketone XLV (method of its preparation see method C) to amindiol XLVI. Optionally, the amindiol XLVI may then be provided with protecting groups which are then sequentially cleaved and condensed with N-protected amino acids or peptide chains as described in Method B to give compound XLVII.

Reaction scheme 5

Preparation of compounds I, wherein R ¹⁰ is hydrogen,

Method (A)

R ⁹ ·

Q ¹ · —HN — CH — COjH ----- ►

Π

R ⁹ *

Qia.-HN - CH

XLvm c — R ¹⁰ »

II o

R ⁹ · qu — πν-- _CH _ _c _ _R io «

II xux ch ₂

Ph ₃ P = CH ₂ epoxidation

Q ^of R / C HN - CH-C-O

R ® »

R ^9b

Q ^1b —HN — CH — CH — CH 2 —NH 2 xxin OH Q ³

OH

Reaction Scheme 5 (cont.)

Method (B)

XLĽX

Os0 ₄

------>

_R 9a

I

Q ^la - HN-CH

ΙΊΠ

RIO.

I — C — ch ₂ —oh I

OH r9. r 10 «• I

Q '—HN — CH — C — CHO

I

OH

LTV

XXVL ------ ► U

LD

Method (C)

T from ^c < ²

CH-C = O

Río.

Q ³ —NH,

------- ►

R9b-CH,

Q ^1b -HN-CH-C-O

LV1 R ^10b

LVD

I

OH

R ^, _8x

R ²⁰ ·

RIO.

NH — CH — C — CH, —N — CH, - ³ OH

R ⁹ "

I

Q ³

D10b p9b

I | R ^{19 b} R ^{18 b}

C-CH-NHF-C-C-N ^ e

OH Q ^{R 2 b}

LVID

Method (D)

LIX

LV ------------- tutorial animation

LVH

LVM

Reaction Scheme 5 illustrates methods A to D that can be used to prepare compounds of Formula I wherein R is not hydrogen.

According to Method A, the protected amino acid II can be converted by known methods (see, for example, Gordon et al., Tetrahedron Lett. 28, 1603 (1987)) to the ketone XLVIII. For example, conversion of amino acid II to methyl pyridyl intermediate intermediate pyridyl ester (Weinrab et al., Tetrahedron Lett. 22, 3815 (1981)) (not shown) and subsequent reaction with an organolithium or organomagnesium compound provides ketone XLVIII. The obtained ketone can then be converted to olefin XLIX by Wittig or Peterson reaction, which can then be epoxidized by the methods described above. The epoxide L thus formed can be condensed with an amino alcohol XXVII to an amindiol LI. Then, optionally, sequentially or simultaneously cleavage of the Q ¹ groups can be accomplished using known methods by condensation with N-protected amino acids or peptide chains to give compound LII.

Alternatively, Method B can be used to convert olefin XLIX directly to cis-diol LIII using osmium tetroxide or potassium permanganate (Kochi et al., Metal Catalyst Oxidations of Organic Compounds, pp. 162-171, 294-296, Academic Press). (1981)) and the diol LIII then oxidized to the aldehyde LIV as described above. The aldehyde LIV can then be subjected to reductive amination in the presence of amino alcohol XXVII to the amidiol LI, which can then be converted to the amidiol LII by the methods described above.

Another route is shown in Method C. According to Method C, epoxide L can be condensed with a primary amine or ammonia Q ³ -NH ₂ by the methods described above to form the aminoalcohol LV, which can be condensed with epoxide LVI (for preparation see Method A) to amindiol LVII. As discussed above, or may be sequentially or simultaneously removing the protective group Q ^1, and the resulting amino groups coupled to N-protected amino acids or peptide chains to give compound LVIII.

As shown in Method D, it is also possible to subject the amino alcohol LV by the above-described reductive amination methods in the presence of the aldehyde LIX (preparation see Method B) to produce the compound LVII, and then also by the methods described above, e.g. to compound LVIII.

Reaction scheme 6

Q

Preparation of compounds I wherein R = hydrogen

Method (A)

LXTV

- 47 Reaction Scheme 6 (cont.)

Method (B) (R ^8a is -CH 2 R ^22a ; R ^8b is -CH 2 R ^22b )

R ⁹ ·

Q ¹ * - HN - CH - CH - CH

I

OH _{2 2} —N — CH ₂ —CH Q ⁴

R ^9b

I - CH - NH - Q ^1b

I OH

XXHIa

9b

I

D -Q "

2) R ^22a —CHO cL ₂ leductive animation

Ŕ ²² ·

I

OH

LXV

_; a detergent

LXVd

Reaction Scheme 6 (cont.)

Method (C) (R ⁸ = CH ₃ )

1) -Q “xxnia ------ * ► o

2) CH ₃ C-O-CH _{2 R} 9a

I I

HN-CH -CH - _CH2-N "CH ₂ -CH CH-NH

_CH3 ^θ Η Q ⁴ and _H

LXV (R ²² = H)

QLB

3) BH ₃ . SMe ₂

taidanzovacie änidlo

LXVI (R ²²¹ = H) see last step of method B h

LXVL (R ^ h)

Reaction Scheme 6 illustrates methods A, B, and C which can be used to prepare compounds of formula I wherein R 0 is not hydrogen.

In Method A, the amino alcohol XVII may be protected as described to give compound LX (Bergmann, Chem. Rev. 53, 309 (1953)) and non-basic alkylated nitrogen (Benoiton et al., Can. J. Chem. 49, 1968 (1971)) with a base such as sodium or potassium hydride, sodium or potassium hexamethyldisilazide and the like, and then, for example, an alkylating agent such as alkyl iodide, bromide, chloride, tosylate, triflate and the like. Q ^a is an activating group, which supplies hydrogen to the nitrogen atom to which they are attached, acidity and light odštiepitelnosť a base, as described above, as a group, forming together with the -N (R) a carbamate or an amide group. The resulting amino alcohol LXI can then be deprotected to form compound LXII, condensed with epoxide XXI or chloroketone XXII (as described above, the corresponding bromoacetone may be used), followed by reduction to amidine diol LXIII as described above, which may optionally be provided with a central amine protecting group and sequential or simultaneous cleavage of Q ¹ groups and condensation with N-protected amino acids or peptide chains to form LXIV.

It is also possible, as shown in Method B, to remove one of the protecting groups Q a ^or Q ^Ib in amíndiole XXII (which may be prepared from amíndiolu XXIII by methods known to those of skill), and to subject the resulting amine of the methods described above by treatment under conditions of reductive amination of the presence of a compound of formula R ²² -CHO wherein R ²² j _is hydrogen or alkyl, to yield LXV. Q ⁴ includes alkyl and the groups included in the definition of Q ¹ . Alternatively, the amine formed can be coupled to LXVI by known methods. Alternatively, a similar process can be performed at the other end of the molecule to form an amindiol, such as LXVII.

In Method C, compounds can be prepared wherein R ⁸ is a methyl group by cleavage of the amidiol XXIIIa protecting group, wherein

Q ⁴ is not formyl, formylation of the resulting amine and reduction of the obtained formamide to a methylated amine using a borane-dimethylsulfide complex (Krishnamurthy, Tetrahedron Lett. 23, 3315 (1982)). The methylated amine LXV (R ^22a = H) can optionally be condensed with an N-protected amino acid or peptide chain to form LXVI (R ^22a = H) and the LXVI compound converted to LXVII (R ^z = H) as described above.

- 51 Reaction scheme 7

Preparation of compounds I wherein p and / or q is not 0

Method (A)

Q ^la HN - (CH jCOjR ²³

Lxvm n9a alk / lava γ

--------- Q ^la HN - (CHL · CH-CO ₂ R ⁹ -X ²³ l

D reduction | lxk

2) cxiciacia

QLA-HN - (CH ₂₎ p -CHO -CH

LXX

1) Wittig

2) mCPBA

R'b

Q ^la HN - _{(CH2) pa} 'CH - CH

CH _{; -N-CH-CH-CH2-NH-Q} ^lb

OH

Q ³ Č) H

LXXn

OH

LXXHI

Reaction Scheme 7 (cont.)

Method (B) _R 9a

I

LXXI Q ³ - ^ Q ¹ * - HN '(CH 2 -CH-CH-CH, -NH

OH Q ³

LXXTV

R ' ^b _{/ C} H ₂

Q ^1b - NH - (CH 2 p 3, -CH-CH-O

LXXV 'R ⁹ · R? B

Q ^u HN - (CH) ^ - CH-CH-CH-N-CH _2, -CH = CH - (CH - NH ~ Q ^lb

OH Q ³ oh

LXXVI

Reaction Scheme 7 (cont.)

Method (C)

BrPh ₃ P-CH ₂ Q 2 -HN-CH-CHO-LXXVn xxxm

Q ¹ * HN - CH - _(CH2)

LXXVm ľxxix

HN-CH- (CH ₂ ) _{q and} -CHO

LXXX

Wittig

-CH = CH - (CH ₂ ) _qa . _I —OH

2) mCPBA

R ⁹ *

I

QU-HN-CH - _{(CH2) q} / L * ²

CH “O

LXXXI xxvn

R ⁹ ', "R" ^b , "I"

Q ^u HN-CH - (CH _{2) q R-CH-CH,} -N-CH, -CH-CH-I &apos; IQ ³ OH

LXXXH • NH — Q ^1b

R '' ^{, 9} 'f

Q ² * fNC-C 4 -NH-CH- (CH ₂ ) _{q and} -CH-CH, -No ^ 1 '1

OH Q ³

R ^9b, R ^18b R _x ^L9b _-CH2 "CH -NH-CH? -C-C-N] y Q _p? H ^2b O ^R2"

LXXXní

- 54 Reaction Scheme 7 (cont.)

Method (D)

Q ³ —NH,

LXXXI ------- = *

LXXXIV

Q ³

R ^% / CH

I / I

QIB-HN-CH - _(CH2) -O-CH _qb

LXXXV í

θ ^Η OH

Q ¹ · —HN-CH - (CH 2 -CH-CH ₂ —N — CH ₂ —CH - (CH ₂ ) _qb Q ³

R ^9b

I

NH-CH

QLB

LXXXV1

method

R ’i

Q ¹ —HN-CH-C

II m o —CHN,

LEI

R '

Q ¹ —HN —CH — CH, —CO 3 H

LXXXVĽ

D reduction

2) oxidation

R ⁹

Q ¹ —HN —CH —CH, —CHO

LXXXVHI

Reaction Scheme 7 explains methods A to E which can be used to prepare compounds of formula I wherein p and / or q is not zero.

In Method A, the amino ester LXVIII (R ²³ may be unsubstituted lower alkyl, aryl or aryl-lower alkyl), wherein p _a = 1-4 and q = 0, alkylated via an enolate anion (formed by reaction of an ester with a base such as lithium diisopropylamide) , lithium bis (trimethylsilyl) amide and the like) by treatment with R ^9a -X, wherein X is halogen, tosylate, mesylate and the like, to form the ester LXIX. The ester can be reduced directly to the aldehyde LXX by diisobutylaluminum hydride or by a two-step conversion to the primary alcohol with a hydric reducing agent and then oxidation to the aldehyde as described above. The aldehyde can be converted directly to epoxide LXXI by reaction with a sulfonium- or arsonium-ylide or a Wittig or Peterson reaction to give the corresponding olefin (not shown) followed by epoxidation as described above. The epoxide may be condensed with an amino alcohol XXVII to form an amidiol LXXII, from which optionally the sequential or simultaneous deprotection may be carried out and condensed with the above-described N-protected amino acids or peptide chains to form LXXIII. The LXVIII starting ester for Method A may be prepared in a manner known per se, for example, by the methods described in J. March, Advanced Organic Chemistry, John Wiley (1985) (see pages 1157-1158).

Method B describes a process for preparing compounds wherein both p a _and P _b > zero. The epoxide LXXI is reacted with ammonia or a primary amine Q ³ -NH ₂ to form compound LXXIV followed by condensation with epoxide LXXV (which can be prepared in an analogous manner to the higher epoxide LXXI) to give compound LXXVI. Optionally, it is then possible to sequentially or simultaneously remove the protecting groups from the compound LXXVI and condense it with the N-protected amino acids or peptide chains as described above.

Method C describes a process for the preparation of compounds wherein q _a = 2-4 and p = zero. Wittig reaction of hydroxyphosphorane LXXXVII with protected aminoaldehyde XXXIII affords an olefin LXXVIII, which can be reduced to saturated alcohol LXXIX under catalytic hydrogenation conditions. After oxidation of the alcohol LXXIX to the aldehyde LXXX, conversion to the epoxide LXXXI can be accomplished by Wittig reaction followed by treatment with m-chloroperoxybenzoic acid (mCPBA). The epoxide LXXXI is then condensed with the amino alcohol XXVII as described above to give the aminediol LXXXII. Optionally, the amino groups may then be sequentially removed and condensed with N-protected amino acids or peptide chains to form compound LXXXII. The starting hydroxyphosphorane LXXXVII can be prepared by reacting the appropriate haloalcohol with triphenylphosphine under standard conditions.

Method D illustrates a method by which compounds where both q a _and q> 1 and p = 0 can be prepared by reacting LXXXI epoxide with ammonia or a primary amine Q-N 1 · 4 to form LXXXIV. This compound can then be condensed with LXXXV epoxide (prepared, for example, by the method used above for the preparation of LXXXI epoxide) to give the aminediol LXXXVI. Optionally, the amino groups may then be sequentially or simultaneously deprotected and may be condensed with N-protected amino acids or peptide chains as described above.

Method E illustrates a process for the preparation of intermediates that can be used in the preparation of aminedioles where q = 1 and p = 0. The intermediate aldehyde LXXXVIII can be prepared by the Arndt-Eistert reaction (Meier and Zeller, Angew. Chem. Int. Ed. Engl. 14, 32 (1975)) of diazoketone III to give the carboxylic acid LXXXVII. Conversion of the carboxylic acid to the aldehyde can be accomplished by reduction and oxidation as described above. The aldehyde can then be converted to the desired aminediol by the method described in Methods C and D.

- 57 Reaction scheme 8

Preparation of compounds I wherein R ⁹ = hydrogen

R ⁹

I

Q'-HN-CH-CO 3 H

Π

1) base

2) R ⁹ '-Y

3) H ₃ O ⁺

Q ¹ -

XC

R ²⁴ -C-R ²⁵

H +

LXXXIX

Reaction Scheme 8 illustrates a process for preparing compounds of Formula Q ·

Where R is not hydrogen.

As shown, the N-protected amino acid II can be converted to acetal LXXXIX, wherein R ¹⁴ and R ²² are independently hydrogen or unsubstituted lower alkyl. By treatment with a base such as lithium diisopropylamide,

R ⁹ '-Y, where Y may be a subsequent reaction with Cl, Br, I or triflate and the compound by hydrolysis of the acetal to form the α-substituted amino acid XC. The amino acid XC can be converted to the aminediols of formula I by the methods outlined in Schemes 1-7. Unnatural optically active α-amino acids can be prepared, for example, by the methods described in Evans et al., J. Am. Chem. Soc. 112, 4011 (1990), and Oppolzer et al., Tetrahedron Lett. 30, 5603 (6009). Alternative methods are also described in Williams, RM, Synthesis of Optically Active α-Amino Acids, Pergamon Press: Oxford (1989).

Reaction scheme 9

Alternative methods of preparation of intermediates

Method (A)

R ⁹ . I

Q-NH-CH-CH = CH ₂

IX

D HOXha _r l

2) base. I / Q Q -HN-CH-CH I

VI

Method (B)

1X bishydroxylation (1H-CH-CH-CH3)

XCI. ^{0H 0H}

Ar) i '

Protect Primary OH

R ²¹ SO ₂ C1 or

ArSO ₂ Cl

Deprotect Primary OH

XCIII

Reaction Scheme 9 (cont.)

Method (C)

HOCH ₂ CH = CHR ⁹ asymmetric / ° \

CHCH ₂ CH - CHR ⁹

XCIV

XCVII + Q ^{* 1 * * * * VI}

XCI Episode Reduction «<---------- Method

XCV n ₃ '

N 3 -CH-CH-CH2

I I

OH OH

XCVI

ID1

XCVI or

1)

CH ₃ -C (OCH ₃ ) ₃

PPTs

V ch ₃ c

XCVIII

2)

CH ₃ COCl (Br, I) or (CH ₃ ) ₃ Si-Cl (Br, I) ⁰

II n ₃ -ch-ch -ch ₂ -occh ₃

Cl (Br, I)

XCIX reduction

R ⁹

I h ₂ n-ch-ch ₂

X / o

Q ^J

VI

Cl

1 '

Reaction Scheme 9 (cont.)

Method (E)

see. XCVI ---------------> c Method (B) Reaction scheme 9

Method (F)

R ⁹ 1 R ⁹ 1) SOC1 ₂ Q ¹ -HN-CH-CH-CH ₂ 1 1 OH OH * "Q ^ H N-CH-CH ₂ CH 2) oxidation / \ x ° / ° XCI 0 0

CXXIV

Intermediates for the preparation of compounds of formula I may also be prepared by Methods A to F according to Reaction Scheme 9.

In this regard, the invention provides a novel process for preparing a halohydrin of the formula

R ⁸ I R ⁹ I R ¹⁰ R ² II 1 Q ¹ - E - N - 1 C I 1 1 -C-CHX I hall 1 R ⁹ 1 OH where Q ¹ , E, R ² , R ⁸ , R ⁹ , R ⁹ And R ¹⁰ are as defined above, especially if Q, R is not the same as R ⁹ (preferably if one of the

substituents R ⁹ and R ⁹ 'hydrogen) and is chlorine or bromine in which an olefin of formula

with HOX2.

The HOX _hal compound for use in the method of the invention may be formed in situ, for example by contacting N-chlorosuccinimide, N-bromosuccinimide, Br ₂ or Cl ₂ with water. The preferred molar ratio of HOX _ha the starting olefin is about 1: 1 to about 3: 1.

In a preferred embodiment, the novel process of the invention further comprises preparing an epoxide of formula

R ⁸ I R ⁹ I R ¹⁰ I R ² I 1 Q ¹ - E - N - 1 C - 1 c - 1 CH 1 \ / R ⁹ ' 0

contacting the aforementioned halohydrin with a base.

The base used may be any basic compound allowing the conversion of a halohydrin to an epoxide such as alkali metal hydroxides (e.g. sodium or potassium), alkali metal hydrides (e.g. sodium or potassium), alkali metal carbonates (e.g. sodium or potassium) or amine bases (e.g. tri-). A preferred base to halohydrin molar ratio is about 1: 1 to about 5: 1.

The temperature used in the said halohydrin and optionally epoxide formation steps is preferably about -78 to about 50 ° C. These steps are preferably carried out in an organic solvent such as dioxane or tetrahydrofuran. During the formation of the epoxide, an alcohol (e.g. methanol) is preferably used, for example by adding to said organic solvent, if the process is carried out in a single vessel, especially if the base is other than the amine base. The time used should be sufficient to form halohydrin and optionally epoxide.

The above novel process of the invention preferably (i.e. at a molar ratio greater than 1: 1) produces halohydrins with a relative stereoconfiguration

R ⁸ R ⁹ R 'R ² , I! ? ia —e — n — c — c— chxm

R ⁹ OH over the corresponding stereoisomers

R ⁹ R ⁹ R <R ^2, T 1 TI

Q - E - N - C - C - CHXhal

R ⁹ 'OH

The above process of the invention, including a preferred additional step of epoxide formation, is therefore particularly preferred when epoxides with relative stereoconfiguration are desired.

R ^{10 2} R 7 IC-CH \ /

R ⁹ 'θ because these compounds are preferably formed with a molar ratio of more than 1: 1 compared to (i.e. in the corresponding stereoisomers r ⁸ R ⁹ R ¹⁰ R ²

I! T I

Q ¹ - E - N - C - c - CH /

R ⁹ '0

Starting olefins can be prepared, for example, according to Luly et al., J. Org. Chem. 52, 1487-1482 (1987).

Method A explains the novel method of the invention. Olephine IX is converted to halohydrin (not shown) by treatment with aqueous bromine or N-bromosuccinimide or N-chlorosuccinimide and then with a base such as potassium carbonate or potassium or sodium hydroxide and the like. to form epoxide VI.

As shown in Method B, olefin IX can be converted by treatment with osmium tetroxide or potassium permanganate or other known methods (Kochi et al., Metal Catalyst Oxidations of Organic Compounds, pp. 162-171, 294-296, Academic Press (1981)). Jacobsen et al., J. Am. Chem., Soc., 110, 1968 (1968); Sharpless et al., J. Org. Chem. 57, 2768 (1992)) to the diol XCI. The diol XCI can be reacted with a sulfonyl chloride (e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride; Ar represents aryl) to the sulfonate XCII; or it is possible to selectively protect the primary hydroxyl group XCI (see Greene, Protective Groups in Organic Synthesis) and the secondary hydroxyl group sulfonylated followed by cleavage of the protecting group from the primary hydroxyl group to form XCIII. The sulfonate esters XCII or XCIII can be independently converted to epoxide VI by treatment with a base such as sodium or potassium hydroxide or an alkylamine base such as triethylamine; the latter reaction with XCIII proceeds with an inversion of the configuration on the secondary hydroxyl group.

In Method C (see Thompson et al., J. Am. Chem. Soc 115, 801 (1993) and Bennett et al., JCS Chem. Commun. 737 (1993)), olefin XCIV can be converted by asymmetric epoxidation (Gao et al. J. Am. Chem., Soc., 109, 5765 (1987)) to epoxide XCV. The starting olefin XCIV can be readily prepared by one skilled in the art by known methods (e.g., Wittig reaction, March, Advanced Organic Reactions, pages 839-841 and pages 845-854 (third edition)). XCV epoxide can be converted to azidodiol XCVI by treatment with an azide anion, for example by reaction with sodium azide and titanium bisisopropoxide (Caron et al., J. Org. Chem. 53, 5185 (1988); Omaka et al., Chem. Lett. 1327 (1986)). Azidodiol can be reduced by the methods described in Reaction Scheme 2, Method E above, to the amidiol XCVII. By protecting the amine by known methods, for example, according to Greene, Protective Groups in Organic Synthesis, compound XCI can be obtained.

Alternatively, according to Method D, azidodiol XCVI can be converted to a mixture of haloacetates XCVIII and XCIX by treatment with 2-acetoxyisobutyryl halide or by treatment with trimethyl orthoacetate and PPT followed by treatment with acetyl halide (e.g. acetyl bromide) or trimethylsilyl halide (e.g. Soc., 95, 4025 (1973); Thompson et al., Ibid 115, 801 (1993); Kolb et al., Tetrahedron 48, 10515 (1992)). The haloacetates XCVIII and XCIX may be treated with a base such as sodium methoxide or sodium or potassium carbonate to form azidoepoxide C. Reduction of azidoepoxide to aminoepoxide C1 followed by amine protection by known methods affords epoxide VI.

Alternatively, according to Method E, azidodiol XCVI can be converted to epoxide C by analogous methods to those described above (Reaction Scheme 9, Method B).

In Method F, the diol XCI can be converted to the CXXIV cyclic sulfate by first treating thionyl chloride to form the cyclic sulfite (structure not shown) and then oxidizing with potassium permanganate or ruthenium chloride / sodium periodate and the like. (Lohray, Synthesis, 1035 (1992); Gao et al., J. Am. Chem. Soc. 110, 7538 (1988)). The compound CXXIV or the intermediate sulfite may be converted to the amidioles by the methods described above for the conversion of epoxides VI and / or XXI.

Reaction scheme 10

Alternative methods for preparing compounds I, wherein A ^and A * = ³ and ^D = D ^ ³

Method (A)

CII

4) R ³ -C-OH

O thiensating agent

Reaction Scheme 10 (cont.)

Method (C)

1) -Q ^la

XVI

2) R ³ (R ¹ -OH

About the reagent reagent

R ^9a , I

R = -C-NH-CH-CH-CH2 NH2

II I reduction · <-----------

(i) cm

2)

XXII reduction cv + A ^C

1) _ _Q ib

2)

CII

Reaction Scheme 10 illustrates methods A to C that can be used to prepare compounds of Formula I wherein A ^a is the same as A ^b and D ^a is the same as D ^b (symmetrical compounds).

According to Method A, one equivalent of bis-amine CXXIV (prepared as XI, where A ^c is replaced by Q ³ ) using the above described coupling reagent such as DCC, EDCI, BOP, BOP-CI, DPPA and the like. (for alternative condensation conditions, see Bodanszky, Principles of Peptide Synthesis, pp. 9-58, Springer-Verlag (1984)) condenses with carboxylic acid (prepared by standard techniques, wherein R ³ is as defined above and is compatible with the conditions used in condensation reaction) to form the amidiol CII. If the bis-amine CXXIV A ^{c is} hydrogen, the central amine to which it is attached may optionally be protected as described above.

According to method B, the process can be carried out gradually. It is to phase separate the group Q a ^and Q ^lb in CXXV (prepared as XXIII where ^Ac replaces ^Q3) and the resulting amine coupled with a carboxylic acid to give the compound CII. When A ^{c is} hydrogen, the central amine to which it is attached may optionally be protected as described above.

Method C begins with removal of the group Q a ^and coupling of the resulting amine with the carboxylic acid to form an azido alcohol CIII. The azido group can be reduced and the resulting amino alcohol CIV condensed with epoxide XXI or haloketone XXI followed by reduction to the amidiol CV (see reaction scheme).

3). The central amine may optionally be protected with A ^c . Cleavage of group Q ^1b and the above condensation with carboxylic acid gives CII.

Reaction scheme 11

Alternative methods for the preparation of compounds I,

CXXV

II is a cross-linking agent

Reaction Scheme 11 (cont.)

Method (B)

R ^9a I

Q ^1a -HN-CH-CH-CH ₂ -N ₃

OH

1)

2)

R ^3a -C -OH

II o

R ^3a -C-NH-CH-CH-CH ₂ -N ₃

II ⁰ OH

XVI

CVII census reagent see Method (C)

------------- ► Scheme 10

R ^9b

I

CVIII

1)

-Q ^lb

2)

^R3b -C-OH

II is a clear agent

CVI

Reaction Scheme 11 (cont.)

Method (C)

OH q23

Q ^la

R ^9a

I

HN-CH-CH-CH2N3

reduction

XXII

R ^19a \ /

N-C-C

I 2 _R 2 ° aq reagent

NH-CH-CH-CH ₂ -N ₃

Q ^2a

\ /

N-C-C reduction

CXI 1) + A ^C 2) -Q ^lb 3) R ³ -C-OH II 0 cross-linking agent R ^9a A ^c 1 R ^9b I 1 1 CH-CH-CH2-N-CH2 1 -CH-CH-NH-CR ³ 11 OH About OH ^υ

CXII

Reaction Scheme 11 (cont.)

Method (D)

Q ^la pl9b _p 18b \ z ^R o R '- _Q 2b

20b J wb la

R ^9a

I

CXIII

1)

2)

CXIV Hydroxyquid _ _Q 2b _R 19b _p 18b ^R \ z ^R -scy OR ^20b J _w b

II

D Cl-C-OR ³

2) -P (removal of protecting groups) n ^19b \ z

R ^18? O

CXV

Reaction Scheme 11 (cont.)

Method (E)

1) R ^{3 is} -N = C = O or

R ³ -NHCOCl

2) ~ P _hyd (cdstransiie protecting groups)

CXVI

Method (F)

CXIV

1)

2) r ³ -c-oh

II o Tarfensic agent removal protecting groups

R ^18? O

CXVII

Scheme 11 illustrates methods A to F, which can be used to prepare compounds of formula I wherein A ^and differing from ¹³ and / or D ^and differs from ^Db (unsymmetrical compound).

According to methods A and B can be prepared unsymmetrical compound Using the method of Scheme 10. In the method A are sequentially cleave the group Q a ^and Q ^b and the resulting amines coupled to carboxylic acids to give the compound of CVI. When A ^{c is} hydrogen, the central amine to which it is attached may optionally be protected as described above. Such compounds can be prepared using Method B from azidoalcohol XVI and by analogous procedures to Method C of Reaction Scheme 10.

According to Method C, unsymmetrical compounds can be prepared by analogous procedures to Reaction Schemes 2, 3 and 10. The method begins with cleavage of the Q group and condensation of the resulting amine with N-protected amino acids or peptide chains to give CIX. The azide group can be reduced and the resulting amino alcohol CX condensed with epoxide XXI or halo ketone XXII followed by reduction according to methods C to E of Scheme 2 to amindiol CXI. Alternatively, it is possible to protect the central amine and cleave the group Q ^1b and condense the resulting amine by analogous procedures to Method A of Reaction Scheme 10 with the appropriate carboxylic acid to give the aminediol CXII.

Method D starts from compound CXIII (prepared as in XXIV, where A ^c replaces Q ³ ), where w = 0 to 4. Hydroxyl groups can optionally be protected, for example, with an ethoxyethyl group as described by Greene, Protective Groups in Organic Synthesis (Phyd indicates a hydroxyl protecting group). The group ^Q2b can then be cleaved and condensed to form the amine CXIV with chloroformate, thereby forming the CXV carbamate after cleavage of the hydroxyl protecting groups. When A ^{c is} hydrogen, the central amine to which it is attached may optionally be protected as described above.

According to Method E, the amine CXIV can be condensed with an isocyanate or carbonyl chloride to form the urea CXVI after cleavage of the protecting groups. When A ^{c is} hydrogen, the central amine to which it is attached may optionally be protected as described above.

According to Method F, the amine CXIV can be condensed using the methods outlined in Scheme 10 with a carboxylic acid to form the amide CXVII after cleavage of the hydroxyl protecting groups. When A ^{c is} hydrogen, the central amine to which it is attached may optionally be protected as described above.

Reaction Scheme 12 ⁼ a Preparation of Compounds I wherein R 1

Substituted (hydroxyphenyl) methyl analog

CXIX

1) R ²⁶ -OH

R ²⁶ -X, CXX base

CXXII

CXX / thesis

CXXI

method

2) -P ^J / R

Reaction Scheme 12 illustrates methods A and B that can be used to prepare compounds of Formula I wherein R is a substituted (hydroxyphenyl) methyl group.

Compound CXVIII, where the nitrogen carries P ^1a or P ¹ (P ¹ denotes a nitrogen protecting group) and wherein the hydroxyl groups are protected (P ² denotes a hydroxyl protecting group), in Method A, can be prepared by methods described by Green, Protective Groups in Organic Synthesis. In particular, said nitrogen and hydroxyl oxygen may be linked by a monocarbon group to form an oxazolidine ring. The phenol can then be reacted with a suitable CXIX alcohol (where R ²⁶ is a lower alkyl group) in the presence of a phosphine (e.g. triphenylphosphine) and a reagent such as diethyl or diisopropylazodicarboxylate to give the substituted phenol CXXI (Mitsunobu, Synthesis, 1). Varasi et al., J. Org. Chem., 52, 4235 (1987).

Alternatively, phenol CXVIII can be reacted with a base such as potassium carbonate, sodium or potassium hydride, sodium or potassium bis (trimethylsilyl) amide, and the like. and a suitable activating alkyl compound CXX, wherein X may be a halogen such as bromine, chlorine or iodine, or with a sulfonate ester such as trifluoromethylsulfonate (ie -O-SO ₂ -CF ₃ ) to form CXXI. Compound CXX can be prepared by methods known to those skilled in the art.

Amino diol CXXI can also be prepared by Method B. To convert phenol CXXII (preparation see Reaction Scheme 1 and Methods A and B in Reaction Scheme 9) to epoxide CXXIII, a method analogous to Method A is used. by analogous procedures to Methods A, B and E of Reaction Scheme 2 and Methods A and B of Reaction Scheme 3.

Compounds of formula I wherein R ¹¹ is not hydrogen may be prepared, for example, by known methods by coupling a hydroxyl protecting group such as those described in Greene.

Reaction Schemes 1 to 12 may be readily modified by one of ordinary skill in the art to prepare particular compounds of the invention. For example, the coupling and deprotection of protecting groups can be conveniently utilized in their preparation.

Preferred compounds of the invention are those containing the following preferred groups:

A ^and A 1 preferably independently represent:

(A) hydrogen (B) alkyl, such as unsubstituted lower alkyl or hydroxyalkyl, (C) a group

^R3 - C - Cl

R ⁴ Z where

Z is sulfur or most preferably oxygen,

^R3 is preferably alkyl such as unsubstituted lower alkyl (e.g. methyl or tert-butyl), arylalkyl (e.g., benzyl), and heterocycloalkyl (e.g., pyridylmethyl or benzimidazolylmethyl) and

R ⁴ is preferably alkyl such as unsubstituted lower alkyl (e.g. methyl) or most preferably hydrogen, (D) a group

R ⁶ O

I r ⁵ - c - o - c where

R ⁵ is preferably hydrogen, carbocyclo (e.g. indenyl), alkyl such as unsubstituted lower alkyl (e.g. methyl, ethyl or tert-butyl) or alkyl substituted with one or more amino, substituted amino (e.g. amino, substituted with formyl, phenyl, benzyl or benzyloxycarbonyl), halogens (e.g. fluorine), aryl (e.g. phenyl), hydroxy (e.g. mono or dihydroxy) or protected hydroxy, heterocyclo (e.g. dihydroindazolyl (optionally substituted with oxo and / or benzyl)), alkoxy (such as unsubstituted) lower alkoxy (e.g. methoxy) or arylkoxy (e.g. benzyloxy)) aryloxy (e.g. phenoxy) or arylaminocarbonyl (e.g. phenylaminocarbonyl); aryl (e.g. phenyl or biphenyl); heterocyclo (e.g., imidazolyl (optionally substituted with trityl and / or phenyl), oxazolyl (optionally substituted with phenyl),

2-furo [2,3-c] pyridinyl, 2-furo [3,2-b] pyridinyl,

2-furo [2,3-b] pyridinyl, quinoxalinyl, benzothiazolyl, quinolinyl, benzimidazolyl (optionally substituted with benzyloxymethyl), pyridyl, indolyl, oxazolidinyl (optionally substituted with oxo), dihydroisoindolyl (optionally substituted with oxo), 1,3-dioxolane (optionally substituted with methyl groups), dihydroquinazolinyl (optionally substituted with oxo group) or benzoxazolyl); or alkynyl (e.g. phenylalkynyl); most preferably R ^{5 is} hydrogen, alkyl (unsubstituted or substituted, preferably hydroxyalkyl), aryl or heterocyclo;

R ⁶ and R ⁷ are preferably hydrogen or alkyl, such as unsubstituted lower alkyl (e.g. methyl) or hydroxyalkyl; or two of R 1, R ⁸ and R ⁷ together with the carbon atom to which they are attached form a carbocyclo group (e.g. cyclobutyl or cyclopentyl (optionally substituted by hydroxy) or indanyl (optionally further substituted by hydroxy or protected hydroxy)) or heterocyclo (e.g. oxetanyl, tetrahydrofuryl (optionally substituted with hydroxy), tetrahydro-1,1-dioxothienyl, tetrahydropyranyl or benzimidazolyl (optionally substituted with methyl));

(E) a group

R ³ - C II z

where

Z is sulfur or most preferably oxygen,

R ³ is preferably H, aryl (e.g. phenyl or naphthyl), alkyl which is unsubstituted (e.g., ethyl or t-butyl) substituted by one or more groups consisting of oxo, hydroxy (e.g., mono- or dihydroxy) or protected hydroxy, aryloxy (e.g. phenoxy or naphthyloxy), alkoxy (e.g. methoxy, benzyloxy or benzimidazolylpropoxy), aryl (e.g. phenyl), heterocyclo (e.g. benzimidazolyl, 1,3-dioxolane (optionally substituted with methyl groups), indolyl, pyridyl or dihydroindazolyl (optionally substituted with oxo) ), oxime, alkoxyimino (e.g. methoxyimino), amino or substituted amino (e.g. benzyloxycarbonylamino), alkylaminocarbonyl (e.g.

N-methylaminocarbonyl), arylaminocarbonyl (e.g. phenylaminocarbonyl), alkylaminocarbonyloxy (e.g. N-methylaminocarbonyloxy) or fluoro (e.g. to form trifluoromethyl); carbocyclo (e.g. cyclopentyl or cyclohexyl) (optionally substituted with methyl and / or hydroxyl groups) or indanyl (optionally further substituted with hydroxy); or heterocyclo (e.g. quinolinyl), pyrrolidinyl (optionally substituted with methyl and / or oxo groups), oxazolidinyl (optionally substituted with methyl and / or oxo groups), dihydroisoindolyl (optionally substituted with formyl), tetrahydrofuryl (optionally substituted with hydroxy and / or methyl groups) or benzimidazolyl) ; most preferably R ^{3 is} carbocyclo or alkyl, wherein the carbocyclo and alkyl groups are substituted, in particular by one or more of hydrogen, aryl, heterocyclo, alkylaminocarbonyl or fluoro (especially to form trifluoromethyl); or (F) a group

R ³ - SO ₂ or

R ³ - SO where

R ³ is alkyl, especially unsubstituted lower alkyl.

The most preferred substituents A ^a or A ^b are the groups (C), (D) and (E) mentioned.

A ^c is most preferably hydrogen. When A ^{c is} other than hydrogen, preferred A ^c groups are alkyl-OC (O) - such as trialkylsilylalkyl-C (O) - (e.g., trimethylsilylethoxycarbonyl), fluorenylalkyl83

O-C (O) - (e.g. fluorenylmethoxycarbonyl) or arylalkyl-O-C (O) - (e.g. benzyloxycarbonyl), arylalkyl (e.g. benzyl) or unsubstituted lower alkyl (e.g. methyl).

E is preferably a single bond or a peptide chain containing 1 or 2 amino acids. Preferred are those amino acids where, in formula _r18 R19 \ /

- N - C - C I

R ²⁰ 0

R ¹⁸ is hydrogen or unsubstituted lower alkyl (e.g. methyl),

R ¹⁹ is hydrogen, aryl (e.g. phenyl) or most preferably lower alkyl, which is unsubstituted (e.g. methyl, isopropyl or tert-butyl) or substituted, in particular by one or more hydroxy (or protected hydroxy), amino, aminocarbonyl, fluorine ( for example to give trifluoromethyl), phenyl or hydroxyphenyl or

R ¹⁸ and R ¹⁹ together with the carbon atom to which they are attached form a cycloalkyl group (e.g. cyclopentyl), and

R ²⁰ is hydrogen or unsubstituted lower alkyl (e.g. methyl).

R ¹ and R ² are most preferably hydrogen. When R ¹ and R ² other than hydrogen, the preferred groups R ^2, and arylalkyl (e.g. benzyl).

R ⁸ is most preferably hydrogen, alkyl, especially unsubstituted lower alkyl (e.g. methyl); R ⁸ and R ⁹ together with the atoms to which they are attached form a heterocyclo group (for example pyrrolidinyl or tetrahydroisoquinolinyl); R ⁸ and R ¹¹ together with the atoms to which they are attached form a heterocyclo group (for example 2,2-dimethyloxazolidinyl); or R ⁸ and A ^a or A ^b (described above) together with the atoms to which they are attached form a heterocyclo group (for example 5,5-dimethyl-2-oxo-oxazolidinyl). Most preferably, R c is hydrogen.

R ⁹ is most preferably alkyl, especially unsubstituted lower alkyl (e.g. sec-butyl or isobutyl) or substituted lower alkyl, especially:

(A) cycloalkyl (e.g. cyclohexylmethyl), (B) heterocycloalkyl, especially heterocyclomethyl (e.g. indolylmethyl, pyridylmethyl or quinolinylmethyl), (C) arylalkenylalkyl, especially when aryl is substituted with an Ar (sub) or (D) arylalkyl group, e.g. phenylethyl or especially groups of the formula - CH

Ar (sub) wherein Ar (sub) is (i) hydrogen, (ii) hydroxy, (iii) alkenyl (e.g. ethenyl), (iv) unsubstituted lower alkyl (e.g. ethyl) or (v) alkoxy, especially unsubstituted lower alkoxy ( for example methoxy), alkoxyalkoxy (for example methoxyethoxy, methoxybutoxy, benzyloxyethoxy or benzyloxypropoxy), hydroxyalkoxy (for example hydroxyethoxy, hydroxypropoxy or hydroxybutoxy), arylalkoxy (for example benzyloxy), heterocycloalkoxy (for example morpholinylpropoxy, morpholinylethoxy, 3-oxoethoxyethoxy), , imidazolylethoxy, 2-oxooxazolidinylethoxy, 3-methyl-2-oxo-imidazolinylethoxy, 2-hydroxy-2-pyridylethoxy), aminoalkoxy (e.g. aminoethoxy) or aminocarbonyloxyalkoxy (e.g. aminocarbonyloxyethoxy), especially when the amino group is unsubstituted or mono- or disubstituted e.g. methyl) or aryl (e.g. tolyl), heterocyclocarbonylalkoxy (e.g. morpholinylcarbonylethoxy, morpholinylcarbonylmethoxy and or piperidinylcarbonylmethoxy), heterocyclooxyalkoxy (e.g. pyridyloxyethoxy), alkoxycarbonylalkoxy (e.g. ethoxycarbonylmethoxy) or

86 carboxyalkoxy (e.g. carboxymethoxy).

When R ^{9 is} other than alkyl, preferred R ⁹ groups are hydrogen, aryl, alkenyl, carbocyclo or R ⁹ and R ⁸ together with the atoms to which they are attached form a heterocyclo group (for example pyrrolidinyl or tetrahydroisoquinolinyl).

Q *

R is preferably hydrogen.

R ³ · ® is most preferably hydrogen. When R ³ · ^{O is} other than hydrogen, preferred groups R ^{10 are} arylalkyl (e.g. benzyl), unsubstituted lower alkyl (e.g. methyl), or R ¹⁰ and R ¹¹ together form a kethoxy group.

R ¹¹ is most preferably hydrogen. When R ^{11 is} other than hydrogen, preferred groups are R ³ · ³ · alkoxyalkyl (e.g. ethoxyethyl), unsubstituted lower alkyl (e.g. methyl), R ¹¹ and R ⁸ together with the atoms to which they are attached form a heterocyclo group (e.g. 2-dimethyloxazolidinyl) or R ¹¹ and R ¹⁰ together form a keto group.

p and q are preferably zero.

Particularly preferred compounds of the invention are the compounds and their salts and / or stereoisomers, prepared as the title compounds

the compounds in the Examples no. 2, 21, 76, 93 104 162 175, 178, 209. 224, 226, 234, 246, 257 162 271. 282. 293 297. 298 304 308. 311. 322, 327, 331 333 334 336, 339. 344. 352. 355, 356 359. 366. 368, 377 and 383.

Industrial usability

Specific proteases mediate functions, such as enzymes that cleave peptide bonds and control or broaden the cleavage of precursors by proteins at the site of living organisms, the biological spectrum to produce active proteins in post-translational processing of polypeptides. For example, retroviral proteases cleave large precursor polypeptides produced in infected cells into smaller protein components or subunits, which then associate into functional viral structures. Because the proteases encoded by the viral genome play a critical role in virus replication, these enzymes are targets of therapeutic agents.

Retroviruses are viruses that contain two copies of their RNA genome, one of which is copied into double stranded DNA using the retroviral reverse transcriptase enzyme (RT). Another retroviral enzyme ribonuclease H is part of the RT protein and facilitates DNA: DNA duplex synthesis. A third retroviral enzyme called integrase cleaves a copy of the double-stranded virus DNA into the chromosome of the host cell. The fourth retroviral enzyme cellular protease is critical in the viral replication process by cleavage

polypeptide precursors with structural proteins. to required enzyme Compounds of the Invention inhibit retroviral protease and thus viral replication and they are especially suitable for treatment

and / or preventing retroviral infections caused by such pathogenic organisms.

Examples of retroviruses encoding proteases whose replication can be inhibited by the compounds of the invention include human HTLV-I and HTLV-II lymphotrophic viruses, human immunodeficiency viruses such as HIV-1, HIV-2 or mutants thereof (AIDS pathogens), feline leukemia virus and simian immunodeficiency virus. Protease inhibition can be determined by the methods described below in the Examples section. Of course, the compounds of the invention, as well as to inhibit the replication of one retrovirus, can be used to simultaneously inhibit the replication of two or more retroviruses.

The compounds of the invention are particularly useful for inhibiting human immunodeficiency virus (HIV) protease and thus for preventing and / or treating HIV infections (HIV-1, HIV-2 and mutants thereof), including the treatment of subsequent pathological conditions such as AIDS.

The HIV protease is a retroviral protease that processes the polyprotein precursor gag into core proteins and the polyprotein precursor pol into reverse transcriptase, integrase and protease itself. HIV protease is essential for the proper processing of these polyproteins and the production of infectious viral particles as protease gene leading to immature morphology.

demonstrates that mutations to non-infectious viral particles Thus, HIV protease inhibition is an attractive object of HIV antiviral therapy.

The use of the compounds of the invention for inhibiting HIV protease includes, but is not limited to, treating a variety of stages of HIV infection, such as treating or preventing AIDS or AIDS related complex (ARC), treating both symptomatic and asymptomatic HIV infected patients and treating actual or potential HIV exposure. For example, the compounds of the invention are useful in the treatment of HIV infection in suspected previous exposure to HIV, for example, in the case of blood transfusion, accidental needle puncture, or contact with patient blood during surgery.

As mentioned above, the compounds of the invention may be useful in the treatment and / or prevention of infections caused by other retroviruses. Examples of human pathogenic retroviruses in addition to human immunodeficiency viruses are HTLV-1 and HTLV-2. Examples of viruses pathogenic to other species are feline leukemia virus and simian immunodeficiency virus.

The invention also encompasses pharmaceutical compositions comprising at least one compound of the invention capable of inhibiting a retroviral protease in an amount to this effective and pharmaceutically acceptable carrier or diluent. The compositions of the invention may be formulated using, for example, conventional solid or liquid carriers or diluents and other pharmaceutical additives of the type suitable for the intended form of application. The compounds may be. administered, for example, orally, i. j. for example in the form of tablets, capsules, granules or powders, parenterally, for example by subcutaneous, intravenous, intramuscular or intranasal injection or infusion (for example in the form of sterile injectable aqueous or non-aqueous solutions or suspensions), nasally, for example in inhalation spray or rectally in the form of suppositories, in dosage units containing non-toxic pharmaceutically acceptable carriers or diluents. For example, the compounds may be administered liposomally.

For oral administration, the compositions may be prepared by known methods of formulating pharmaceutical compositions. As suspensions, for example, they may contain microcrystalline cellulose to increase the volume, alginic acid or sodium alginate as a suspension stabilizer, methylcellulose to increase the viscosity, and known sweeteners or flavoring agents. As immediate release tablets, the compositions of the invention may comprise microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other known excipients, binders, extenders, disintegrants, diluents and lubricants.

For nasal aerosol or inhalation administration, the compositions may be prepared by known methods of formulating pharmaceutical compositions as saline solutions using benzyl alcohol or other suitable preservatives, absorption aids to increase availability, and / or other known solubilizing or dispersing agents.

When administered in the form of injectable solutions or suspensions, the compositions may be formulated by known methods using nontoxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution or other suitable dispersing or wetting and suspending agents. including mono- or diglycerides and fatty acids including oleic acid.

For rectal administration in the form of suppositories prepared by non-irritating glyceride normal in rectal>

by known methods of mixing with a base, such as cocoa esters or solid temperatures, but the cavity and thus release the drug.

may be drug formulations with suitable synthetic polyethylene glycols which are melted and / or melted butter,

The pharmaceutical compositions of the invention may contain the compound or compounds of the invention in an amount effective to inhibit retrovirus replication, preferably in an amount effective to treat and / or prevent HIV infection. An effective amount of a compound of the invention can be determined by one skilled in the art and is an amount of about 1 to about 150 mg / kg of body weight of active ingredient per day. It will be understood that the particular dosage level for a particular subject may vary and depends on various factors including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the species, age, body weight, general health, sex and nutrition of the subject. and duration of administration, frequency of excretion, combination of drugs and severity of a particular condition.

Virus hosts that are preferred subjects for the treatment and / or prevention of retroviral infections preferably include mammalian species such as humans and pets such as dogs, cats and the like. The dosage for an adult human is preferably about 10 to about 50 mg / kg body weight per day and can be administered in a single dose or in divided doses, for example, one to four times daily.

The compounds of the invention may be used alone or in combination with other suitable tetrapeutic agents suitable for the treatment of retroviral infections, for example with other antiviral agents such as AIDS, agents, immunomodulators, antibiotics or vaccines.

Other therapeutic agents may include, but are not limited to: AL-721, interferon beta, (dideoxycytidine), d4T, antiviral agents such as polymanoacetate, ganciclovir, DDC DDI (dideoxyinosine), Foscarnet (trisodium phosphonoformate),

HPA-23, eflornitine, peptide

T (octapeptide sequence),

Reticulose (nucleophosphoprotein),

AZT, ansamycin

LM 427, trimetrexate, UA-001, ribavirin, α-interferon, acyclovir, 3TC, PMEA, nevirapine, pyridinones (e.g. L-697,661), BHAP (e.g. U-90152), α-APA derivatives (e.g. R 18893), TIBO derivatives (e.g. R 82913) and RO 31-8959; immunomodulators such as bropirimine, Ampligen (mismatched RNA), anti-human α-interferon antibody, Colony Stimulating Factor (GM-CSF), CL246,738, IMREG-1, IMREG-2, diethyldithiocarbamate, interleukin-2, inosine pranobex, methionine enkephalin, MTP-PE (muramyltripeptide), thymypentine (TP-5, thymic compound), recombinant erythropoietin, naltrexone, TNF (tumor necrosis factor) and antibiotics such as Pentam 300 (pentamidine isethionate).

In particular, the HIV protease inhibitors of the invention may be used in combination with other antiretroviral therapies in the treatment of AIDS. Such combination therapies may include, but are not limited to, combinations of a compound of the invention with other (e.g., inhibitors other than the invention) HIV protease inhibitors (e.g., RO 31-8959); nucleoside and non-nucleoside reverse transcriptase inhibitors such as nevirapine, pyridinones (e.g. L-697,661), BHAP (e.g. U-90152), α-APA derivatives (e.g. R 18893) and TIBO derivatives (e.g. R 82913); tat inhibitors, for example RO24-7429; drugs that inhibit the binding of the virus to CD ₄ receptors; RNase inhibitors, intergase or rev, and immunomodulators such as IFN-α (α-interferon).

Said compounds used in combination with the compounds of the invention are used, for example, in the amount indicated in the respective medical manual or as determined by the skilled person.

For example, said combination therapies may be performed simultaneously or sequentially.

The invention also provides methods of inhibiting retroviral proteases by contacting the respective protease with a compound of the invention capable of such inhibition, and in particular treating and / or preventing retroviral infections. Treatment and / or prevention of human immunodeficiency virus infection is preferred. The methods of the invention preferably comprise the step of administering to the subject in need thereof an effective amount of one or more compounds of the invention capable of treating and / or preventing a retroviral infection. Other therapeutic agents, such as those mentioned above, may be used in conjunction with the compounds of the invention.

The compounds of the invention are also suitable for the preparation of other compounds of formula I. For example, one compound of the invention may be used in the preparation of another compound of the invention which has a higher activity against the same or different retrovirus than the parent compound.

DETAILED DESCRIPTION OF THE INVENTION

The invention is explained in connection with the following

examples the preparation of the compounds according to the invention but which are not

intended to limit the scope or spirit of the claims. The following abbreviations are used in the examples:

ph phenyl Bn benzyl tBu tertiary butyl Me methyl et ethyl ts tosyl (p-toluenesulfonyl) bz benzoyl Phe phenylalanine wall valine TMS trimethylsilyl TBS or TBDMS t-butyldimethylsilyl FMOC fluorenylmethoxycarbonyl Teoc trimethylsilylethxoycarbonyl Boe tert Cbz or From carbobenzoxy (or carbobenzyloxy or benzyl- oxycarbonyl THF tetrahydrofuran Et ₂ O EtOAc diethyl ether ethyl acetate DMF dimethylformamide MeOH methanol EtOH ethanol i-PrOH isopropanol t-BuOH t-butanol DMSO dimethyl sulfoxide DME 1,2-dimethoxyethane HMPA hexamethylphosphoric triamide

HOAc or AcOH acetic acid

TFA trifluoroacetic acid

a) compound 1a (iv)

i) a solution of diazomethane-Et ₂ 0

To a mixture of 40% aqueous KOH (75 mL) and Et ₂ O (255 mL), cooled to 0 ° C, was added portionwise 1-methyl-3-nitro-1-nitroguanidine (23.85 g, 162.2 mmol). ). The mixture is mixed several times during each addition. After 10 min, the resulting yellow Et ₂ O layer was decanted through 0 ° C KOH and dried at 0 ° C for 2.0 h.

(ii) Compound 1a (ii)

To the solution

N-Boc-L-phenylalanine (14.34 g,

54.05 mmol) in dry THF (80 mL), cooled to -20 to -25 ° C (bath dry ice-CCl ₄ ) is added over 5 min isobutyl chloroformate (7.01 mL, 54.05 mmol) then 4 mL. -methylmorpholine (5.94 mL, 54.05 mmol) and stirred for 20 min. The white precipitate was filtered off under argon and washed with about 70 mL dry THF. The combined tetrahydrofuran mixed anhydride solution was cooled to -5 ° C and poured into a pre-prepared solution of diazomethane in Et ₂ O at 0 ° C. The resulting yellow solution was left at 0 ° C for 2.0 h and then at room temperature overnight. The solution was then purged with H ₂ O (300 mL) and a nitrogen residue was bubbled through the brine for min to give a yellow residue, overnight over P ₂ O ₅ ^per %) of the title α-diazoketone used immediately in the purification reaction.

Concentration and drying over g (94

The substance (400 dried and then Et ₂ O (400 mL), mL) was added, saturated NaHCO ₃ (300 mL) over anhydrous MgSO ₄ . Vacuum which was triturated with high vacuum hexane gave 14.72 as a pale yellow solid, in the next step without further purification.

Claims (2)

light blue solution, min, then bubbled for 15 min Over 5 min, was added dropwise in hexane (10.4 mmol) and then stirred for 1 h at -78 ° C and then recooled to -78 ° C and allowed to cool to -78 ° C. warmed to (5.0 mL), Et ₂ O (100 mL) filtered and concentrated by flash chromatography (SiO ₂ , hexane-EtOAc from 1: 1 to 1: 4 to give%) as a yellowish oil. A solution of mmol) in CH ₂ Cl ₂ (10.0 mL) was bubbled into the solution for 15 min. The solution was stirred at -78 ° C 30 N ₂ until the blue color disappeared. DIBAL-H (10.4 mL, 1.0 M solution) The solution was a solution (3.0 mL). with brine The mixture was stirred for 2 h, an oil which was subjected to a gradual gradient of 355c (0.234 g, 35) 10 ml dry hexane. 2 h at -20 ° C Then, MeOH room temperature was added dropwise and MgSO ₄ (15 g) was added. vacuum on 100 yellow ml) d) Compound 355d Compound 355c (0.331 g, 1.31 mmol) and Compound 175c (0.183 g, 0.655 mmol) were treated with DEAD (0.228 g, 1.31 mmol) and Ph ₃ P (0.343 g, 1 H) at room temperature for 24 h. 31 mmol) in THF. The solution is concentrated in vacuo and absorbed onto celite. Flash chromatography (100 mL SiO ₂ ) with hexane-EtOAc gradient from 95: 5 to 1: 1 gave 355d (0.301 g, contaminated with 1,2-dicarbethoxy546 hydrazine, isolated only one of the two possible diastereomers) as a light yellow viscous oil . e) Compound 355e Compound 355d (0.301 g) was dissolved in anhydrous THF and n-Bu ₄ NF.H ₂ O (0.204 g, 0.779 mmol) was added at room temperature. The yellow solution was stirred for 1.5 h. The volatiles were removed in vacuo and the residue was purified by flash chromatography (SiO ₂ , 100 mL) using a 1: 1 to 1:10 hexane-EtOAc gradient to give 355e (0.096 g, for 2 steps 37%) as white solid. f) Compound 355f Compound 355e (0.030 g, 0.075 mmol) and compound 16b (0.025 g, 0.090 mmol) were heated at 60 ° C in MeOH (0.20 mL) for 4 h. The volatiles were removed in vacuo and the residue was purified rapidly 547 chromatography on SiO ₂ (100 mL) eluting with a gradual gradient of CH ₂ Cl ₂ -MeOH-NH ₄ OH from 99: 1: 0.1 to 92: 8: 0.8 to give a white solid (0.026 g, 52 %). This material was further purified by preparative HPLC (Polymer Labs PLRP-S column, 25 x 300 mm, particle size 10 µmη, step gradient A: B from 70:30 to 40:60, A = H ₂ O-MeCN-NH ₄ OH 90: 10: 0.2, B = MeCN-H ₂ O-NH ₄ OH 90: 10: 0.2) and then lyophilized from dioxane-H ₂ O to give the title compound 355f (0.021 g, 41%) as white solid (single diastereomer of undetermined configuration). Melting point: 68-72 ° C (dec.); [α] _D = -4.0 ° (c = 0.10, MeOH) MS (FAB): (M + H) &lt; ^{+ &gt}; = 681. Example 356 Preparation of 1,1-dimethylethyl ester (1S- [1R *, 2S * (2S *, 3 R *)]] [3 - [[3 - [(2,4-dihydroxy-2,3,3-trimethyl-l-oxobutyl) amino] -2-hydroxypropyl 4-phenylbutyl] amino] -2-hydroxy-1- (phenylmethyl) propyl] carbamic acid, Isomer A (Compound 356b) a) Compound 356a HO. A solution of CH ₃ MgCl (3 M in THF, 14.32 mL, 43 mmol) was added at -78 ° C to a solution of dihydro-4,4-dimethyl-2,3-furanedione (5 g, 39 mmol) in 30 mL THF. The mixture was allowed to warm to room temperature, diluted with Et ₂ O, and diluted HCl was added. The organic layer was washed with sat. NaHCO ₃ , dried (MgSO ₄ ) and concentrated in 50 mL THF, a solution of LiOH (583.4 mg, 24.3 mmol) in 25 mL water was added and the mixture was refluxed for 24 h. The mixture was concentrated, the residue was dissolved in 30 mL of water, washed with Et ₂ O, and the aqueous layer was lyophilized to give 3.0 g of a light solid. This material (1.0 g) was dissolved in 5 mL of water which was taken up in vacuo 548 acidified with 10% HCl, extracted with EtOAc and the organic phase dried _(MgSO4), concentrated, and the residue was purified with 0.815 g of compound 356A as colorless oil. b) Compound 356b (single isomer per *) A mixture of compound 54 (200 mg, 0.45 mmol) and compound 356a (129.8 mg, 0.90 mmol) in 1 mL of dry DMF was heated at 100 ° C for 14 h and at 145 ° C for 2 h, concentrated and the residue concentrated. The residue was purified by flash chromatography to give a 1: 1 mixture of two diastereomers (per *). This material was subjected to preparative TLC (silica gel plates 0.5 mm / CH ₂ Cl ₂ -MeOH-NH ₄ OH 9: 1: 0.1, developed twice) to give the title compound 356b (11 mg, 4) as the slower eluting isomer. , 1%) as a white solid. Melting point: 73-75 ° C; [ _α ] _D = + 8 ° (c = 0.15, MeOH); R _f (SiO ₂₎ 0.23 (CH ₂ Cl ₂ -MeOH-NH ₄ OH 8: 2: 0.2); MS: 588 (M + H) &lt; ^{+ &gt};. Example 357 Preparation of [1S- [1R *, 2S * (2S *, 3R *)] - 1,1-dimethylethyl ester] - [3 - [[3 - [(2,4-dihydroxy-2,3,3-trimethyl-1- oxobutyl) amino] -2-hydroxy-4-phenylbutyl] amino] -2-hydroxy-1- (phenylmethyl) propyl] carbamic isomer B (Compound 357) 549 Compound 357 (white solid) was isolated as the slower eluting isomer of preparative TLC as shown in Example 356b. Melting point: 71-75 ° C; R _f (SiO ₂₎ 0.20 (CH ₂ Cl ₂ -MeOH-NH ₄ OH 8: 2: 0.2); MS: 588 (M + H) &lt; ^{+ &gt};. Example 358 Preparation of [1S- [1R *, 2S * (2S *, 3R *)] 1,1-dimethylethyl ester]] [3 - [[3 - [[(1,1-dimethylethoxy) carbonyl] amino] -2-hydroxy- 4- [4- (2-hydroxy-2-methylpropoxy) phenyl] butyl] amino] -2-hydroxy-1- (phenylmethyl) propyl] carbamate, (Compound 358b) a) Compound 358a Compound 346a was reacted with CH ₃ MgBr analogous 550 following Example 158a to give compound 358a b) Compound 358b Compound 358a the allowed react with compound 16b analogous procedure than in the example 226b to create the title Compound 358b (white solid agent). Melting point: 85-88 'C; (a) _D = -4.5 " (c = 0.11, CH ₃ OH) MS (FAB): (M + H) = 632; Example 359 Preparation of [1R *, 2S * (2S *, 3R *)] - N- [2-hydroxy-3 - [[2-hydroxy-3 - [[(2-hydroxy-1,1-dimethylethoxy) carbonyl] amino] -4] -phenylbutyl] amino] -1 (phenylmethyl) propyl] -N ^2- (2-methoxycarbonyl) -3-methyl-L-valinamide (Compound 359b) a) Compound 359a 551 To a solution of 246a (0.036 g, 0.191 mmol) in 3 mL of 0 ° C CH ₂ Cl ₂ was added HOBT hydrate (0.035 g, 0.261 mmol) then EDCI (0.037 g, 0.191 mmol). The mixture was stirred for 0.5 h at 0 ° C, then compound 333b (0.1 g, 0.174 mL) was added followed by N-methylmorpholine (0.058 mL, 0.522 mmol) and 0.5 mL DMF. The resulting solution was stirred at room temperature for 20 h. The mixture was diluted with EtOAc and washed with sat. NaHCO ₃ and brine. The organic phase was dried _(MgSO4) and concentrated in vacuo. The obtained residue was subjected to flash chromatography on silica gel eluting with a gradual gradient of CH ₂ Cl ₂ -MeOH-NH ₄ OH 98.9: 1: 0.1 to give compound 359a (0.096 g, 74%) as a white solid. MS (FAB): (M + H) &lt; ^{+ &gt}; = 745. Solution of compound 359a (0.095 g, 0.127 mmol) in 3 mL HOAc-THF-H ₂ O 3: 1: 1 was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and subjected to flash chromatography on silica gel eluting with a successive gradient of CH ₂ Cl ₂ -MeOH-NH ₄ OH 98.9: 1: 0.1 to 89: 10: 1 to give a solid which triturated twice with Et ₂ O to give compound 359b (0.07 g, 87%) as a white solid. Melting point: 93-104 C; [α] _D = -21.2 ⁰ (c = 0.2, CH ₃ OH). MS (FAB): (M + H) &lt; ^{+ &gt}; = 631. Elemental analysis for C ₃₃ H ₅₀ N ₄ O ₆ .3.03H ₂ O: H, 8.24; N, 8.18. Found: C, 57.92; H, 7.66; N, 8.09. Example 360 Preparation of [1S- (1R *, 2S *)] - [Iminobis [2-hydroxy-1- (phenylmethyl) -3,1-propanediyl]] - bis [carbamic acid 1,1-dimethylethyltetrahydro-1,1-dioxo-3-thienyl ester ] (Compound 360c) a) Compound 360a Compound 360a was prepared from tetrahydrothiophen-3-one in two steps using the procedure of Dodda et al., J. Heterocyclic. Chem., 27, 1453 (1990). b) compound 360b Compound 360a was converted to compound 360b in an analogous manner to Example 149d. c) Compound 360c (1: 1 mixture of isomers) 553 Compounds 360b and 54 were converted to the title compound 360c (white solid) in 13% yield in a manner analogous to Example 147d (DMF used only). Melting point: 197-201 ° C; MS (FAB): 606 (M + H) &lt; ⁺ &gt; ^. Elemental analysis for C ₃₀ H ₄₃ N ₃ O ₈ S: calculated: 59.49%, H 7.15, N 6.94, S 5.29, found C 59.44, H 7.17, N 7.07, S 5.23. Example 361 Preparation of [1S- [1R *, 2S * (2S *, 3R *)] - 1,1-dimethylethyl ester] [3 - [[3 - [[(2,2-dimethyl-1-hydroxy-cyclohexyl) carbonyl] amino] 2-Hydroxy-4-phenylbutyl] amino] -2-hydroxy-1- (phenylmethyl) propyl] carbamate, Isomer A (Compound 361b) a) Compound 361a HO COOH The 2,2-dimethylcyclohexanone is converted to compound 361a by a three-step procedure analogous to the preparation of compound 321c. b) compound 361b rs = \ (single isomer per * unspecified absolute stereochemistry) 554 Compound 361a was reacted with compound 54 in a manner analogous to Example 321d. The crude product is chromatographed on a 2.5 x 25 cm silica gel column as follows: 1% MeOH / CH ₂ Cl ₂ , 2% MeOH / CH ₂ Cl ₂ , 2.5% MeOH / CH ₂ Cl ₂ , 3-4.75 MeOH / CH ₂ Cl ₂ + 0.3-0.75% NH 4 OH in increments of 0.25%, respectively.