AP597A - Retroviral protease inhibitors. - Google Patents

Abstract

The invention relates to certain retroviral protease inhibitors,

Description

RETROVIRAL PROTEASE INHIBITORS

TECHNICAL FIELD

The invention relates to certain hydrocarbon derivatives bearing polar substituents and their use in the inhibition of retroviral proteases, for example in the 5 treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS). The invention also relates to processes for preparing such hydrocarbon derivatives bearing polar substituents, to pharmaceutical compositions comprising them and to methods for the treatment or prophylaxis of retroviral infections. The invention also relates to a process for enhancing the water-solubility of a pharmaceutical or veterinary substance.

io BACKGROUND ART

Human immunodeficiency virus (HIV) is a pathogenic retrovirus causing AIDS and its related disorders. The development of antiviral chemotherapy against AIDS has been the subject of an intense research effort since the discovery of HIV. (For a recent review on molecular targets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533i5 1544). The HIV Proteases (HIV PR), and aspartyl proteases, were first suggested as a potential target for AIDS therapy by Kramer et al. (Science 231, 1580 (1986)). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al. Chimica Oggi, May 1991, pp 6-27 and Huff J.R., J. Med. Chem. 34, 20 2314-2327 (1991)). Of the classical transition state mimics for aspartyl proteases, the hydroxy ethylene, dihydroxyethylene, hydroxyethylamine and phosphinic acid isosteres appear to provide the greatest affinity for HIV PR, Many inhibitors of HIV PR have been shown to have an antiviral activity at concentrations in the nanomolar range in the different cell systems and are described as such in the patent literature.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide compounds useful as retroviral protease inhibitors. It is another object of the present invention to provide pharmaceutical compositions comprising compounds useful for the treatment or prophylaxis of retroviral infections. It is a further object of the present invention to provide methods for the treatment or prophylaxis of retroviral infections, in particular AIDS. Other objects of the present invention are to provide processes for preparing compounds useful as retroviral protease inhibitors, and processes for enhancing the water-solubility of pharmaceutical or veterinary substances, in particular retroviral protease inhibitors.

SUMMARY OF THE INVENTION

The invention provides compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which *9 9 0 0 06 /d/dV

AP.00597 are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome.

In the following description of the invention, the teaching of each of the publications mentioned is incorporated herein by reference.

In a broad form the invention is directed to compounds of the general formula (I) or pharmaceutically acceptable salts or prodrugs thereof:

W-(A)_n-B-(A*)_m-V (I)

More particularly, in a first embodiment of the invention there are provided compounds having the structure represented by formula (IA):

Rl · Ri 9 Ri 9*

I I I

Ro-n-c-b‘-c-_{Yi (IA)}

R-13 Rl3* wherein Rj* is selected from the group consisting of R_b P(O)(OR₇)R₈, S(O)_ZOR₇ and S(O)_zNR₇R₈, wherein z is 1 or 2 and R₇ and R₈ independently have the meaning of R20 as defined below, or R₇ and R₈ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, wherein:

Rj is selected from the group consisting of R$ and a solubilising group Px which is labile in vivo, wherein Rg is selected from the group consisting of hydrogen, R₂q as defined below, C(D)OR2i, C(D)SR2i, C(D)NR₂₁R₂₂, C(NR₂₁)R₂₂, C(NR₂i)OR₂₂, and C(NR₂i)NR₂₂R₂₃, wherein R₂i, R₂₂ and R₂₃ independently are selected from hydrogen and R₂o> or R₂i and R₂₂ together, or R₂₂ and R₂₃ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, wherein D is O or S;

r/P/ 94 / 0 0 6 67

Px is selected from the group consisting of Px*,

.Px* ^R , and wherein D is O or S, R is H or C_rC4 alkyl, and wherein Px* is selected from:

AP.00597

R20 is selected from the group consisting of optionally substituted (Ci-Ci8)alkyl, optionally substituted (C₂-C₁₈)alkenyl, optionally substituted (C₂-C^alkynyl, optionally substituted (Cj-Cjgjcycloalkyl, optionally substituted ^-CigjcycloalkyKCj-C^alkyl, optionally substituted (C3-C₁₈)cycloalkyl(C₂-Cig)alkenyl, optionally substituted (C3-Cjg)cycloalkyl(C₂-Ci₈)alkynyl, optionally substituted (Cg-C^jaryl, optionally substituted (C₆-C₂₄)aryl(C_rC₁₈)alkyl, optionally substituted (C₆-C₂₄)aryl(C₂-Cig)alkenyl, optionally substituted (Cg-C₂₄)aryl(C₂-Cjg)alkynyl, optionally substituted (Cj-Cig)acyl, optionally substituted heterocyclic, optionally substituted heterocyclic(Ci-Cj₈)alkyl, optionally substituted heterocyclic(C₂-Cj₈)alkenyl, and optionally substituted heterocyclic(C₂-C 1 g)alkynyl;

R₁₀ and R₁₂ independently have the meaning of Rg as previously defined;

R₁₂* and R₁₃* are independently selected from the group consisting of F, Cl, Br, I and R₅ wherein R5 is selected from the group consisting of H, CF₃, C(D)OR₁q3,

C(D)SRiq3 C(D)NRiq₃Ri₀₄ and R₂q as previously defined, wherein D is as previously defined, and wherein R|q₃ and R^ have the meaning of Rg as previously defined, or Riq₃ and Rjo₄ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein;

Ri₃ is selected from the group consisting of

F, Cl, Br, I, Rg as previously defined, and R₂₀₀, wherein R₂oo is selected from the group consisting of CN, NCO, NCS, OCN, SCN, N₃, ORgQ, SRgg,

DiC(D₂)Rgo, D[C(D₂)D3RgQ, DjCfD^NRgoRgi, NR$oC(Di)R$i,

AP/P/ 94 / 0 0 6 67

AP.00597 ’ NReoCiDJN^!^, NR₆₀OR₆], amidino, guanidino, S(O)R60, S(O)₂DjRgQ, S(O)NR₆₀R₆₁, S(O)2NR₆₀R₆₁, DiS(O)R^q,

DjS(0)₂ORgo. D₁S(O)NR₆₀R₆₁, D_lS(O)₂NR₆₀R₆₁, P(D₁)(D₂R₆₀)R₆₁,

P(D₁)(D₂R_6o)D₃R₆₁, P(D₁)(D₂R₆₀)NR₆₁R₆₂, P(Di)R₆₀R₆,, D₁P(D₂)(D₃R₆₀)R₆₁,

D₁P(D₂)(D₃R₆₀)D₄R₆₁, D₁P(D₂)(D₃R₆o)NR₆₁R₆₂, DjPfD^jRgQRgj,

NR^qNR^jR^ and ONR^qR^j, wherein Dj, D₂, D₃ and D₄ independently have the meaning of D as previously defined, and Rg₀, Rgj and Rg₂ independently have the meaning of Rg as previously defined or any two or more of Rg₀, R₆₁ and R₆₂ form part of a saturated or unsaturated cyclic, bicyclic or fused ring io system as defined herein;

or R₁₂ and R₁₃ together are selected from the group consisting of =0, =S, = C

X = NORg0, =NRgo, -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (Cj-CjJalkylidene as defined herein and Rg₀ and R₆₁ are as previously defined;

is B* is selected from the group consisting of

				M |	ZM	m2 | *
ZM	Mt I '	m2	D II	* —c— I	—Ο- Ι	1 —Ο- Ι
I -N— —	I -N—	I — N— 9 ,	II —c	- ’ Rl4*	Rl4 4 9	Rl4
0 / \ c-c— I I Rl4*Rl4					OR18	SRi8
Rl4	*x.r/Rl4** 4	R14*	. Z*M - Co ,-CC. 4	I -ο- ι OR-|g , and	I —Ο- Ι sr19

AP/P/ 9 4 / 0 0 6 67 o

wherein:

2o R_l4* and R₁₄** are independently selected from the group consisting of hydrogen, R₂₀ as previously defined, CF₃, C(D*)OR₄q, C(D*)SR₄q and C(D*)NR₄₀R₄₁, wherein R₄₀ and R₄₁ independently have the meaning of R₂₁ and R₂₂ as previously defined or R₄q and R₄₁ form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

R₁₄ is selected from the group consisting of F, Cl, Br, I, R₁₄* as previously defined and R₂qq as previously defined,

Z is a saturated or unsaturated (C₂-C₄)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R₁₄* as previously defined,

AP.00597 c

o

Z* is a saturated or unsaturated (C₁-C3)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R₁₄* as previously defined,

Mj is selected from the group consisting of OR₁₅, SR₁₅ and NR₁₅R₁₇, wherein R15 is selected from the group consisting of:

Px as previously defined,

R^ as previously defined, •Px .D.

Px

Px ^D , ^R , wherein Px and D are as previously defined and R is H or C_rC₄ alkyl, and a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and

R₁₇ has the meaning of Rg as previously defined, or

Rj₅ and Ri₇ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

M and M* are independently selected from the group consisting of as previously defined, OCN, SCN, YR₇, Y* and N = CR3oR3j, wherein Y, Y* and R2 are as defined below, and R30 and R₃₁ independently have the meaning of R20 as previously defined,

M₂ is selected from the group consisting of R₁₄* as previously defined, -CR₃₀*=Y** and -CR3q* = NR₁₇*, where Y** is as defined below, R₃₀* has the meaning of R₂o as previously defined, and R₁₇* has the meaning of Rg as previously defined,

R^ and Rig independently have the meaning of R20 as previously defined or Rig and R19 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

Y is absent or is selected from<the group consisting of:

AP/P/ 94 / 0 0 6 67

	0'	0-
•N=N—	—N=N —	—N=N
	+ »	+
0	0	O
II	II	II
N-S —	—N-S —	—0—s-
1	1 II	II
R50	R50O	0

II

-S-N—

I

R50

II

-S-N— II I ^{0 R}50

II —o-s—

II —s-o

AP.00597

O

II —s-o—

II o

ί o

II —O-P-N—

I I ^R5lO ^R50

O

II —p-Ν— R51O R

O

II —s-s—

II »

o

II —N-P —

I I ^R50O^R51

II

-N-P— I I

R50OR51

II —s-s—

II

-N-P-ΟΙ I ^R5oC*^R51

II

-ρ—o—

D**R —s-s—

II —p-oOR₅₁

O

II —P-N — I I ^R5lO ^R50

-o0

II

-P — or₅,

O

II

-O-P—

D‘*R₅₂ and

-o-p-oD**R wherein D** is selected from the group consisting of a bond, O, S and NR50, R50 has the meaning of R$ as previously defined, R₅₁ has the meaning of Rj5 as previously defined and R₅₂ has the meaning of R₂q as previously defined, or R₅₀ and R₅₁, when present, together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and

R₂ has the meaning of R$ as previously defined,

Y* is selected from the group consisting of

— N-N-Rr — N- 1 1 4 1	z R33 N=C	—N—0—R2*	—o-n-r2.
R50 R51	R50 5	R34 J	R50	R50
0 II —s=o —s=o -	0 II —s=nr117.	D“R115 I	Rl14*
R114*	R114*	R114*	— P=D* , I	— P=D* and I
»			Rl14**	R114**

— N=O < /00667 wherein D* and D** independently have the meaning of D as previously defined; Rji4*, R114**, Rj 15 and R117* have the meaning of R₁₄*, R₁₄**, R_l5 and R₁₇* respectively, as previously defined; R₅q and R₅₁ are as previously defined or R₅₀ and R₅₁ together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein; R₂* is selected from the group consisting of R₂ as previously defined, Px as previously defined, S(O)_zOR₁₂₀ and S(O)_zNR₁₂₀R₁₂₁, wherein z is 1 or 2; R33 and R34 are independently selected from the group consisting of hydrogen and R₂q as previously defined, or R33 and R34 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and R₁₂q and R121 independently have the meaning of R₂q as previously defined, or R₁₂o and R₁₂₁ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

R30 is as previously defined, and

AP.00597

Y** is selected from =N-NR[₁₅Ri₁7 and = N-OR₁₁₅, wherein R₁₁₅ and R₁₁₇ have the meaning of R^ and R^ respectively, as previously defined, or Rl 15 and Rjp together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and

Y1 is selected from the group consisting of

-N-N-R,·

I I * R50 R51 —n-o-r₂

I ^R5O —O-N-R, and wherein R₅q, R51 and R₂* are as previously defined;

and wherein any group selected from Rj, Ri*, R₂, R₂*, R9, Rjj, Rj₂, R13. R50 and R51 10 may, together with any other group selected from Rj, Rp, R₂, R₂*. R9*, R₁₀, Rp, R₁₂, R13, R50 and R₅₁ form one or more saturated or unsaturated cyclic, bicyclic or fused ring system(s) as defined herein, and wherein any tertiary amino nitrogen atom may be replaced by the group Ν—ό , and, wherein any hydroxyl, mercapto or amino group may be protected by a 15 protecting group which is labile in vivo·, provided that the compound of formula (IA) comprises at least one solubilising group Px, as previously defined or, wherein the compound of formula (IA) includes two functional groups capable of being derivatised by a solubilising group Px, said two functional groups being in sufficiently close proximity to one another, comprising a cyclic structure including a structural unit selected from:

O

C> OH

X —χ; x₂°x^H

-Xi X,0 0 X

-χ; xzand ^Xly'° p^-OH -X^ OH

AP/P/ 94 / 0 0 6 67 wherein Xj and X₂ are independently selected from O, S and NR₆ wherein R5 is as previously defined.

As used herein, the term (Cj-C^alkyr includes within its meaning straight and 25 branched chain alkyl groups having from 1 to 18 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dime thy lbutyl, 2,2-dimethylbutyl,

3.3- dimethylbutyl, 1,2-dimethy lbutyl, 1,3-dimethy lbutyl, 1,2,2-trimethylpropyl,

1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl,

3.3- dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl,

1.4- dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, octyl, 6-methyIheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexvl, decyl, 1-, 2-,

1,3-dimethy lpenty 1, 1,1,3-tr imethy lbutyl,

AP. 00597

3- , 4-, 5-, 6-, 7- or 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyIoctyI, 1-, 2-, 3- or

4- propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5, 6- or 7-ethyInonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or

8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1- or 2-pentylheptyl, tridecyl, tetradecyl, hexadecyl, octadecyl and the like.

As used herein, the term (C₂-C₁₈)alkenyl includes within its meaning ethylenically mono-, di- or poly-unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkenyl groups are io vinyl, allyl, l-methyl vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-l-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,

4-pentenyl, 1,3-pentad ienyl, 2,4-pentadienyl, 1,4-pentadienyl, 3-methyl-2-butenyI,

1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1,3-octadienyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, is 1-decenyl, 3-decenyl, 1-undecenyl, oleyl, linoleyl and linolenyl.

As used herein, the term (C2-Cig)alkynyl includes within its meaning mono-, di- and poly-acetylenically unsaturated alkyl groups having from 2 to 18 carbon atoms, and may be straight-chain or branched. Examples of such alkynyl groups are ethynyl, propynyl, n-butynyl, n-pentynyl, 3-methyl-l-butynyl, n-hexynyl, methyl-pentynyl and

2o (C₇-C₁₂)alkynyl.

As used herein, the term (C₃-C^cycloalkyl refers to otionally unsaturated mono-, di- or polycyclic alkyl groups having from 3 to 18 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, 25 cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, eye looc tad ienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, (C9_C₁₂)cycloalkynyl, bicyclo[2.2. ljheptanyl, bicyclo[2.2. ljheptenyl, bicyclo[2.2.1]heptadienyl, bicyclo(2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[3.3.1]nonyl, bicyclo[3. l.OJhexyl, bicyclo[4.1.0]heptyl, bicyclo[3.2. ljoctyl, bicyclo[3.3.0]octyl, bicyclo30 [3.3.0]octenyl, bicyclo[3.3.1]nonyl, bicyclo[4.4.0]decyl, adamantyl, tricyclo[5.2.1.0²’⁶]decyl and the like.

As used herein, the term (C3-Cig)cycloalkyl(C₁-C₁₈)alkyl refers to a (C_rC₁₈)alkyl group as defined above, substituted with a (C3-C₁₈)cycloalkyl group as defined above. Examples of cycloalkylalkyl groups include cycloalkyl-loweralkyl groups, 35 such as cycloalkylmethyl, cycloalkylethyl, cycloalkylpropyl, cycloalkylbutyl, cycloalkylisopropyl, cycloalkylisobutyl, cycloalkylpentyl and cycloalkylhexyl, wherein the cycloalkyl is as exemplified in the preceding paragraph.

As used herein, the term (C₃-Ci₈)cycloalkyl(C₂-C₁₈)alkenyl refers to a (C₂-C₁₈)alkenyl group as defined above, substituted with a (C3-C₁₈)cycloalkyl group as

AP/P/ 9A/00667

AP.00597 defined above. Examples of cycloalky lalkenyl groups include cycloalkyl-loweralkenyl groups, such as cycloalkylethenyl, cycloalkylpropenyl, cycloalkylbutenyl, cycloalkylisobutenyl, cycloalkylpentenyl and cycloalkylhexenyl, wherein the cycloalkyl is as exemplified above under (Cj-C^cycloalkyl.

As used herein, the term ^-C^cycloalkyl^-Cjgjalkynyl refers to a (C2-C₁g)alkynyl group as defined above, substituted with a (C₃-C|g)cycloalkyl group as defined above. Examples of cycloalkylalkynyl groups include cycloalkyl-loweralkynyl groups, such as cycloalky Iethynyl, cycloalkylpropynyl, cycloalky lbutynyl, cycloalkylpentynyl and cycloalkylhexynyl, wherein the cycloalkyl is as exemplified above io under (C₃-Cig)cycloalkyr.

As used herein, the term (Cg^^aryl refers to single, polynuclear, conjugated and fused residues of aromatic hydrocarbons having from 6 to 24 carbon atoms. Examples of such groups are phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, acenaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, 15 dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, indanyl, azulenyl, chrysenyl and the like. In all cases, any available position of the fused or conjugated bicyclic system can be used for attachment to the remainder of the molecule of formula (IA).

As used herein, the term (C₆-C24)aryl(Ci-Cjg)alkyl refers to a (CpCjgjalkyl 20 group substituted with one or more (C6-C24)aryl groups as previously defined. Examples of such groups are aryl-loweralkyl groups such as arylmethyl, arylethyl, arylisopropyl, arylpropyl, arylbutyl, arylisobutyl, arylpentyl and arylhexyl, wherein the aryl is as exemplified in the preceding paragraph, such as benzyl, diphenylmethyl, 2-phenylethyl, 1-phenylethyl, naphthylmethyl, 3-phenylpropyl, triphenylmethyl, 1,3-diphenylpropyl, 225 or 3-P-naphthylpropyl, 2-benzyl-propyl and the like.

As used herein, the term (C7-C25)aralkyl refers to an alkyl group substituted with an aryl group, wherein the total number of carbon atoms in the aryl-substituted aikyl group is from 7 to 25. Optional substituents for (C₇-C₂5)aralkyl are as defined below with respect to (Cg^^arylfCpC^gjalkyl.

As used herein, the term (Cg^^aryKCpCjgjalkenyl refers to a (Cj-C₁₈)alkenyl group substituted with one or more (Cg^^aryl groups as previously defined. Examples of such groups are aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under (Cg^^aryl such as styryl, cinnamyl, 2-naphthylethenyl, l-phenyl-2-methyl-l-propenyl, 2-phenyl-2-butenyl and the like.

As used herein, the term (Cg-C26)aralkenyl refers to an alkenyl group substituted with an aryl group, wherein the total number of carbon atoms in the arylsubstituted alkenyl group is from 8 to 26. Optional substituents for (Cg-C26)aralkenyl are as defined below with respect to (C6-C₂4)aryl(C₂-C₁₈)alkenyl.

AP/P/ 94 / 0 0 6 67

AP.00597

As used herein, the term (C₆-C24)aryl(C₁-C₁₈)alkynyr' refers to a (Cj-Cisjalkynyl group substituted with one or more (C6-C₂4)aryl groups as previously defined. Examples of such groups are aryl-loweralkenyl groups such as arylethenyl, arylpropenyl, arylbutenyl, arylisobutenyl, arylpentenyl and arylhexenyl, wherein the aryl is as exemplified above under (C₆-C₂4)aryl such as phenylethynyl and the like.

As used herein, the term (C₈-C₂6)aralkynyl refers to an alkynyl group . substituted with an aryl group, wherein the total number of carbon atoms in the arylsubstituted alkynyl group is from 8 to 26. Optional substituents for (C₈-C₂6)aralkynyl are as defined below with respect to (C6-C₂4)aryl(C₂-C₁₈)alkynyl. io As used herein, the term (Cj-C^jacyl refers to a group R₃₀₀C(O)- or

R₃OoC(S)-, wherein R₃₀₀ is selected from the group consisting of hydrogen, (C_rC₁₈)alkyl, (C₂'C₁₈)alkenyl, (C₂-C₁₈)alkynyl, (C₃-C₁₈)cycloalkyl (C₃-C₁₈)cycloalkyl(C_rC₁₈)alkyl, (C₃-C₁₈)cycloalkyl(C₂-C₁₈)alkenyl, (C₃-C ₁₈)cycloalkyl(C₂-C₁₈)aikynyl, (C₆-C₂₄)aryl, (C₆-C₂4)aryl(C_rC₁₈)alkyl, (C₆-C₂4)aryl(C₂-C_lg)alkenyl, (C₆-C₂₄)ar>'l15 (C₂-C₁₈)alkynyl, heterocyclic, heterocyclic(Ci-C₁₈)alkyl, heterocyclic(C₂-C₁₈)alkenyI, and heterocyclic(C₂-Ci₈)alkynyl.

Examples of acyl groups include Ioweralkylcarbonyl such as formyl, acetyl, propionyl, butyryl; loweralkenylcarbonyl such as pivaloyl, acryloyl, vinylacetyl, crotonoyl, 3-pentenoyl, 4-pentenoyl; and loweralkynylcarbonyl such as propioloyl, 220 butynoyl and 3-butynoyl, any of which may be substituted with cycloalkyl, aryl or heterocyclic as exemplified herein, as, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 1-cyclopentenylcarbonyl, cyclopentylacetyl, cyclohexylcarbonyl, l-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl, cyclohexylacetyl, cyclohexenylacetyl, l,4cyclohexadienylacetyi, bicyclo[2.2.1]hept-2-ylcarbonyl, bicyclo25 [2.2,l]heptylacetyl, bicyclo[2.2.1]hepten-2-ylcarbonyI, bicycIo[2.2.2]oct-2-ylcarbonyl, bicyclo[2.2.2]octylacetyl, bicyclo[2.2.2]octyl-3-propionyl, bicyclo[2.2.2]octen-2-ylcarbonyl, -bicyclo[3.3.1]non-9-ylcarbonyl, bicyclo[3.3.l]non-9-ylacetyl, bicyclononyl-3propionyl, bicyclo[4.4.0]dec-2-ylcarbonyl, bicyclo[4.4.0]dec-2-ylacetyl, 1-adamantylcarbonyl, 2-adamantylcarbonyl, 1-adamantylacetyl, 2-adamantylacetyl, tricyclo[5.2.1.0²>⁶]dec-8-ylacetyl, benzoyl, phenylacetyl, diphenylacetyl, triphenylacetyl,

3-phenylpropionyl, dibenzylacetyl, a-naphthoyl, β-naphthoyl, α-naphthylacetyl, βnaphthylacetyl, indenylcarbonyl, indanylcarbonyl, phenanthrenylcarbonyl, 9-fluorenylcarbonyl, pyrrolylcarbonyl, pyrrolylacetyl, furylcarbonyl, furylacetyl, thienylcarbonyl, thienylacetyl, pyrazinylcarbonyl, pyrazinylacetyl, pyrrolidinylcarbonyl, pyrrolidinyl35 acetyl, pyridylcarbonyl, pyridylacetyl, pyrimidinylcarbonyl, pyrimidinylacetyl, piperidylcarbonyl, piperidylacetyl, piperazinylcarbonyl, piperazinylacetyl, morpholinylcarbonyl, morpholinylacetyl, thiomorpholinylcarbonyl, thiomorpholinylacetyl, indolylcarbonyl, indolylacetyl, quinolylcarbonyl, quinolylacetyl, isoquinolylcarbonyl, isoquinolylacetyl, quinoxalinylcarbonyl, benzofuranylcarbonyl, benzofuranylacetyl, indolinylcarbonyl,

AP/P/ 94 / 0 0 6 67

AP.00597 indolinylacetyl, 1,2,3,4-tetrahydroquinolylcarbonyl, 1,2,3,4-tetrahydroquinolylacetyl,

1.2.3.4- tetrahydroisoquinolylcarbonyl, 1,2,3,4-tetrahydroisoquinolylacetyl, cyclohexylacryloyl, cinnamoyl, styrylacetyl and phenylpropioloyl.

As used herein, the term heterocyclic refers to any saturated or unsaturated 35 to 16-membered monocyclic, bicydic or polycyclic ring containing one or more heteroatom independently selected from oxygen, nitrogen and sulphur. The term heterocyclic includes any group in which a heterocyclic ring is fused to one or more benzene, naphthalene or cycloalkane rings. Sulfur-containing heterocyclics may be substituted at sulfur with one or two oxygen atoms. Examples of heterocyclics are io pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl, perhydropyridazinyl, pyrazolyl, pyrazoldinyl, 2,3,5,6-tetrahydropyrazinyl, phthalazinyl, 1,2,3,4-tetrahydrophthalazinyl, f perhydrophthalazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl, piperidyl, tetrahydrofuryl, imidazolyl, oxazolyl, thiazolidino, oxazolidinyl, isoxazolyl, is isothiazolyl, isoxazolidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolinyl, benzothienyl, benzisoxazolyl, benzo isothiazolyl, benzothiadiazolyl, tetrazolyl, triazolyl, thiadiazolyl, benzimidazolyl, pyrrolinyl, quinuclidinyl, 1,4-thioxanyl, 1,3-thioxanyl, azanorbomyl, isoquinuclidinyl, pyranyl, furazanyl, azepinyl, ΙΗ-indazolyl, 2,3-dihydro-lHindazolyl, quinoxalinyl, cinnolyl, 1,2,3,4-tetrahydrocinnolinyl, pteridinyl, naphthyridinyl,

2o 4H-quinolizinyl, benz[e]indolyl, benzoxazinyl, benzoxadiazolyl, benzothiazinyl, benzotriazolyl, carbazolyl, β-carbolinyl, l,2,3,4,5,6-hexahydro-p-carbolinyl, phenanthridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl, thiatriazolyl, , oxadiazolyl, thiadiazolyl, chromanyl, thiachromanyl, isochromanyl, chromenyl, cyclohexa[b]pyrrolyl, cyclohepta[b]pyrrolyl, cyclohexa[d]pyrazolyl, cyclohexa[b]pyridyl,

3) 25 cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl, cyclohexa[b]-l,4-oxazinyl, cyclohexa[b]1.4- thiazinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperazinyl, thiomorpholinyl, S,Sdioxo-thiomorpholinyl, indolinyl, S,S-dioxo-l,2,3-benzothiadiazolyl, S,S-dioxo-l,2thioxanyl, S,S-dioxo-1,4-thioxanyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, hexahydroquinolyl, hexahydroisoquinolyl, l,2,3,4-tetrahydro-3,l-benzodiazinyl, 3,4-dihydro-3H-4,l-benzoxazinyl, 3,4-dihydro-3H4,1-benzothiazinyl, 2,3,4,5-tetrahydro-lH-5,l-benzazepinyl and 5,6-dihydrophenanthridinyl and the like.

Configurations which result in unstable heterocyclics are not included within the scope of the definition of heterocyclic or saturated or unsaturated cyclic, bicydic or fused ring system.

As used herein, the term heterocyclic(Ci-C₁₈)alkyl refers to a (Cj-C^Jalkyl group as previously defined, which is substituted with a heterocyclic group as previously defined. Examples of such groups are heterocyclic-loweralkyl groups such as heterocyclicmethyl, heterocyclicethyl, heterocyclicisopropyl, heterocyclicpropyl, heterocyclicZ.9900/V6 Idl'dV

AP. 00597 butyl, heterocyclicisobutyl, heterocyclicpentyl and heterocyclichexyl, wherein the heterocyclic is as exemplified in the preceding paragraph.

As used herein, the term heterocyclic(C₁-Cig)alkenyl refers to a (Ci-Cig)alkenyl group as previously defined, which is substituted with a heterocyclic 5 group as previously defined. Examples of such groups are heterocyclic-loweralkenyl groups such as heterocyclicethenyl, heterocyclicpropenyl, heterocyclicbutenyl, heterocyclicisobutenyl, heterocyclicpentenyl and heterocyclichexenyl, wherein the heterocyclic is as exemplified above under heterocyclic.

As used herein, the term ”heterocyclic(Ci-Cig)alkynyl refers to a io (C₁-C₁g)alkynyl group as previously defined, which is substituted with a heterocyclic group as previously defined.

As used herein, the term alkylidene refers to divalent radicals derived from alkyl groups. Examples of such radicals are -CH?-, -CH2CH2-, -CH=CH-,

-CH2CH2CH2-, -C( = CH₂)CH₂-, -CH₂CH=CH-, -(CH₂)₄-, -ch₂ch₂ch=ch-,

-CH?CH = CHCH₂- and -(CH₂)_r- where r is 5-12. The term also refers to such radicals in which one or more of the bonds of the radical from part of a cyclic system, and to such radicals wherein one or more carbon atoms is replaced by O, S or NH. Examples of such radicals are groups of the structure

AP/P/ 94/0 0667

AP.00597

ί > » 1 » J

Ν.

Ο'

Ν=>

— Ν

£9 9 0 0 / i 6 /d/dV and similar groups, including those shown above wherein any N or O atom is replaced by S.

io As used herein the term saturated or unsaturated cyclic, bicyclic or fused ring system refers to a stable cyclic system of up to 16 carbon atoms, wherein said ring system may contain: for 3- and 4-membered rings, one heteroatom; for 5-membered rings, one or two heteroatoms; for 6- and 7-membered rings, one to three heteroatoms; for 8- and 9-membered rings, from one to four heteroatoms; for 10- and 11-membered is rings, from one to five heteroatoms; for 12- and 13-membered rings, from one to six heteroatoms; for 14- and 15-membered rings, from one to seven heteroatoms; and for 16-membered rings, from one to eight heteroatoms; the heteroatom(s) being independently selected from oxygen, nitrogen and sulphur; which ring system may be substituted with one or more substituents independently selected from: R^q and a group T, where R150 has the meaning of R20 as previously defined, and where T is selected from the group

AP.00597 consisting of -F, -Cl, -Br, -I, -CF₃, -CN, -NCO, -NCS, -OCN, -SCN, -OR’, -NR'R, -NR'C(O)R, -NR'C(O)OR, -NR'C(O)NRR’, -NO?, -SR', -S(O)R’, -S(O)?R', -S(O)OR', -S(O)₂OR', -S(O)NR'R. -S(O)₂NR’R”, =0, =S, =N₂, = NOH, = NOR’, -NR’OR’, -CHO, -OC(O)R', -OC(O)OR’, -OC(O)NR'R”, -C(O)R’, -C(O)OR',

-C(O)NR'R, -OC(S)R', -OC(S)OR', -OC(S)NR’R, -C(S)R', -C(S)OR’, -C(S)NR’R”, -SC(O)R', -SC(O)OR', -SC(O)NR'R, -C(O)SR', -SC(S)R', -SC(S)OR’, -SC(S)NR'R, -C(S)SR’, -C( = NR’)OR, -C( = NR')SR”, -C(=NR’)NRR', -OS(O)R’, -OS(O)₂R’, -OS(O)OR'. -OS(O)₂OR’, -OS(O)NR'R”, -OS(O)?NR'R, NR'S(O)₂NRR',

-NR'S(O)?R, -NHC( = NH)NR’, -C( = NH)NR’, -P(O)(OR')R, -P(O)(SR')R,

-P(O)(OR')OR, -P(O)(OR')NRR', -P(O)R'R, -OP(O)(OR’)R”, -OP(O)(OR’)OR”, -OP(O)(SR’)OR, -OP(O)(OR')NR”R', -OP(O)R'R”, and R’, R” and R’” are , independently selected from the group consisting of hydrogen, (C₁-C₁₈)alkyl, typically (C,-C₁₂)alkyl; (C₃-C₁₈)cycloalkyl, typically (C₃-C₁₂)cycloalkyl; (C₃-C₁₈)cycloalkyl(C_rC₁₈)alkyl, typically (C₃-C₁₂)cycloalkyl(C_rC₆)alkyl; (C₆-C₂4)aryl, typically is (C₆-C₁₆)aryl; (C₆-C₂₄)aryl(C_rC₁₈)alkyl, typically (C₆-C₁₀)aryl(C_rC₆)alkyl; (C₂-C₁₈)alkenyl, typically (C₂-C₁₂)alkenyl; (C₆-C₂₄)aryl(C₂-C₁₈)alkenyl, typically (C₆-C₁₀)aryl(C₂-C₆)alkenyl; (C₂-C₁₈)alkynyl, typically (C₂-C₁₂)alkynyl; (C₆-C₂₄)aryl(C₂-C₁₈)alkynyl, typically (C₆-C₁₀)aryl(C!-C₆)alkynyl, heterocyclic, heterocyclic(C₁-C₁₈)alkyl, typically heterocyclic(C!-Ci₂)alkyl, heterocyclic(C₂-Ci₈)alkenyl, typically heterocyclic(C₂-C₁₂)20 alkenyl and heterocyclic(C₂-C₁₈)alkynyl, typically heterocyclic(C₂-C₁₂)alkynyl, and wherein R’, R and R’” may be optionally substituted with up to six groups independently selected from hydroxy, (C_rC₆)alkoxy, (C_rC₆)aryloxy, (C_rC₆)thioalkoxy, (C₁-C₆)thioaryloxy, (Ci-C₆)alkoxy(C_rC₆)alkoxy, amino, (C_rC₆)alkylamino, di(C[-C,5)alkylamino, fluoro, chloro, bromo, iodo, carboxy and (C₁-C₆)alkoxycarbonyl. θ 25 Examples of saturated or unsaturated cyclic, bicyclic or fused ring systems are the heterocyclic and cyclic alkylidene groups exemplified above.

As used herein, the term optionally substituted (Cj-Cj^alkyl refers to a (C!-C₁₈)alkyl group as defined above wherein one or more hydrogen atoms are replaced by one or more substitutents T as previously defined.

Examples of substituted (C_rC₁₈)alkyl groups include hydroxy-Ioweralkyl such as hydroxymethyl, hydroxyethyl and 3-hydroxypropyl; loweralkoxy-loweralkyl such as methoxymethyl, 2-methoxyethyl, 2,2-dimethoxyethyl and 3-methoxypropyl; aryloxyloweralkyl such as phenoxy methyl, phenoxyethyl, α-naphthyloxymethyl and β-naphthyloxyethyl; arylloweralkoxy-Ioweralkyl such as benzyloxymethyl, benzyloxyethyl and

3-benzyloxypropyl; halo-loweralkyl such as chloromethyl, trifluoromethyl, 2-fluoro-, 2-chloro-, 2-bromo- or 2-iodo-ethyl, 2,2,2-trifluoro-ethyl, 2,2,2-trichloro-ethyl, 3-chloropropyl and 3-bromopropyl; amino-loweralkyl such as aminomethyl, 2-aminoethyl, 3aminopropyl, 5-aminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl and 3-phenylaminopropyl; carboxy-loweralkyl such as carboxymethyl, carboxyethyl and 3-carboxyAP.00597 propyl; acylloweralkyl such as acylmethyl, acylethyl, acylpropyl, acylisopropyl, acylbutyl, acylisobutyl, acylpentyl and acylhexyl wherein the acyl is as exemplified above under (Cj-C₁₈)acyl; acyloxy-loweralkyl such as acetoxymethyl, acetoxyethyl,

2- acetoxypropyl, 3-acetoxypropyl, propionyloxyethyl and 3-propionyloxypropyl; lower5 alkylcarbonylamino-loweralkyl such as acetylaminomethyl, acetylaminoethyl, 2-acetylaminopropyl, propionylaminomethyl and propionylaminoethyl; loweralkylaminocarbonylamino-loweralkyl, such as dimethylaminocarbonylaminoethyl; sulfonyl-loweralkyl such as methylsulfonyl-methyl, ethylsulfonyl-methyl, tert-butylsulfonyl-methyl, phenylsulfonylmethyl, phenylsulfonylethyl, 4-toluenesulfonylethyl and 4-toluenesulfonylmethyl; cyanoio loweralkyl such as cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyano-propyl, 2-cyanobutyl, 3-cyanobutyl and 4-cyanobutyl; oxo-loweralkyl such as 2-oxo-propyl, 2-oxo-butyl,

3- oxo-butyl, 2-, 3- or 4-oxo-pentyl and 2,4-dioxo-pentyl; and loweralkyl groups substituted with two or more than different substitutents as exemplified above.

As used herein, the term optionally substituted (Ci-Cjg)alkenyr' refers to a is (Ci-Cig)alkenyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defined.

As used herein, the term optionally substituted (C j-Chalky nyl refers to a (Cj-Cjgjalkynyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents T as previously defined.

As used herein, the term optionally substituted (C3-C₂4)cycloalkyl refers to a (C3-C24)cycloalkyl group as defined above wherein one or more hydrogen atoms are replaced by a substituent or substitutents independently selected from R^IV and T as previously defined, wherein R^IV is selected from (Ci-C₁₈)alkyl, (C2-Cig)alkenyl, (C₂-C₁₈)alkynyl, (C₃-C_I8)cycloalkyl, (Cj-C^cycloalkyfrCj-C^alkyl, (C₃-C₁₈)cycloQ 25 alkyl(C₂-C₁₈)alkenyl, (C₃-C₁₈)cycloalkyl(C₂-C₁₈)alkynyl, (C₂-C₁₈)acyl, (C₆-C₂4)aryl(C2-Ci₈)acyl, heterocyclic, heterocyclicfCj-Cigjalkyl, heterocyclic(C₂Ci₈)alkenyl, and heterocyclic(C₂-Ci₈)alkynyl, and wherein R^IV may be substituted with up to six groups independently selected from hydroxy, amino, (Ci-Cg)alkoxy, (CpCgjalkoxyCCpCgjalkoxy, amino, (Cj-Chalkylamino, diiCj-C^alkylamino, fluoro, chloro, bromo, iodo, carboxy and (C^-C^alkoxycarbonyl.

As used herein, the term optionally substituted (C3-C₂4)cycloalkyl(Ci-C₁₈)alkenyl refers to a (C3-C₂4)cycloalkyl(C₁-C₁₈)alkenyl group as defined above which are substituted in the cycloalkyl group by a substituent or substitutents independently selected from the substituents defined above for (C3-C₂4)cycloalkyl, and/or substituted in the alkenyl group by one or more substituents T as previously defined.

As used herein, the term optionally substituted (C3-C₂₄)cycloalkyKCpCjgjalkynyl refers to a (C3-C₂4)cycloalkyl(Ci-Ci₈)alkynyl group as defined above which are substituted in the cycloalkyl group by a substituent or substitutents

AP .00597 independently selected from the substituents defined above for (C3-C₂4)cycloalkyl, and/or substituted in the alkynyl group by one or more substituents T as previously defined.

As used herein, the term optionally substituted (C<5-C₂4)aryl refers to a (Cg-C24)aryl group as defined above wherein one or more hydrogen atoms are replaced 5 by a substituent or substitutents independently selected from R^v and T*, wherein T* is selected from the group consisting of -F, -Cl, -Br, -I, -CF₃, -CN, -NCO, -NCS, -OCN, -SCN, -OR', -NR'R, -NR'C(O)R”, -NR’C(O)OR”, -NR'C(O)NR”R', -NO₂, -SR', -S(O)R', -S(O)₂R', -S(O)OR’. -S(O)₂OR', -S(O)NR'R, -S(O)₂NR’R”, -NR'OR’, -CHO, -OC(O)R’, -OC(O)OR', -OC(O)NR'R, -C(O)R', -C(O)OR', -C(O)NR'R, 10 -OC(S)R', -OC(S)OR’, -OC(S)NR'R”, -C(S)R', -C(S)OR', -C(S)NR’R”, -SC(O)R', -SC(O)OR', -SC(O)NR'R, -C(O)SR’, -SC(S)R', -SC(S)OR', -SC(S)NR'R, -C(S)SR', -C(=NR')OR, -C( = NR')SR, -C(=NR')NRR’, -OS(O)R', -OS(O)₂R', -OS(O)OR', -OS(O)₂OR', -OS(O)NR'R, -OS(O)₂NR'R, NR'S(O)₂NR”R', NR’S(O)₂R,

-NHC( = NH)NR', -C(=NH)NR', -OP(O)(OR')R, -OP(O)(OR')OR,

OP(O)(SR')OR, -0P(O)(0R')NRR', -OP(O)R'R, and R', R and R' are as defined above with respect to the substituent T; and wherein R^v is selected from (C_rC₁₈)alkyl, (C₂-C₁₈)alkenyl. (C₂-C₁₈)alkynyl, (C₃-C₁₈)cycloalkyl, (C₃-C₁₈)cycloalkyl(C_rC₁₈)alkyl, (C₃-C₁₈)cycloalkyl(C₂-C₁₈)alkenyl, (C₃-Ci₈)cycloalkyl(C₂-C₁₈)alkynyl, (C₂-C₁₈)acyl, (C₆-C₂₄)aryl(C₂.C₁₈)acyl, heterocyclic, heterocyclic(C_rC₁₈)alkyl, heterocyclic(C₂-C₁₈)alkenyl, and heterocycIic(C₂-C₁₈)alkynyl, and wherein R^v may be substituted with up to six groups independently selected from hydroxy, amino, (C_rC₆)alkoxy, (C_rC₆)aryloxy, (C_rC₆)thioalkoxy, (C₁-C₆)thioaryloxy, (C_rC₆)alkoxy(C_rC₆)alkoxy, amino, (Cj-C^alkylamino, di(C₁-C₆)alkylamino, fluoro, chloro, bromo, iodo, carboxy and (Cj-C^alkoxycarbonyl. The term optionally substituted (C₆-C₂₄)aryl includes mono-, di- and polysubstituted (C₆-C₂₄)aryl groups.

Examples of substituted aryl groups are loweralkyl-aryl, loweralkenyl-aryl, arylloweralky 1-arylloweralkylcarbonyl-aryl, heterocyclic-aryl and heterocyclicloweralkyl-aryl wherein the aryl group is as exemplified above; halo-aryl such as 4-chlorophenyl,

2,4-dichlorophenyl, l-chloro-2-naphthyl and 4-chloro-l-naphthyl; hydroxy-aryl such as

2-hydroxyphenyl, l-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 2-hydroxy-8-naphthyl, 3,4,5-trihydroxyphenyl and 2,4,5-trihydroxyphenyl; loweralkoxyaryl such as 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl and 1-methoxy-2-naphthyl; carboxyaryl such as 2-carboxy-phenyl, 2-carboxy-l-naphthyl, l-carboxy-2-naphthyl and 9carboxy-2-anthracyl; acyfaryl, wherein the acyl group is as exemplifed above under (C_rCi₈) acyl, such as 4-formyIphenyl, 4-acetylphenyl, 2-benzoylphenyl, 2-methoxycarbonyl-phenyl, 2-ethoxycarbonyl-l-naphthyI, l-methoxycarbonyl-2-naphthyl, 9-methoxycarbonyl-2-anthracyl, 2-carbamoyl-phenyl, 2-carbamoyl-l-naphthyl, l-carbamoyl-2-naphthyl, 4-dimethylaminocarbonyl-phenyl, 4-morpholinocarbonylphenyl,

4-(2-pyridylmethoxy)carbonyl-phenyl and 4-benzyloxycarbonyl-phenyl; nitro-aryl such as

AP/P/ 9 4 / 0 0 6 67

AP.00597

4-nitrophenyl and 2,4-dinitrophenyl; amino- or (substituted amino)-aryl such as 4-aminophenyl, 2,4-diaminophenyl, 4-dimethylaminophenyl, 4-aniIinophenyl, 2-(2,6dichloroanilino)-phenyl, 2,4-di-(benzyloxycarbonylamino)-phenyl and 4-(2-quinolinecarbonylamino)-phenyl; and cyano-aryl such as 4-cyanophenyl, as well as aryl groups substituted with two or more of the substituents exemplified above.

As used herein, the term optionally substituted (Cg-C^jaryKCi-Cjgjalkyl refers to a (C₆-C₂4)aryl(C₁-C₁₈)alkyl group as previously defined substituted in the aryl group with one or more substitutents defined above for (Cg-C^jaryl and/or substituted in the alkyl group with one or more substitutents defined above for (C[-Cig)alkyl. io Examples of such groups are (substituted aryl)-lower-alkyl such as (substituted aryl)methyl, (substituted aryl)ethyl, (substituted aryl)propyl, (substituted aryl)iso-propyl, (substituted aryl)butyl, (substituted aryl)pentyl and (substituted aryl)hexyl, aryl(substituted loweralkyl) such as phenyl(substituted loweralkyl), naphthyl(substituted loweralkyl), biphenyl(substituted loweralkyl), tetrahydronaphthyl(substituted loweralkyl), indenyl15 (substituted loweralkyl) and indanyl(substituted loweralkyl), and (substituted aryl)(substituted loweralkyl), wherein in each case substituted aryl is as exemplified above with respect to optionally substituted (C₆-C₂₄)aryl and (substituted loweralkyl) is as exemplified above with respect to optionally substituted (Ci-Chalky!.

As used herein, the term optionally substituted (C6-C₂4)aryl(Ci-Cig)alkenyl 20 refers to a (C6-C₂4)aryl(C₁-C_]g)alkenyl group as previously defined substituted in the aryl group with one or more substitutents defined above for (Cg-C₂4)aryl and/or substituted in the alkenyl group with one or more substitutents defined above for (Ci-Cig)alkyl.

As used herein, the term optionally substituted (Cg-C^aryKC^C^jalkynyl refers to a (C6-C₂₄)aryl(Ci-Chalky nyl group as previously defined substituted in the aryl 25 group with one or more substitutents defined above for (C₆-C₂₄)aryl and/or substituted in the alkynyl group with one or more substitutents defined above for (Ci-Cig)alkyl.

As used herein, the term optionally substituted (Ci-Cjg)acyl refers to a (Ci-Cig)acyl group as previously defined which may be substituted with one or more groups selected from the substituents defined for (Cj-Cjgjalkyl, and includes within its 30 meaning an acyl residue of a naturally occurring or synthetic amino acid or azaamino acid, or an acyl residue of a peptide chain containing 2-4 naturally occurring or synthetic amino acids and/or azaamino acids.

Examples of substituted acyl groups include acyl residues of any of the naturally occurring or synthetic amino acids exemplified herein, hydroxyloweralkanoyl, lower35 alkoxy loweralkanoyl, acetylloweralkanoyl, cyanoloweralkanoyl, carboxyloweralkanoyl, hydroxycarboxyloweralkanoyl, fluoroloweralkanoyl, chloroloweralkanoyl, bromoloweralkanoyl, thioloweralkanoyl, loweralkanethioloweralkanoyl, aminoloweralkanoyl, loweralkylaminoloweralkanoyl, di-(loweralkylamino)loweralkanoyl, carbamoylloweralkanoyl, loweralkoxycarbonyl, carbamoyl, loweralkylaminocarbonyl and di-(loweralkylamino)AP/P/ 94 / 0 0 6 67

AP.00597 carbonyl, where loweralkanoyl is an alkanoyl group of from 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl, and where loweralkyl signifies a (C_rC₆)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and hexyl.

As used herein, the term optionally substituted heterocyclic refers to a heterocyclic group as previosly defined wherein one or more hydrogen atoms may be replaced with a group selected from the substitutents defined above with regard to optionally substituted (Cg-C24)aryl. Examples of substited heterocyclic groups include io loweralkylheterocyclic, arylheterocyclic, aryloxyheterocyclic, loweralkoxyheterocyclic, oxo-heterocyclic, hydroxyheterocyclic, loweralkoxycarbonylheterocyclic and loweralkanoylheterocyclic.

As used herein, the term optionally substituted heterocyclic(C]-Chalky 1 refers to a heterocyclicfCj-Cjgjalkyl group as previously defined substituted in the heterocyclic is group with one or more substitutents defined above for heterocyclic and/or substituted in the alkyl group with one or more substitutents defined above for (Cj-Cjgjalkyl. Examples of such groups are (substituted heterocyclic)-lower-alkyl such as (substituted heterocyclic)methyl, (substituted heterocyclic)ethyl, (substituted heterocyclic)propyl, (substituted heterocyclic)iso-propyl, (substituted heterocyclic)butyl, (substituted 20 heterocyclic)pentyl and (substituted heterocyclic)hexyl, heterocyclic(substituted loweralkyl) such as pyrrolyl(substituted loweralkyl), indolyl(substituted loweralkyl), quinolyl(substituted loweralkyl), tetrahydroquinolyl(substituted loweralkyl), pyridyl(substituted loweralkyl), morpholinyl(substituted loweralkyl), piperidinyl(substituted loweralkyl), thiomorpholinyl(substituted loweralkyl), thienyl(substituted loweralkyl), 25 furanyl(substituted loweralkyl), benzfuranyl(substituted loweralkyl), pyrrolidinyl(substituted loweralkyl) and iso-quinolyl(substituted loweralkyl), and (substituted heterocyclic)(substituted loweralkyl), wherein in each case substituted heterocyclic is as exemplified above with respect to optionally substituted heterocyclic and (substituted loweralkyl) is as exemplified above with respect to optionally substituted (Cj-C^alkyl. 30 As used herein, the term optionally substituted heterocyclicfC^-Cjgjalkenyl refers to a heterocyclicfC^-C^alkenyl group as previously defined substituted in the heterocyclic group with one or more substitutents defined above for heterocyclic and/or substituted in the alkenyl group with one or more substitutents defined above for (Cj-Cigjalkenyl.

As used herein, the term optionally substituted heterocyclicfC^-Cigjalkynyl refers to a heterocyclic(Cj-Cig)alkynyl group as previously defined substituted in the heterocyclic group with one or more substitutents defined above for heterocyclic and/or substituted in the alkynyl group with one or more substitutents defined above for (C_rC₁₈)alkynyI.

Z.9900/V6 /d/dV

AP.00597

As used herein, the term optionally substituted alkylidene refers to an alkylidene radical as previously defined, in which one or more hydrogen atoms is replaced by substituent(s) independently selected from the substituents defined above in connection with optionally substituted (CfC^alkyl.

As used herein, the term naturally occurring or synthetic amino acid refers to a compound of the formula HN(R4₀₁)(CH(R4(x)))pCOOH, wherein R₄qo and R401 independently have the meaning of R₂₀ as previously defined, and p is 1, 2 or 3, and wherein R₄₀q and R4.01, together with the carbon and nitrogen to which they are bound may together form a saturated or unsaturated cyclic, bicyclic or fused ring system. 10 Examples of naturally occurring or synthetic amino acids include alanine, cyclohexylalanine, anthranilic acid, arginine, asparagine, aspartic acid, cysteine, βphenylcysteine, cystine, glutamic acid, glutamine, glycine, cyclohexylglycine, tetrahydrofuranylglycine, histidine, homoserine, hydroxyproline, isoleucine, leucine, lysine, 4-azalysine, δ-hydroxylysine, methionine, norleucine, norvaline, ornithine, 15 phenylalanine, 4-aminophenylalanine, 4-carboxyphenylalanine, 4-chlorophenyialanine, phenylglycine, 8-phenylserine, proline, serine, threonine, trans-3-hydroxyproline, trans-4hydroxyproline, tryptophan, tyrosine, valine, indoIine-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, α-aminobutyric acid, α,γ-diaminobutyric acid and α,β-diaminopropionic acid. Other amino acids, and peptides derived therefrom, are disclosed in J. S. Davies, ed., Amino Acids and Peptides, Chapman and Hall, London, 1985, the disclosure of which is incorporated herein by reference.

As used herein, the term residue of a naturally occurring or synthetic amino acid refers to a group of the formula -N(R40])(CH(R4qq))_pC(O)-, wherein R400, R401 and p are as defined above with regard to naturally occurring or synthetic amino acid.

As used herein, the term azaamino acid refers to an amino acid in which a

-CHfE^oo)- group has been replaced by a group -N(R₄qi)-, wherein R₄qi has the meaning of R₂o as previously defined.

Suitable pharmaceutically acceptable salts of the compound of formula (IA) are, where the compound of formula (IA) contains a basic nitrogen atom, acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, hydrobromic or hydriodic, or with pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, methylmaleic, fumaric, malic, citric, lactic, mucic, gluconic, · glucoheptonic, glucaric, glucuronic, lactobionic, benzoic, naphthoic, succinic, oxalic, phenylacetic, methanesulphonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethane-1,2disulfonic, laurylsulfonic, toluenesulphonic, benzenesulphonic, naphthalene-2-sulfonic, salicylic, 4-aminosalicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric, glycolic, cinnamic, mandelic, 2AP/P/ 9 4/ 0 0 6 67

AP.00597 phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic, isonicotinic, Ncyclohexylsulfamic or other acidic organic compounds, such as 2- or 3-phosphoglycerate and glucose-6-phosphate. Where the compound of formula (IA) contains an acid group, suitable pharmaceutically acceptable salts of the compound of formula (IA) are addition salts of pharmaceutically acceptable bases such as lithium, sodium, potassium, ammonium, magnesium, calcium and zinc salts, or salts formed with organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, N-methyl-N-ethylamine, mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, tris(hydroxymethyl)methylamine, N,N-dimethyl-N-(2-hydroxyethyl)-amine, tri-(2io hydroxyethyl)-amine, N-methyl-D-glucamine, or tributylamine. Compounds of formula I having acid and basic groups can also form internal salts. Other suitable salts are described, for example, in S. M. Berge, et al., Pharmaceutical Salts J, Pharm, Sci.. 66

1-19 (1977) which is incorporated herein by reference.

The expression prodrug as used herein refers to a pharmaceutically acceptable is derivative of a compound of formula (IA) which is transformed into a compound of formula (IA) after administration of the prodrug to a living animal or human, and which has enhanced stability, delivery characteristics and/or therapeutic value compared to the compound of formula (IA) from which it derives.

The expression protecting group as used herein refers to a group which may be used temporarily to modify a functional group, for example to prevent that functional group from being affected by, or from undesirably affecting the outcome of, a desired reaction involving another functional group in the molecule and/or to prevent premature metabolism of the compound of formula (IA) after administration to a patient before the compound can reach the desired site of action. Suitable protecting groups are described, for example in Greene, T. W., Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 1981) and McOmie, J. F. W., Protective Groups in Organic Chemistry (Plenum Press, London, 1973).

Examples of suitable protecting groups for hydroxyl or mercapto substituents include substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 30 t-butyloxymethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl, benzyl, allyl, triphenylmethyl and the like, other etherifying groups such as 2tetrahydrofuryl, 2-tetrahydropyranyl and vinyl, or by acyl and carbonate groups such as formyl, 2,2-dichloroacetyl, 2,2,2-trichloroacetyl, t-butyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl, or by silyl groups such as trimethylsilyl, t-butyldimethylsilyl, tribenzylsilyl, triphenylsilyl and the like.

Suitable protecting groups for amino substituents include acyl groups such as formyl, acetyl, 3-phenylpropionyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 4-methoxy benzoyl, t-butyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 9AP/P/ 94 / 0 0 6 67

AP.00597 fluorenylmethoxycarbonyl, (2-pyridyl)methoxycarbonyl, quinoline-2-carbonyl, 2trimethylsilylethoxycarbonyl, or trimethylsilyl, or an aminoacyl residue.

Suitable protecting groups for carboxyl substituents include esters, for example methyl, ethyl, tert-butyl, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, methoxymethyl, 5 2-methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2bromoethyl, 2-iodoethyl, 2-trimethylsilylethyl, 2-triphenylsilylethyl, t-butyldimethylsilyl or trimethylsilyl esters.

Suitable protecting groups for carbonyl substituents include acetals such as dimethyl, diethyl, dibutyl and dibenzyl, thioacetals such as S,S-dimethyl and S,S-diethyl, io cyclic acetals and thioacetlas such as 1,3-dioxanes, 1,3-dioxolanes, 1,3-oxathiolanes,

1,3-dithianes and 1,3-dithiolanes, and oximes and hydrazones such as O-benzyl oximes,

O-phenylthiomethyl oximes and Ν,Ν-dimethyl hydrazones.

The expression solubilising group” as used herein refers to a group which may be used to derivatise a functional group so as to enhance the solubility of the compound of 15 formula (I) in water or aqueous media. Examples of solubilising groups for inclusion in the compound of formula (IA) are groups of the following formulae or salts thereof:

AP/P/ 94 / 0 0 6 67

Where the compound of formula (IA) includes two functional groups capable of being derivatised by a solubilising group, the two funtionai groups being in sufficiently

AP . 0 0 5 9 7 close proximity to one another, it will be appreciated that certain of the solubilising groups exemplified above are capable of forming cyclic structures, for example including the following structural units:

C> OH

X

-Xi X₂V

-xi x₂—

Ο Ο —Xi Ό 9

V^z V^z p-OH /X. /^r\ / \

-Xi X₂— __ —X2 o OH or wherein Xj and X₂ are independently selected from O, S and NR₆ wherein R₆ is as previously defined. Solubilising groups in a cyclic structure, such as those exemplifed above, also fall within the meaning of solubilising group as used herein.

Where the solubilising group is acidic, a salt thereof is typically a salt of an alkali metal or ammonia, such as Na+, K⁺ or NH₄ ⁺ . Where the solubilising group is 10 basic, a salt thereof is typically a salt of a strong inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid. Typically, the solubilising group is a sodium or potassium salt of a phosphate or phosphite residue.

Solubilising or protecting groups which are included in the compound of formula (IA) must be amenable to hydrolytic or metabolic cleavage in vivo.

More typically, the compound of the general formula (IA) in this form of the invention has the structure represented by formula (IB):

Ft

50t\^

N'

Ft

550

Ft

551 ^R5Q2 (IB) wherein x and y are both 0,

B is selected from the group consisting of

O / \

-c-c—

I I

Rl4‘R₁₄«

14*' 'C:

i

-Rl4* :o

II —c-

		OR15
OR15	OR18 I	C(R56o)2
I —ο-	—0,—	I —ο-
ι	I „ and	ι
R-14*	ORig	R14*

AP/P/ 94/ 0 0 6 67 wherein Ri₄*, Ri₄**, R15, Ris and R_ig are as previously defined and each R₅₆₀ is independently hydrogen or (Ci-C₄)alkyl,

R₅₀₂ and R506 are independently a group R^qq, wherein R^qq is selected from the group consisting of hydrogen, C(O)OR₆₂i, C(O)SR^_2b C(O)NR₆₂iR622> (C_rC₆)alkyl, (C₂-C₆)alkenyl, (C₅-C₁₀)cycloalkyl, (C₅C ₁₀)cycloalky 1(C _rC₆)alkyl, (C₅-C ₁₀)cycloalkyl(C₂-C₆)alkenyl, (C₆Ci₀)aryl, (C₆-C₁₀)aryl(C_rC₆)aIkyI, (C₆-C₁₀)aryI(C₂-C₆)alkenyl, (C_r

AP. 00597

Cg)acyl, heterocyclic, heterocyclic(Ci-Cg)alkyl and heterocyclic(C₂Cgjalkenyl, each of which may be substituted by up to three substituents selected from the substituents defined above for optionally substituted (Cj-C_l8)alkyr and R^i and R<522 have ^the meaning of R₂₁ and R₂₂ respectively, as previously defined, or R^j and R^ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as previously defined,

R501 is selected from the group consisting of R^qq as previously defined, S(O)OR&}₂, S(O)₂R63₂, S(O)NR63₂R633, δ(Ο)₂^₃₂^₃₃, NH₂, NHR^j and NR|53jR63₂, wherein R^i has the meaning of R$ as previously defined and R^₃₂ and R^₃₃ independently have the meaning of R₂q as previously defined, or R₅₀₁ and R₅₀6 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system, or R^₃[ and R$₃₂, or R$₃₂ and R^33 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as previously defined.

R512 and R542 independently have the meaning of R^qq as previously defined, R522 and R₅₃₂ are independently selected from the group consisting of R^oo as previously defined, F, Cl, Br and I,

R513 and R543 are independently selected from the group consisting of R^oo ^as previously defined and R₂qq as previously defined,

R523 and R533 are independently selected from the group consisting of R^qq as previously defined, F, Cl, Br, I, and R₂qq as previously defined,

R₅5q has the meaning of R$ as previously defined and R551 is selected from the group consisting of Rgso, hydrogen, S(O)OR₆₃₂·, S(O)₂R₆₃₂, S(O)NR6₃₂R6₃₃ and S(O)₂R₆₃₂R₆₃₃, wherein R^q has the meaning of R$ as previously defined and R^₃₂ and ^₃₃ are as previously defined, or R<5₃₂ and R$₃₃ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as previously defined, or R55Q and one of R551 and R502 together form a diazaheterocycle wherein R550, R551 or R5P2 and the two nitrogen atoms to which they are bonded are part of a stable 5 to 10-membered ring which may comprise up to two further heteroatoms selected from O, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which diazaheterocycle may be substituted by one or more of the substituents defined above for optionally substituted (C[-C₁₈)alkyr, and wherein two substituents may together form part of a ring, or one pair selected from R₅j₂ and R₅₁₃, R₅₂₂ and R₅₂₃ (when present), R₅₃₂ and R₃₃₃ (when present), and R542 and R5₄₃, together are =0;

AP/P/ 94/ 00 6 67 c

AP.00597 wherein, when B is other than

Ο

II

or —C— then at least one of

o o

conditions (i) to (xi) below applies:

(i) at least one of R512 and R₅₄₂ is a group ^55, wherein R₆₅₅ is selected from the group consisting of (C₁-C₆)alkyl(C₆-C₁₀)aryl, (C₂-C₆)alkenyl(C₆-C₁₀)aryl, (C₅-C₁₀)cycloalkyl(C₂-C₆)aIkenyl, (C₅-C₁₀)cycloalkyl(C₆-C₁₀)aryl, acyl(C6-Ci₀)aryl, heterocyclic(C_rC₆)alkyl, heterocyclic(C₂-C6)alkenyl, heterocyclic(C(5-C₁₀)aryl, C(D*)OR₂₁*, C(D*)SR₂i* and C(D*)NR₂₁*R₂₂*, wherein D*, R_2J* and R₂₂* are as previously defined, (ii) at least one of R5₂₂ and R532, when present, is selected from the group consisting of ^55 as previously defined, F, Cl, Br and I, (iii) at least one of R513 and R543, when present, is selected from the group consisting of R₆₅₅ as previously defined, and R₂oo as previously defined, (iv) at least one of R₅₂₃ and R533, when present, is selected from the group consisting of R555 as previously defined, F,C1 Br, I and R₂qo as previously defined, (v) R₅₅₀ is a group R$56, wherein R^g is selected from the group consisting of (C_rC₆)alkyl(C₆-C₁₀)aryl, (C₂-C₆)alkenyl(C₆-C₁₀)aryl, (C₅C ₁₀)cycloalkyl(C₂-C₆)alkenyl, (C₅-C ₁₀)cycloalkyl(C₆-C ₁₀)aryl, acyl(C₆C₁₀)aryl, heterocyclic(C_rC₆)alkyl, heterocyclic(C₂-C₆)alkenyl, heterocyclic(C₆-C_l0)aryl, (vi) R₅₅₁ is selected from the group consisting of R555 as previously defined, S(O)OR^3₂, S(O)₂R^32. S(O)NR63₂R633 and S(O)₂Rg₃₂R533, wherein R$32 and ^33 are as previously defined, (vii) R₅₀₂ is selected from the group consisting of R^ as previously defined,

C(D*)SR₂i* and C(D*)NR₂₁*R₂₂+, wherein D*, R₂₁* and R₂₂* are as previously defined, <

(viii) R₅₀₂ and R₅₅₁ are both hydrogen or are both (Cj-C^acyl, (ix) R[4* is selected from the group consisting of C(D*)OR4₀, C(D*)SR4q and C(D*)NR₄₀R₄₁, wherein R40 and R₄₁ are as previously defined, (x) R501 is selected from the group consisting of R^g as previously defined, S(O)OR₆₃₂, 5(0)^32, S(O)NR₆₃₂R₆₃3, S(O)₂R₆₃₂R₆33, nh₂, nhr₆₃₁ and NR63iRg3₂, wherein R^₃₂ and R^₃₃ are as previously defined, (xi) R₅₀i and R_5O6 are both (C_rC₆)acyl,

AP/P/ 94 / 0 0 6 67

AP.00597

OH

I and wherein when B is | or H

O

II c— then at least one of the following conditions also applies:

(xii) x + y > 0, (xiii) x + y = 0 and at least one of R532 and R₅₃₃ is other than hydrogen, (xiv) R₅₀ and R₅₁ together form a diazaheterocycle as previously defined, (xv) at least one of R501, R502. R506 ^and R551 >^s optionally substituted heterocyclic(Ci-Cig)alkyl, and (xvi) at least one of R₅i₂, R542, Rs22> ^532> ^513- ^543> ^523 ^an<l R533 is selected from the group consisting of C(O)OR₆₂i, C(O)SR₆₂i and C(O)NR^2iR^22’ wherein R^i and R₆₂₂ are as previously defined.

Examples of typical unsubstituted diazaheterocycles are:

/9900,06 /d/dV

Another form of the first embodiment of the invention has the structure represented by formula (IQ) below, in which Rj, to Rj independently are -(CH₂)_a^OPy, or R<p wherein a can be 0, 1, 2, 3, 4 or 5, Py is a solubilising group Px as defined herein, R$ is as previously defined and R_a' and Rj' are independently selected from Rj and Rj*, as previously defined

AP.00597

ΟΡν

Ra

R„ (CH2)o-2

Rf

C. I /N.

'C

I Re I Rd Rg 'Rj'

Ri (IQ).

Still other compounds of the first embodiment are those compounds exemplified in International Patent Application no. WO 93/18006, namely:

(i) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)5 amino-4-phenylbutyl]carbazate, (ii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-L-valyl)amino-4-phenylbutyl]carbazate, (iii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]carbazate, io (iv) t-butyl 3-(1 -methyl-3-phenylpropen-3-yl)-3-[(2R or S, 3S)-2-hydroxy-3(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (v) t-butyl 3-(l-methyl-3-phenylpropyl)-3-[(2R or S, 3S)-2-hydroxy-3-(Nquinaldyl-L-asparaginyl)amino-4-phenylbutyl]carbazate, (vi) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-amino-4-phenyli5 butyl]-3,4-diazabicyclo[4.4.0]decane, (vii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbuty 1] -diazabicyclo[4.4. Ojdecane, (viii) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-LvaIyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4. Ojdecane, (ix) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-[N-(2-pyridyl)methoxycarbony l)-L-valy l)amino-4-phenylbuty 1J -3,4-diaza-bicycIo [4.4.0]decane, (x) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutylJ-3,4-diazabicyclo[4.4.Ojdecane, (xi) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lglutaminyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.Ojdecane, (xii) cis-1,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lthreonyl)amino-4-pheny lbutylj -3,4-d iazabicyc lo [4.4.0,d tcane, (xiii) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)3o amino-4-phenylbutyl]-2,3-diazabicycIo[2.2. lJhept-5-ene, (xiv) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyI)amino-4-phenylbutylJ-2,3-diaza-bicyclo[2.2.1Jheptane,

AP/P/ 9 4 / 00 6 67

AP . 0 0 5 9 7 c

c>

(xv) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-Lvalyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane, (xvi) 2-[N-(lS)(2-methyl-l-methoxycarbonylpropyl)carbamoyl]-3-[(2R or S, 3S)-2hydroxy-3-[N-(2-pyridyl)methoxy-L-valyl]amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane, (xvii) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]-2,3-diazabicyclo[2.2.1]heptane, (xviii) l-[2-(2-pyridyl)methoxycarbonylamino-]benzoyl-2-[(2R or S, 3S)-2-hydroxy3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl]-2-isopropyl-hydrazine, (xix) 2-t-butoxycarbonyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]-l,2,3,4-tetrahydrophthalazine, (xx) l-trimethylacetyl-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phyenylbutyl]-2-isopropylhydrazine, (xxi) l-trimethylacetyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl) amino-4-phenylbutyl]-2-isopropylhydrazine, (xxii) l-(t-butylamino)carbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]-2-isopropylhydrazine, (xxiii) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-picolinyI-Lasparaginyl)amino-4-phenylbutyl]carbazate, (xxiv) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxycarbonylanthraniloyl)amino-4-phenylbutyl]carbazate.

(xxv) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (xxvi) t-butyl 3-benzyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyI-L-asparaginyl)amino-4-phenylbutyl]carbazate, (xxvii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methoxycarbonyl)amino-4-phenylbutyl]carbazate, (xxviii) t-butyl 3-cycIohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]carbaza.te, (xxix) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-tiydroxy-3-(N-(l-carbamoyl-methyl)acry loy l)amino-4-pheny lbuty I] carbazate, (xxx) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio2-carbamoyl-methylpropionyl)amino-4-phenylbutyl]carbazate, (xxxi) t-butyl 3-isopropyl-3-[(2R or S, 3S)-2-hydroxy-3-(N-(l-benzoyl-Lasparaginyl)amino-4-phenylbutyl]carbazate, (xxxii) l-t-butyloxycarbonyI-2-[(2R or S, 3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]hexahydropyridazine, (xxxiii) l-t-butyloxycarbonyl-2-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]hexahydropyridazine, and

AP/P/ 94 / 0 0 6 67

AP.00597 (xxxiv) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldyl-3cyano-L-alanyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4,4,0]decane, wherein the 2-hydroxy group has been derivatised with a solubilising group Px as herein defined. Typically, in this form of the first embodiment, compounds (i) to (xxxiv) o

II referred to above are derivatised with a solubilising group selected from /^P;^OH and “ OH

The compounds of formulae (I), (IA), (IB) and (IQ) can exist in optically isomeric forms and the present invention includes within its scope all these forms in all proportions including all diastereoisomers and mixtures thereof and all enantiomers, mixtures of enantiomers and racemic mixtures. Where a double bond occurs in the compound of the invention, the double bond may be present in the cis- (Z) or trans- (E) configuration. It will be understood that only compounds of formula (IA) with combinations of substituents or functional groups which give rise to stable compounds, are within the scope of the present invention.

The compounds of general formula (I) may be prepared by methods known generally in the art. Suitable methods for the synthesis of compounds of formula (I) and intermediates thereof are described, for example, in Houben-Weyl, Methoden der Organischen Chemie; J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley & Sons, New York, 1985); D. C. Liotta and M. Volmer, eds, Organic Syntheses Reaction Guide (John Wiley & Sons, Inc., New York, 1991); R. C. Larock, Comprehensive Organic Transformations (VCH, New York, 1989), H. O. House, Modern Synthetic Reactions 2nd Edition (W. A. Benjamin, Inc., Menlo Park, 1972); N. S. Simpkins, ed. 100 Modern Reagents (The Royal Society of Chemistry, London, 1989); A. Η. Haines Methods for the Oxidation of Organic Compounds (Academic Press, London, 1988) and B. J. Wakefield Organolithium Methods (Academic Press, London, 1988).

For example, a compound of formula (I) may be prepared from synthons W*, {(A)_n-B-(A*)_m}* and V*, wherein each synthon identified thus * is a synthetic precursor of the corresponding portion of the molecule W-(A)_n-B-(A*)_m-V. Thus, a compound of formula (I) may be prepared, for example, in any of the following ways:

(a) by reaction of W-(A)_n-B-(A)_m-G with H-V;

(b) by reaction of W-(A)_n-B-(A)_m-H with G-V;

(c) by reaction of W-Η with G-(A)_n-B-(A)_m-V; and (d) by reaction of W-G with H-(A)_n-B-(A)_m-V;

wherein G is a leaving group such as halogen, typically chlorine, bromine or iodine; a sulfonate such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate or toluenesulfonate; an alkoxy, thioalkoxy, aryloxy or thioaryloxy group such as ethoxy,

AP/F/ 94 / 0 0 6 67

AP. Ο Ο 5 9 7 methoxy, thiomethoxy or phenoxy; acyloxy such as acetyl, trifluoroacetyl or benzoyl; hydroxy; amino or protonated amino; nitrate; phosphate; borate and the like. If appropriate these reactions may be carried out in the presence of a base such as triethylamine, pyridine or other tertiary amine, butyllithium, sodium tert-butoxide or similar, and/or a coupling reagent such as a carbodiimide.

When V is YR₂ where Y is —N=N— , or when V is Y* where Y* is a member of the group —Ν—N—R₂* —N-O-R₂. —O—N-R₂*

III ^Z 1^

R50 R51 R50 . R50 , and the compound of formula (I) may be prepared as shown in Scheme 1 or Scheme la. In io the Schemes and in the Examples herein, the terms Me, Et, Pr, Ph and Bz signify methyl,

C ethyl, propyl, phenyl and benzyl respectively and the following additional abbreviations are used:

	THP t-Bu or Bu1	tetrahydropyranyl, tertiary butyl
15	n-Bu	n-butyl
	iPr or Pr’	isopropyl
	Hal	halogen; i.e., fluorine, chlorine, bromine or iodine
	Ts	para-toluenesulfonyl
	DMF	dimethyl formamide
20	CDI	N, N' -carbonyldiimidazole
	BOP	benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate
	HBT	1 -hydroxybenzotriazole
	AcCN	acetonitrile
25	DMSO	dimethyl sulfoxide
	Py.xSO3	pyridine/sulfur trioxide complex
	QC	quinoline-2-carbonyl
	PC	2-pyridinemethoxycarbonyl
	MC	N-morphol inocarbony 1
30	TMC	N-thiomorpholinocarbonyl
	Val	valinyl
	Asn	asparaginyl
	He	isoleucyl
	Gly	glycinyl
35	Glu	glutaminyl
	Thr	threonyl
	Ala	alanyl

AP/F/ 94 Z 0 0 6 67

AP. Ο Ο 5 9 7

(CN)Ala	cyanoalanyl
(p-F)Bz	4-fluorobenzyl
(p-CN)Bz	4-cyanobenzyl
Z	benzyloxycarbonyl
Boc	t-butyloxycarbonyl
Ac	acetyl
TFA	trifluoroacetyl
CgHn	cyclohexyl.

Scheme 1

W-(A)_n-B-(A*)rnO-N-R₂

R50

W-(A)_n-B-(A*)fnN-OR50

W-(A)_n-B-(A*)mN-N-R₂

R50R51

W-(A)_n-B-(A*)nrN-N-R₂ Η H

AP/P/ 94 / 00 6 67

Oxidation

W-(A)_n-B-(A*)nrN=N-R₂ ) 10

Other compounds of formula (I) may be prepared analogously, by reacting a synthon W-(A)_n-B-(A*)_m-Hal with HV, if appropriate in the presence of a strong base.

AP . 0 0 5 9 7

Scheme 1a

R_aNHNH₂ (RO)₂C(O) base

R_aNHNHC(O)OR

RbHal base

R_a—N—NH2 Rb

R_a—N—NHC(O)OR Rb

R_cHal base

R_a—N— NHR_C Rb

In Scheme la, R represents an alkyl, aryl or aralkyl group, such as t-butyl, phenyl or benzyl. Suitable bases include pyridine, triethylamine and other tertiary amines, alkali metal carbonates and alkali metal hydroxides. The moiety W-(A)_n-B-(A*)_m- may be represented by R_a, in which case Rj, represents R50 as previously defined, and R<. represents R2 as previously defined, or W-(A)_n-B-(A*)_m- may be represented by Rj., in which case Rj, represents R51 and R_a represents R2.

_z^33

When V is Y* where Y* is — n-n=c_s , the compound of formula (I) may be

Rso '^R* prepared from by reacting a hydrazine wherein R51 and R₂* are both hydrogen, which may be prepared as shown in Scheme 1 or Scheme la, with an aldehyde or ketone.

cr oWhen V is YR2 where Y is __Ν=^_ or _^_=N_ , the compound of formula + + (I) may be prepared as shown in Scheme lb j

AP/P/ 94 / 0 0 6 67

Scheme 1b

W-(A)n-B-(A*)m-Hal + R₂-N=N-O’ _νν-(Α)π-Β-(Α*),ττΝ=Ν-Κ2

W-(A)n-B-(A*)m-N=N-O’ + R₂-Hal

W-(A)_n-B-(A*)mN=N-R₂ O

When V is YR₂ where Y is a member of the group

AP.00597 c<

o

0	0	0	O	0
II	II	II	II	||
—S-N— -	-S-N —	—N-S— -	—N-S —	—0—s—
1	II I	1	I II	II
R50 ί	0 R50	R50 ) ί	R5oO	0 ί
		0	0	0
0	0	II	II	II
II	II	—s-o— -	—s-s—	—s-s—
—o-s— -	—s—o—	II	II	II
		0	0 »	O »
0		0	0	0
II		II	II	II
s-s— —P-	-N— - I	-O-P-N— - I I	—N-P — ] I	—N-P-0 I |
r51o »	R50 J	R5lO R50	R50OR51 ί	R5oOR51
0	0	O	0	O
II	II	II	II	II
—P-O- —	-o-p— I	—P-N— I |	—N-P — | |	—p-o- J
j OR51 ί	OR51	R5lO R50	R50OR51	R52 Ϊ
	O	0	0
	II	II	II
—o-	-p— —	-O-P-Ο-	-Ο-P-Ο-
	I	Ι and	ι
	R52 1	OR51	OR51

the compound of formula (I) may be synthesised by coupling a synthon W-(A)_n-B-(A*)_mZ_a with a synthon Z_b, where Z_a includes one of the heteroatoms of Y, and Z_b includes the other heteroatom or atoms, as shown in schemes 2a and 2b:

AP/P/ 94/ 00667

AP.00597

Scheme 2a

CISCQIRz^ w-iAJn-B-iA^mN-i-R

R,

CIS(O)₂R₂

50Q

W-iAJn-B-iA^N-S-R,

RgjO

CIPiOKR^

R50 c

W-(A)_frB-(A‘),_nO-H C

W-fAJff-B-tA’imO-H

W-iAJn-B-tA^S-H

CIP(O)(OR₅₁)R_;

W-(A)_trB-(A*)_rTTN-P-R₂

R50R52

O ^! W-(A)_rT-B-(A*)_rtTN-P-R₂ RgoOR₅₁ O

CIP(O)(OR₅₁)OR₂..... V

-- VV-(A),rB-(A J^N-P-OR

R5oOR₅₁

CISiQJR,.^ _w__(A)n__B__(A._)rnO4_R₂

-Q!§.(.Q).2g2.-> _w__(A)[rB__(A._)rn0_£__R, _CIP(O)(R₅₂)R_{2 w}__(A)n__B__(A*_)(Tr0_£__R

CIP(O)(OR₅₁)R₂ '52

W-(A)_n-B-(A‘)_[TTO-f»-R₂

OR,

CIP(O)(OR₅₁)OR₂ o ” W-(A)n-B-(A‘)_inO-f’-OR₂

OR51

CIS(O)R₂

HSR,

W-(A),r-B-(A*)_mO-4-R₂

W-iAJn-B-iA^S-S-R,

AP/P/ 9 4/ 0 0 6 67

Scheme 2b o

W-Mn-EHA^S-CI

W-Wn-B-mnrS-CI

O

W-(A)n-B-(A*)rn-P-CI

R52

O

W-Mn-EHA^P-CI

OR51

W-(A)n-B—(A*)m-O—P-CI OR51 O

W-(A)n-B-(A*)m&-CI

O

W-(A)n-B-(A*)ffi-S-CI

O o

W-iAJn-B-iA^P-CI

R52

O

W-(A)n-B-(A*)m£-CI

O

W-Wn-B-CA^P-CI

OR

O

II

W-(A)n-B—(A*)m-O-P-CI OR₅i

AP.00597

HNRspRz.

HNR50R2

HNR50R2 hnr₅₀r₂

HNR50R2

O

W-Mo-B-tA^S-N-Rs ^R50

O

W-(A)_lT-B-(A‘)_rtr^-N-R₂ θ ^R50 O R50

W-iAJjrB-iA^^-N-Rz P52 O R50

W-(A)n-B-(A‘)rtrP-N-R₂

OR51

O R50

W-(A)n-B-(A*)m-O-P-N-R₂

OR51

HOR?

HOR₂ hor₂ hsr₂ hor₂

HOR₂

W-(A)_n-B-(A‘)nrS-O-R₂

O

W-(A)_n-B-(A‘)_rirS-O-R₂

O o

W-(A)_n-B-(A‘)nrP-O-R₂

R52

O

W-(A)_n-B-(A‘)n^-S-R₂

O

W-(A)_n-B-(A*)nrP-O-R₂

OR

O tl

W-(A)n-B-(A*)m-O-P-0-R₂

OR51

Analogous methods may be used to obtain the corresponding thionophosphates and thionophosphonates.

When V is C(R₃₀) = Y** the compound of formula (I) may be prepared from a synthon having a ketone or aldehyde function, by condensation with a substituted hydrazine or substituted hydroxylamine corresponding to Y**.

When V is Y*, where Y* is -N=O, the compound of formula (I) may be prepared by oxidising the corresponding primary amine, for example with Caro's acid, or

AP/P/ 94 / 0 0 6 67

AP.00597

H2O2 in acetic acid, or H2O2 with sodium tungstate. It will be appreciated that a compound of formula (I) wherein Y* is -N = O will only be isolable as a nitroso compound when the carbon atom bearing Y* has no ct-hydrogens.

—S=O

When V is Y*, where Y* is or

114*

O

II

-s=o

I

R114* , the compound of formula (I) may be prepared by oxidation of the corresponding thioether

W-(A)_n-B-(A*)_m-S-R₁₁₄, (IV) with hydrogen peroxide and acetic acid. The thioether (IV) may be synthesised by coupling a halide W-(A)_n-B-(A*)_m-Hal with a thiol R₁₁₄* under basic conditions, or by reacting a disulfide R^+SSR^* with an organolithium reagent W-(A)_n-B-(A*)_m-Li derived from the corresponding halide.

OR115	R114‘
—P=O	—P=O
When V is Y*, where Y* is ί or Kii4«	ί , the compound of formula Ri 14*«

(I) may be prepared by the Arbuzov reaction as shown in scheme 3:

Scheme 3 ^R114*

MeO-P

Rl14»* Ri14*

W-(A)n-B-(A‘)nrHal -- w-(A),rB-(A^m-P-O

R-114

0^R115

MeO-P

R114.. 0^R115

W-iAJrt-B-WrfrHal -- W-(A),rB -(Α*),π-Ρ=Ο

Rl14«

AP/P/ 9 4/ 0 0 6 67

The synthon W-(A)_n-B-(A*)_m-Z, where Z is any of the functional groups bound to (A*)_m which are represented in schemes 1 to 3,‘may be prepared by coupling a suitably functionalised fragment W* with a correspondingly functionalised fragment Z*-(A)_n-B(A*)_m-Z. Alternatively, the compound of formula (I) may be synthesised by first coupling V to (A)_n-B-(A*)_m- as described above with reference to schemes 1 to 3, and then coupling the resulting molecule to a functionalised fragment W*. Methods for coupling a precursor of group W with a functionalised fragment Z*-(A)_n-B-(A*)_m-Z are well known in the art, and include methods analogous to those represented in schemes 1 to 3. For example, when W is RjX and X is Y, the coupling may be achieved as described in schemes 1 to 3 above. When W is R_tX and X is NR^, O or S, the coupling may be achieved by any of the known methods for the alkylation of amines, and the

AP.00597 synthesis of ethers and thioethers, respectively. That is, the coupling may be achieved by reacting a fragment Z*-(A)_n-B-(A*)_m-Z wherein Z* is a leaving group such as halogen, sulfonate ester, acetate or trialkylammonium salt, with RjRjqNH, RjOH or RjSH, if necessary in the presence of strong non-nucleophilic base such as butyllithium, sodamide or potassium tert-butoxide. Compounds in which X is S(O) or S(O)₂ may be prepared by the oxidation of the corresponding compound in which X is S. Compounds in which W is -CN, -C(R₅) = NR₃, -C(R₅) = NOR₃, -C(D)OR₃, -C(D)SR₃ or -C(D)NR₃R4 may be prepared from the fragment Z*-(A)_n-B-(A*)_m-Z wherein Z* is an aldehyde, ketone or carboxyl group as shown in Scheme 3a.

io Scheme 3a c=nor₃

II —c-ci

R₃ONH₂ c=o r₃nh₂ r₃sh

II —c-sr₃

Lawesson's

Reagent

Lawesson's

Reagent

Lawesson's

Reagent s

II

-c-sr₃ s

-C-OR₃ s

—c-nr₃r₄

P₂O₅

Y ,, )c=nr₃ -c»n

Compounds in which W is -N = CR₅R₅* may be prepared by reacting the C- fragment Z*-(A)_n-B-(A*)_m-Z, where Z* is NH₂, with an aldehyde or ketone having group(s) R5 and R₅* bound to the carbonyl.

The fragment Z*-(A)_n-B-(A*)_m-Z may be prepared by methods which depend on the nature of B. Where B is a substituted carbon atom, the fragment may be conveniently prepared from a fragment E-C(O)-E*, in which E is a fragment Z*-(A)_n and E* is a fragment (A*)_m-Z, as shown in scheme 4:

AP/PZ 94 / 0 0 6 67

AP .0 0 5 9 7

which are starting materials for compounds of formula

L 9 9 0 0 / Ί 6 /d/dV

Fragments ll

E—C—E* (I) are known compounds or analogs of known compounds which can be prepared by 5 methods analogous to methods used for preparation of the known compounds. The

O synthesis of known fragments ii may be found with reference, for example, to E—C—E*

Beilsteins Handbuch der Organischen Chemie or to J. Buckingham, ed., Dictionary of Organic Compounds 5th Edition (Chapman & Hall, New York, 1982). Alternatively, a functionalised group E may be coupled to a group E*C(O)H, or a functionalised group E* io may be coupled to a group EC(O)H, followed by oxidation. For example, a halide EBr may be coupled to E*C(O)H with an organolithium or organomagnesium reagent derived

AP . Ο Ο 5 9 7

from EBr, followed by oxidation of the resulting secondary alcohol to the corresponding ketone, if desired. Alternatively a carboxylic acid EC(O)OH may be converted to an activated derivative, such as an ester or amide: for example an amide obtained by reaction of the carboxylic acid with N,O-dimethyl hydroxylamine hydrochloride in the presence of a carbodiimide and tertiary base, followed by addition of an organolithium or organomagnesium reagent derived from E*Br, E*C1 or E*I.

/ \

When B is an epoxide of the type the fragment E-B-E* may be

Rl4*Rl4“ prepared from the corresponding olefin by reaction with a per-acid such as trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid. Suitable olefins for conversion io to the fragment E-B-E* are commercially available or may be synthesised by known methods, for example by means of the Wittig reaction or by an elimination reaction of an alcohol, alcohol sulfonate, ester, halide or the like.

OH OH ! I

When B is a diol of the type —C—C— , the compound of formula (I) may Rl4*Rl4‘* conveniently be prepared by reductive coupling of aldehydes EC(O)H and E*C(O)H as is described in/. Org. Chem 55, 4506 (1990) and U.S. Patent No. 5,294,720.

When B is a heteroatom or substituted heteroatom, the fragment Z*-(A)_n-B(A*)_m-Z is a substituted amine, phosphine or phosphine oxide, or is an ether, thioether, sulfoxide or sulfone. Substituted amines, ethers, thioethers, sulfoxides and sulfones may be prepared as described above. Secondary or tertiary phosphines may be prepared by 20 alkylation of the corresponding primary or secondary phosphine as described, for example, in J. D. Roberts and M. C. Caserio, Basic Principles of Organic Chemistry (W.A.Benjamin, Inc., New York, 1965).

In any of the reactions described above, it may be necessary to protect reactive group(s) in the compound of formula (I) other than those participating in a desired 25 coupling or oxidation reaction using suitable protecting group(s) in order to carry out the desired coupling or oxidation reaction without chemically affecting those reactive groups. Suitable protecting groups for this purpose are described in the works of Greene and

McOmie referenced above.

The compounds of formula (IB) wherein x and y are both 1 may be prepared as 30 generally described above. A compound of formula (IB) which is

OH R_c /I'k

R_aR_bN N R_d

L 9 9 0 0 / ‘z 6 /d/dV

H

AP. Ο Ο 5 9 7 where R_a and R_p have the meaning of R₅qi and R₅₀₆ as previously defined and R_c and R^ have the meaning of R₅5! and R₅₀₂ as previously defined, may be prepared from ethylene cyanohydrin by the method shown in Scheme 5.

Scheme 5

-CN OH

BrMg

OCH₂O(CH₂)₂OCH₃ 'OBz

TsOH/MeOH

OCH2O(CH2)₂OCH3 (Vc)

R_aRbN'

OCH₂O(CH₂)₂OCH₃ 2 S'io^³ OBz * 3. R_aRt,NH/DMF

AP/P/ 94 7 ΦΟ'6 67

OH

R_aRbN

Rc

N ^N'Rd H

ZnBryCH₂CI₂

A substituted compound of formula (IB) may be prepared by the general method of Scheme 5, with the substituents R₅₁2, R513, R522, ^-523 ’ R532. R533, R542. R543 ^anil R550 being introduced, as desired, into the compounds of formula (Va), (Vb), (Vc) and (Vd) shown in Scheme 5 by the methods illustrated in Scheme 5a.

AP. Ο Ο 5 9 7

Scheme 5a (Va) C A o cr ,CN

1. NaNH,

2. RHal

1. NaNH₂

RHal Sd^O''~A^CN R R R’

5a-1 (Vb)

1. NaNHj

OBz (Vb) (Vc) HO'

R R'

R R’

2. RHal 0 0

LiR, CO OBz OCH₂O(CH₂)₂OCH₃ OBz

TsCI, MejSO

A

R R’ R

O

0

OBz

R R' J=O R

OBz

H pCH₂O(CH₂)₂OCH₃ qAA^^oBz

RMgHal

5a-4

R R' OCH₂O(CH₂)₂OCH₃ R OCH₂O(CH₂)₂OCH₃

V 1 1. Me₂CO, Ai(0Bu‘)3 1 I _

HO ^^ O Bz 3- HO Bz

2. R'MgHal (Vd) R_aR_bN

OCH₂O(CH₂)₂OCH3 -A RNH₂ hAd

OCH₂O(CH₂)₂OCH₃

OCH₂O(CH₂)₂OCH₃

R_aRbN^j 1- HNO₂

Am-NHj 2. LiAIH₄

H ' , N

5a-5

AP/P/ 94 / 0 0 6 67

In reaction 5a-l shown above, it will be appreciated that the step of introducing the second substituent R' will only be carried out if it is desired that both R₅₂₂ and R₅₂₃ 5 be other than hydrogen. The reactions shown in 5a-2 and 5a-3 may be repeated, if desired, so as to introduce a second substituent on the carbon atom bearing R or RC(0). The second substituent can be the same as or different from the first. Where one or both of R₅₂₂ and R₅₂₃ is acyf, this group may be introduced as shown in reaction 5a-3 with respect to compound (Vb). Where R₅₂₂ and R₅₂₃ are both hydrogen, the io reactions shown in 5a-2 and 5a-3 may give mixtures of products and in that case it may be preferable to introduce the desired groups R₃₃₂, R543, R542 and R₅₄₃ by replacing the

Ar . 0 C 5 9 7 ethylene bromohydrin shown in Scheme 5 with a suitably substituted bromohydrin obtained from the corresponding olefin as shown in Scheme 5b. It will be appreciated that the nature of the groups R532, R543, R542 and R₅₄₃ will determine the stereochemistry of the addition of HOBr to the olefin and of the opening of the epoxide.

Scheme 5b

Compounds of formula (IB) wherein B is other than -CH(OH)- may be prepared by the methods shown in Scheme 4 after oxidation of the secondary alcohol to the corresponding ketone.

t

The compounds of formula (IB) wherein B is a substituted carbon atom and y is 0 can be prepared by reacting a compound of formula (II), (IIA) or (IIB)

R506 R522 R542

I ^⁵¹²1 I

Rso^

I R523 II R543

R513 0

AP/P/ 94 / 0 0 6 67 (IIB) wherein R₁₄*, R501. &502> ^506- ^512’ ^-513- ^522> ^523’ ^542 and R543 have the 15 significance given earlier and Hal is a group selected from -Cl, -Br or -I, with a compound of formula (ΠΙ)

R551

H-NN.

R550 (III)

502 wherein R502» R550 ^an<^ R551 have the significance given earlier. Where a compound of formula (Π) is used, the reaction may be followed by oxidation of the resultant secondary

AP.00597 alcohol to the corresponding ketone. This ketone may be used for elaboration of the substituents on B as shown in Scheme 4.

A compound of formula (II), (IIA) or (IIB) may be prepared from a β-amino acid or a β-amido acid as shown in Scheme 6. A compound of formula III may be prepared as shown in Scheme la.

Scheme 6

R501

R50

R522 c_bc''°

B51

R506 R522

Ab

R50A c (A

I 852C.H

R50 Rm

OH

1. Li, MeNH₂

2. H₃O*

R506 R522 n

4A A

H

CrOj/Pyr

Ra '542 ,

Ph —S~C — R$43 NMe_z f M

F\513

X⁴² Ph—S-C^_Rs43 NMe₂

CrOj/Pyr

R501'

I R523J, R513 Rl4*

R501' •^N'iAc{

I *523 A'

R513 I R543 H

-R542

AP/P/ 94 / 0 0 6 67

R501'

AT , •W

A

Hals, H3O* '513

1523

-R542 'Hal

543

An alternative route to the β-aminoaldehyde shown in Scheme 6 is by reduction of the methyl ester of the corresponding β-amino acids using diisobutylaluminium hydride.

β-amino acids, or β-amido acids, may conveniently be prepared by the Mannich reaction of an amine or amide with an enolisable ketone in the presence of formaldehyde or another aldehyde.

A compound of formula (IB) wherein x and y are both 0 may be prepared by 15 reacting a compound of formula (IIC) or (IID)

AP. Ο Ο 5 9 7

Rsof

R506 Η

I 1 x?

-Ri >542

Rs°⁶ O

I R^5q 11 f?*^4z

1 /Hal

Γ\5Ο1 x-* w

R51:

R543

Rs3 R543 (lie) ₍ (HD) with a compound of formula (III) as shown above. An analogous procedure, utilising a primary or secondary amine rather than a hydrazine as shown in formula (ΠΙ) yields a hydroxy diamine. A compound of formula (IIC) may be prepared from an α-amino acid by a method analogous to that shown in Scheme 6, such as described in the following: Evans, B.E., et al., J. Org. Chem., 50, 4615-4625 (1985);

Luly, J.R., et al., J. Org. Chem., 52, 1487-1492 (1987);

C Handa, B.K., et al., European Patent Application No. 346.847-A2 (1989) and

Marshall, G.R., et al., International Patent Application No WO91/08221.

Suitable α-amino acids may be prepared, for example, by the Strecker synthesis, starting from an appropriate ketone. The overall route to the compound of formula (IIC) is shown in Scheme 7. Other suitable methods are described in Coppola, et al. Asymmetric Synthesis. Construction of Chiral Molecules using Amino Acids (Wiley

Interscience, New York, 1987).
Scheme 7	NaCN, NH4CI	R512. NH2 r513^cn	H3O+	Rs^CiOJOH
^513
					RC(O)CI
D NHC(O)R R5,2-H7<R542 R513° R543	P C R542R532	R512 NHC(O)R R513CHO	1. Li, MeNH2	R512. NHC(O)R R513 /XC(O)OH
	2. HaO*

AP/P/ 94/00667

Where W is a nitrogen-containing group, and one of Rj and R₁₀ is a protected amino acid residue, the coupling of the protected amino acid residue may be accomplished as shown in Scheme 8, in which the amino acid (designated AA) protecting group is 20 benzyloxycarbonyl, designated Z. Methods for the formation of peptide bonds and for the protection of peptide residues are described, for example, in Gross and Meienhofer, eds., The Peptides, (Academic Press, New York, 1983). Suitable other coupling agents include l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and diphenylphosphoryl azide (DPPA).

AP . Ο Ο 5 9 7

Scheme 8

OH

1. CDI, dioxane

z' AA-WHAJ-B-iA^-V

Numerous synthetic routes exist to substituted hydrazines, including the hydrazines of formula (III), useful in the synthesis of compounds of formula (IA). The 5 hydrazine intermediates (III) can be obtained using known methods such as those described in the following:

Dutta, A.S., et al., J. Chem. Soc. Perkin Trans. I, (1975) 1712-1720,

Ghali, N.I., et al., J. Org. Chem., 46, 5413-5414 (1981),

Gante, J., Synthesis (1989) 405-413 and io Houben-Weyl's Methoden der Organische Chemie, vol. 16a, Part 1, pp 421-855;

Georg Thieme Verlag, Stuttgart (1990)

Other methods for preparing substituted hydrazines are illustrated in Scheme 9.

Scheme 9

R ^XN-NH₂

R 9

NH?

R¹'

NaOBr

R^,z

LiAIHxOrZn/HCI R orHyPt \i-nh₂

R^IZ (x= 1 or2) r-nh₂

Hj/catalyst R - N - N - R ordiimiSe;

,LiAIH₄

R-NH-NH-R

Zn/NaOH

0-, or r-no₂

CF₃C(O)OOH r=n-oh

Per-acid

Compounds of formula (I) wherein a group selected from Rj, Rp, R₂, R₂*, Rg,

R_lb R₁₂, R50 and R₅₁, together with another group selected from R_1? R^, R₂, R₂*, R₉*, R₁₀, R_n, Rj₂, R₅o and R₅₁ forms a cyclic, bicyclic or fused ring system may be prepared by variants on the above methods which will be readily apparent to persons skilled in the art in the light of the foregoing.

^9 9 0 0 /76 /d/dV

AP. Ο Ο 5 9 7

An example of a method of preparing one class of cyclic compounds of formula (I) is presented in Scheme 10;

Scheme 10

HsN.

OH R

I'

N^./H

Imidazole, (A)n (A*)rn N R51 (Me)₂Bi/SiCI,

DMF

Me₂Bu^tSi • 'SO

H₂N. /hk _XH (A)n (A*)m

R51

O ,x

N <A)n N /(A·) ,R 'RSO (1) Alkylation, etc (optional) (2) Bu₄NT‘

CDI,

Dioxane

HO

O

I

Me₂Bu^tSi

Compounds in accordance with the present invention which do not include a solubilising group Px typically exhibit low to very low water solubility. Inhibitors of HIV proteases which have hitherto been described, and many other pharmaceutically or veterinarily active substances also typically exhibit low to very low water solubility. This property tends to cause the bioavailability of such substances to be relatively low. There 10 is thus a need for a HIV protease inhibitor having enhanced water solubility. Surprisingly, it has been found that the inclusion of a solubilising group Px as defined herein in a substance having low to very low water solubility results in enhancement of the water solubility of the substance. Thus, substances in accordance with the invention which include a solubilising group Px exhibit superior bioavailability, including superior 15 oral bioavailability, compared to compounds in accordance with the invention which do not include a solubilising group Px.

Thus, according to a second embodiment of the present invention, there is provided process for enhancing the water-solubility of a pharmaceutical or veterinary substance, comprising derivatising a functional group of said substance with a solubilising group Px,

AP/P/ 94 / 0 0 6 67 wherein Px is selected from the group consisting of Px*,

Αχ.

AP . 0 0 5 9 7

'Px' ^R , and Px* is selected from;

.Px* wherein D is O or S, R is H or C_rC₄ alkyl, and wherein

O

II ^Ρ_;ΟΗ

OH ,P-OH

OH

O

II .P~OH

H

O O

II II

J^O^OH OH OH

-OH '0

said functional group being capable of being derivatised with said solubilising group Px.

Generally, a compound according to the first embodiment includes at least one solubilising group Px as defined above. More generally, a solubilising group .in a to compound of the first embodiment or in the method of the second embodiment is selected ⁰ ° from /^P;^OH and /-^P;^OH .

OH H

Typically, a solubilising group is introduced into the molecule as the last stage of its synthesis. For example, a solubilising group P(O)(OH)₂ may be introduced to a free amino, hydroxy or mercapto group by reaction of the amino, hydroxy or mercapto group 15 with dimethyl chlorophosphate, followed by mild hydrolysis to remove the methyl ester groups. Other solubilising groups referred to above may be introduced by analogous methods; that is, by reaction of an amino, hydroxy, mercapto or other group capable of being derivatised with a solubilising group, with a reagent PxX’, suitably protected if necessary (for example as methyl-or benzyl esters), wherein Px is as defined above and X' 2o is a leaving group such as Cl, Br, OH, OS(O)₂R and the like, where R is C_rC₆ alkyl, for example methyl, C₆-C₁₀ aryl, for example phenyl or 4-methylpheny 1, or C₇-Cn

AP/P/ 94 / 0 0 6 67

AP . Ο Ο 5 9 7 arylalkyl, for example benzyl. Alternatively, a solubilising group P(O)(OH)₂ may be introduced to a free hydroxy group by reaction with phosphorous acid and mercuric salts in the presence of a tertiary amine, as described by Obata and Mukaiyama in J. Org. Chem., 32, 1063 (1967). As a further alternative, an amino, hydroxyl or mercapto group may be reacted with phosphorous acid preferably in the presence of a coupling agent such as dicyclohexylcarbodiimide and pyridine to yield a molecule possessing the solubilising group -OP(O)(OH)H. Optionally, this group may be oxidised to the corresponding phosphate derivative, for example using bis(trimethylsilyl) peroxide (see Scheme 14 below for an illustration of this method). A further process for the introduction of a io group -P(O)(OH)₂ is described in Australian patent application no. 54311/86, and involves the reaction of an amino, hydroxy or mercapto group with certain diesters of amides of phosphorus acid, followed by oxidation and hydrolysis of the resulting intermediate compounds.

Suitable reagents for the introduction of a solubilising group -NO₂ are lower alkyl nitrates such as methyl nitrate or ethyl nitrate, and acyl nitrates such as acetyl nitrate or benzoyl nitrate.

Other methods for the preparation of precursors of compounds of formulae (I), (IA), (IB) and (IQ) referred to herein are disclosed in US Patent Nos. 5,116,835, 5,126,326; 5,132,400; 5,145,957; 5,198,426; 5,212,157; 5,215,968; 5,212,667; 20 5,294,720; and 5,25)6,604; International Patent Application Nos. 91/08221; 91/10442; 92/151319 and 92/21696; European Patent Application Nos. 0528242; 0519433 and 0432595 and Australian Patent Application Nos. 35700/89; 53716/90; 63221/90; 71319/91; 71320/91; 71323/91; 82313/91; 83206/91; 87594/91; 90531/91; 90851/94; 90925/91; 91251/91; 91332/91; 18355/92; 26424/92; 37160/93; 38808/93 and 44930/93, the disclosures of each of which are incorporated herein by reference..

A third embodiment of the invention is directed to pharmaceutical compositions comprising a compound of formula (IA) together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients.

In a fourth embodiment of the invention there is provided a method for inhibiting 30 retroviral proteases in a mammal in need of'such inhibition, comprising administering to the mammal an effective amount of a compound of the first embodiment or of a composition of the second embodiment. In one form of the third embodiment, there is provided a method for the treatment or prophylaxis of HIV viral infections such as AIDS.

For inhibiting retroviral proteases or the treatment of HIV viral infections, a 35 composition of the second embodiment may be administered orally, topically, parenterally, e.g. by injection and by intra-arterial infusion, rectally or by inhalation spray.

For oral administration, the pharmaceutical .composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, including lyophilised powders,

AP/P/ 94 / 0 0 6 67

AP. Ο Ο 5 9 7 solutions, granules, suspensions, emulsions, syrups and tinctures. Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.

Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, io polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of Wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, 15 waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono30 or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.

The emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.

For topical administration, the pharmaceutical composition may be in the form of a cream, ointment, gel, jelly, tincture, suspension or emulsion. The pharmaceutical composition may contain pharmaceutically acceptable binders, diluents, disintegrating agents, preservatives, lubricants, dispersing agents, suspending agents and/or emulsifying agents as exemplified above.

ΑΡ/Γ7 94 / 0 0 6 67

AP. Ο Ο 5 9 7

For parenteral administration, the compound of formula IA or its salt may be prepared in sterile aqueous or oleaginous solution or suspension. Suitable non-toxic parenterally acceptable diluents or solvents include water, Ringer's solution, isotonic salt solution, 5% dextrose in water, buffered sodium or ammonium acetate solution, 1,35 butanediol, ethanol, propylene glycol or polyethylene glycols in mixtures with water. Aqueous solutions or suspensions may further comprise one or more buffering agents. Suitable buffering agents include sodium acetate, sodium citrate, sodium borate or sodium tartrate, for example. Aqueous solutions for parenteral administration are also suitable for administration orally or by inhalation.

io For rectal administration, the compound of formula IA is suitably administered in the form of an enema or suppository. A suitable suppository may be prepared by mixing the active substance with a non-irritating excipient which is solid at ordinary temperatures but which will melt in the rectum. Suitable such materials are cocoa butter, waxes, fats, glycerol, gelatin and polyethylene glycols. Suitable enemas may comprise agents as exemplified above with reference to forms for topical administration.

Suitably, an inhalation spray comprising a compound of formula IA will be in the form of a solution, suspension or emulsion as exemplified above. The inhalation spray composition may further comprise an inhalable propellant of low toxicity. Suitable propellants include carbon dioxide or nitrous oxide.

The dosage form of the compound of formula IA will comprise from 0.01% to

99% by weight of the active substance. Usually, dosage forms according to the invention will comprise from 0.1% to about 10% by weight of the active substance.

The compound of formula IA may be administered together or sequentially with one or more other active substances known or believed to have anti-viral activity. 25 Examples of such other active substances include AZT, acyclovir, ddC, ddA, trisodium phosphonoformate, castanospermine, rifabutin, ribaviran, bropirimine, phosphonothioate oligodeoxynucleotides, dextran sulfate, α-interferon and ampligen.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph showing the transformation of the compound of Example 5 30 (Prodrug) into the compound of Example 20 of International Patent Application No.

PCT/AU93/00103 (Drug) in rabbit's blood in vitro.

Figures 2 and 3 are graphs showing the transformation of Prodrug into Drug in vivo following intravenous and intramuscular (respectively) administration to a rabbit.

BEST MODE OF CARRYING OUT THE INVENTION

Methods for the preparation of compounds of formula (IB) wherein x and y are both 0, B is -CH(OH)- and R506- R513. R542 ^and R543 ^are hydrogen are described in the following Schemes 11 and 12:

AP/P/ 94/00667

AP.00597

Scheme 11

R512 <0 +

R501—N-C-C-C-H i I I i

Η Η Η H

R550 h-n-n-r₅₀₂

R551

Γ (i) iPrOH; 60-90°C;12hr Yield 70-90%, or (ii) AI₂O₃; ether, RT; 12-24hr, Yeld 30-45%

Scheme 12	R512		R551
R501 N-	—C—C-CHj-Hal I II	+ Η-Ν-N— R502
H	I u Η O		R550 (i) Nal/DMF or AcCN; 1 hr; RT; (ii) NaHCO3 or tertiary amine; 2-12 hr; RT (iii) NaBI-14; 30 min; RT

R501\

/9 9 0 0 / *> 6 ,'d/dV

Scheme 13 presents an example of a method of preparation of Examples 11 and

12, commencing with the product of Scheme 12 in which R₅₀i is benzyloxycarbonyl, R512 is methoxycarbonyl, R55Q and R₅₅₁ together form a 3,4-diazabicyclo[4.4.0]decane system and R₅q₂ is tert-butoxycarbonyl:

AP . Ο Ο 5 9 7

, ΗΒΤ, EtN(i-Pr)₂/DMF, RT, 12 hrs

AP/P/ 94 / 0 0 6 67

Scheme 14 presents an example of a method of preparation of compounds of formula shown in Table 4 below, in which the solubilising group Px is P(O)(OH)H or

P(O)(OH)₂:

AP. Ο Ο 5 9 7

Scheme 14

H₃PO₃; DCC; Pyridine 60’C

ι. (Me₃SiO)₂NH

2. (Me₃SiO)₂

3. MeOH

4. H₃O* *

Compositions of the third embodiment may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending, grinding, 5 homogenising, suspending, dissolving, emulsifying, dispersing and mixing of the compound of formula (IA) together with the selected excipient(s). carrier(s), adjuvant(s) and/or diluent(s).

In the method for the treatment of HIV viral infections in accordance with the fourth embodiment of the invention, a compound of the first embodiment will usually be io administered orally or by injection. A suitable treatment may consist of the administration of a single dose or multiple doses of the compound of formula (IA) or of a composition of the third embodiment. Usually, the treatment will consist of administering from one to five doses daily of the compound of formula (IA) for a period of from one day to several years, up to the lifetime of the patient. Most usually, the treatment will 15 consist of the administration of the compound of formula (IA) for a period of from one day to one year.

The administered dosage of the compound of formula IA can vary and depends on several factors, such as the condition of the patient. Dosages will range from O.Olmg to 200 mg per kg. Usually, the dose of the active substance will be from O.Olmg to 25 mg per kg of body weight.

Examples of dosage forms in accordance with the invention are as follows:

1. Tablet

AP/P/ 94 / 0 0 6 67

Compound of formula IA Starch

0.01 to 20 mg, generally 0.1 to lOmg 10 to 20 mg

AP . Ο Ο 5 9 7

	Lactose	100 to 250 mg
	Gelatin	0 to 5 mg
	Magnesium stearate	0 to 5 mg
5 2.	Capsule Compound of formula IA	0.01 to 20 mg, generally 0.1 to lOmg
	Glycerol·	100 to 200 mg
	Distilled water	100 to 200 mg
	Saccharin	0 to 2 mg
10	Methyl Paraben	1 to 2 mg
	Polyvinylpyrrolidone	0 to 2 mg
3.	Injectable solution Compound of formula IA	0.01 to 20 mg, generally 0.1 to lOmg
	Sodium chloride	8.5 mg
15	Potassium chloride	3 mg
	Calcium chloride	4.8 mg
	Water for injection, q.s. to	10 ml
4.	Elixir Compound of formula IA	0.01 to 20 mg, generally 0.1 to lOmg
20	Sucrose	100 mg
	Glycerol	2ml
	Carboxymethylcellulose	20mg
	Cherry flavour	2 mg
	Water	q.s. to 10 ml

AP/P/ 94/ 00667

Ο 25 EXAMPLES

The following Examples describe the preparation of compounds according to the inventionand are intended to illustrate the invention. The Examples are not be construed as limiting in any way the scope of the present invention. Starting materials for the syntheses described in the following Examples¹ are described in International Patent

Application No. PCT/AU93/00103. In these Examples, melting points were taken on a hot stage apparatus and are uncorrected. Proton and phosphorus NMR spectra were recorded at 100 MHz or 300MHz on Perkin Elmer R32 or Bruker EM 300 spectrometers, respectively, in CDCI3 unless otherwise stated. Chemical shifts for proton NMR are ppm downfield from tetramethylsilane; chemical shifts for P³¹ NMR are ppm downfield from l,2-bis(diphenylphosphino)ethane external standard. Thin layer chromotography (TLC) was performed on silica gel 60-F254 plates (Merck). Compounds were visualized by ultraviolet light and/or 2% aqueous potassium permanganate solution. The composition

AP . Ο Ο 5 9 7 (by volume) of the TLC solvent systems were (A) hexane/ethyl acetate 3:2, and (B) concentrated NH₄OH/isopropanol 1:3.

Example 1

4S,5S-5,6-Dibenzyl-l,2-(cis-l,2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro1,2,6-triazepine

Step A: 4S,55-5-benzyl-1,2-(cis-l,2-cyclohexane)dimethyl-4-t-butyldimethy Isily loxy-7-oxoperhydro-1,2,6-triazepine: Hydrogen chloride gas was bubbled through the solution of 0.51 g (1.26 mmol) of cis-l,6-3-t-butoxycarbonyl-4-[(2S,3S)-2-hydroxy-3-amino-4io phenylbutyl]-3.4-diazabicyclo[4.4.0]decane (isomer having R_f (A) = 0.16 when eluted with 8% methanol in dichloromethane) in 10 ml of 1% solution of methanol in methylene chloride for 30 min at room temperature. After purging the excess of hydrogen chloride with nitrogen gas the solvent was removed under reduced pressure to give 0.42 g (100% yield) of the hydrochloride salt of cis-l,6-4-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]15 3,4-diaza-bicyclo[4.4.0]decane as a hygroscopic, white solid. This was dissolved in 1 ml of dry DMF and 0.114 g (1.68 mmol) of imidazole and 0.21 g (1.38 mmol) of tbutyldimethylsilyl chloride were added under nitrogen. The resulting mixture was stirred overnight at room temperature and evaporated to dryness in vacuo. The residue was diluted to 20 ml with ethyl acetate, washed with saturated sodium bicarbonate and dried 20 over anhydrous potassium carbonate and filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 20 ml of dry dioxane.

To this, 0.204 g (1.26 mmol) of 1,1'-carbonyldiimidazole was added and the resulting mixture was stirred for 24 hrs at room temperature. After evaporation of the solvent under reduced pressure the residue was diluted to 15 ml with ethyl acetate and washed with water (3x) and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel; hexane/ethyl acetate 3:2) gave 0.095 g (17% yield) of the title compound, melting at 145 - 146°C; Rf (A) = 0.43; NMR 0.07, 0.09 (s,s 6Η, CH₃); 0.94 (s, 9Η, t-butyl CH₃); 1.2 - 2.0 (m, 10H, cyclohexane CH₂, CH); 2.5 - 2.8 (m, 4H, CH₂-3, benzyl CH₂); 3.2 - 3.7 (m, 4H, dimethyl CH₂); 3.9 - 4.0 (m, 3H, CH-4,5, NH); 7.1 - 7.32 (m, 5H, aromatic).

£9 9 0 0 06 /d.dV

AP. 0 0 5 9 7

Step B: 4S, 5S-5,6-dibenzyl-l, 2-(cis-l,2-cyclohexane)dimethyl-4-t-butyldimethylsilyloxy-7oxo-perhydro-1,2,6-triazepine: 4.5 mg (0.15 mmol) of 80% dispersion of sodium hydride in mineral oil was added to a solution of 0.0665 g (0.15 mmol) of the product of Step A in 0.2 ml of dry DMF at room temperature. After stirring for 30 min at room temperature, 0.0179 ml (0.15 mmol) of benzyl bromide was then added. The resulting mixture was stirred overnight, then diluted to 15 ml with ethyl acetate and washed with water, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography gave 0.029 g (36% yield) of the title compound as a heavy io syrup; R_f (A) = 0.77; NMR -0.35, -0.18 (s, s, CH₃); 0.8 (s, 9H, t-butyl CH₃); 1.2 - 2.2 (m, 10H, cyclohexane CH₂, CH); 2.56 - 4.18 (m, 12H, benzyl CH₂, dimethyl CH₂,

CH₂-3, CH-4,5); 6.8 - 7.4 (m, 10H, aromatic).

Step C: 4S, 5S-5,6-Dibenzyl-l, 2- (cis-1,2-cyclohexane)dimethyl-4-hydroxy-7-oxo-perhydro1,2,6-triazepine: A mixture of 29 mg (0.0543 mmol) of the product of Step B and 0.0426 is g (0.163 mmol) of tetrabutylammonium fluoride hydrate in 1 ml of anhydrous acetonitrile was stirred at 45±5°C for 3 hrs and evaporated to dryness. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate 3:2) to give 0.019 g (86% yield) of the title compound as a colourless foam; Rf (A) = 0.26; NMR 1.2 - 2.1 (m, 18H, cyclohexane CH₂, CH, OH, 3.5 x H₂O); 2.6 - 4.0 (m, 11H, benzyl CH₂, dimethyl CH₂,

CH₂-3, CH-5); 4.83 (m, 1H, CH-4); 7.0 - 7.4 (m, 10H, aromatic).

Example 2

4S,5S-l,5>6»Tribenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-l,2,6-triazepine

AP/P/ 9 4/ 0 0 6 67

Step A: 4S, 5S-5-benzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-l, 2,625 triazepine: When t-butyl 3-isopropyl-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbazate was substituted for cis-1,6-3-t-butoxycarbonyl-4-[(2S,3S)-2-hydroxy-3-amino4-phenylbutyl]-3,4-diazabicyclo[4.4.0]decane in Step A of Example 1 the identical process afforded the title compound in 20% overall yield; melting point = 131 - 132°C (hexane); R_f (A) = 0.18; NMR 0.10, 0.11 (s, s, 6H, silyl CH₃); 0.95 (s, 9H, t-butyl so CH₃); 1.1-1.35 (m, 6H, isopropyl CH₃); 2.8 - 3.2 (m, 5H, CH₂-3, CH-5, benzyl CH₂);

AP . Ο Ο 5 9 7

3.45 (m, IH, isopropyl CH); 4.18 (m, IH, CH-4); 4.41 (m, IH NH-6); 5.63 (s, IH, NH1); 7.1 - 7.4 (m, 5H, aromatic).

Step B: 4S,5S-1,5,6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-l,2,6triazepine·. A mixture of 0.07 g (0.185 mmol) of the product of Step A and 0.012 g (0.371 mmol) of sodium hydride in 0.2 ml of dry DMF was stirred for 30 min at room temperature, then 0.0441 ml (0.371 mmol) of benzyl bromide was added. The resulting mixture was stirred overnight and worked up as described in Step B of Example 1. The purification of the crude product by column chromatography (silica gel, hexane/ethyl acetate 3:2) save 0.031 g (30% yield) of the title compound as a colourless syrup; Rf (A) io = 0.74, NMR -0.28, -0.22 (s.s, 6H, silyl CH₃); 0.8 (s, 9H, t-butyl CH₃); 1.0 - 1.35 (m,

6H, isopropyl CH₃); 2.35 - 3.3 (m, 5H. CH₂.₃, CH-5, 5-benzyl CH₂); 3.45 - 3.82 (m, 2H, isopropyl CH, CH-4); 4.0 - 5.38 (m, 4H, 1,6-benzyl CH₂); 6.6 - 7.8 (m, 15H, aromatic).

Also, the fractions with Rf (A) = 0.63 were combined and evaporated to dryness under 15 reduced pressure to give 0.061 g (70% yield) of 4S,5S-5,6-dibenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-l,2,6-triazepine as a colourless solid; NMR 0.11 (d,

6H, silyl CH₃); 0.93 (s, 9H, t-butyl CH₃); 1.24 (m, 6H, isopropyl CH₃); 2.4 - 3.4 (m, 5H, CH₂-3, CH-5, 5-benzyl CH₂); 3.75 (m, IH, isopropyl CH); 4.0 - 4.7 (m, 3H. CH-4, 6-benzyl CH₂); 5.05 (m, IH, NH); 7.0 - 7.7 (m, 15H, aromatic).

2o Step C: 4S,5S-1,5,6-Tribenzyl-2-isopropyl-4-hydroxy-7-oxo-perhydro-l, 2,6-triazepine: When the title compound of Step B was substituted for 4S,5S-5,6-dibenzyl-l,2-(cis-l,2cyclohexane)-dimethy!-4-t-butyldimethyIsilyloxy-7-oxo-perhydro-l,2,6-triazepine in Step C of Example 1, the identical process afforded the title compound with 98% yield as a

C foam; Rf (A) = 0.68; NMR (CDC1₃) 1.07, 1.19 (d, d, 6H, isopropyl CH₃); 1.58 (s, IH,

OH); 2.6 - 3.15 (m, 5H, CH?-3, CH-5, 5-benzyl CH₂); 3.2 - 5.3 (m, 6H, isopropyl CH, CH-4, 1,6-benzyl CH₂); 6.8 - 7.6 (m, 15H, aromatic).

Example 3

4S,5S-5,6-dibenzyI-2-isopropyl-4-hydroxy-7-oxo-perhydro-l,2,6-triazepine

AP/P/ 94/00667

When 4S,5S-5,6-dibenzyl-2-isopropyl-4-t-butyldimethylsilyloxy-7-oxo-perhydro-l,2,6triazepine was substituted for 4S,5S-l,5,6-tribenzyl-2-isopropyl-4-t-butyldimethylsilyloxyAP.00597

7-oxo-perhydro-l,2,6-triazepine in Step C of Example 2 the identical process afforded the title compound in 88% yield; melting point = 191 - 193°C; Rf (A) = 0.17; NMR (DMSO-d₆, 80°C) 2.5 - 3.0 (m, 4H, CH₂-3, 5-benzyl CH₂); 3.28 (m, IH, CH-5); 3.6 (m, IH, CH-4); 3.8 (m, IH, isopropyl CH); 4.2 - 4.7 (m, 3H, 6-benzyl CH₂; OH); 5.41 (m, IH, NH); 7.0 - 7.4 (m, 10H. aromatic).

Example 4 t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaIdyl-LasparaginyI)amino-4-phenylbutyl carbazate

io To a mixture of 0.4 g (0.67 mmol) of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl carbazate and 0.12 g (1.47 mmol) of anhydrous phosphorous acid in 1.5 ml of anhydrous pyridine was added 0.28 g (1.4 mmol) of dicyclohexylcarbodiimide at room temperature under nitrogen, with stirring. After stirring for 2 hours at 60°C, the solvent was evaporated under reduced pressure and is the residue was treated with 28 ml of 0.1 ml aqueous sodium bicarbonate and vigorously stirred for 1 hour at room temperature. The precipitate was filtered off and washed with water and the filtrate was acidified to pH ~ 1.5 with concentrated hydrochloric acid. The product was taken up by extraction with ethyl acetate (3 x 50 ml), and the organic phase was dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.42 g (95% yield) of the title product as a colourless solid; Rf (B) = 0.62; H^JNMR (CDCI3); 1.08 (m, 6H, isopropyl CH3); 1.41 (s, 9H, t-butyl CH3); 2.7 - 4.8 (m, 14H, asn CH2, butyl CH2-1, 4; CH-2,3; isopropyl CH; P-OH x 2H2O); 5.12 (m, IH, asn CH); 5.89 (s, 0.5 H, PH); 6.2 - 8.5 (m, 15.5 H, aromatic, amide NH, 0.5 PH); 9.02 (m, IH, asn NH); P³¹NMR (CDC13) 14.99 (J_P._H = 636 Hz).

/9 9 0 0 /76 /d/d

AP.0 0 5 9 Ί

Example 5 t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldyl-LasparaginyI)amino-4-phenylbutyI carbazate

c

A suspension of 0.4 g (0.6 mmol) of the product of Example 4 in 2 ml of hexamethyldisilazane was stirred for 45 min at 120 ± 5 °C. At this point the reaction mixture became homogeneous. To this 0.3 ml of bis(trimethylsilyl)peroxide (Cookson,

P.G et al., J. Organometal. Chem., 1975, 22, C31) was added and stirring was continued for 1 hour at the above temperature. The reaction mixture was cooled to room io temperature, then evaporated to dryness in vacuo. The residue was dissolved in 20 ml of methanol, evaporated to dryness under reduced pressure and redissolved in 12 ml of 0.1 ml aqueous sodium bicarbonate. The resulting mixture was acidified to pH-1.5 with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate (3 x 50 ml). The combined organic phase was dried over anhydrous magnesium is sulfate and evaporated to dryness to give 0.39 g (96% yield) of the title compound as a colourless solid; Rf(B) = 0.07; H’NMR (CDCI3): 1.2 (m, 6H, isopropyl CH₃); 1.4 (s, θ 9H, t-butyl CH₃); 2.8 - 4.2 (m, 8H, asn CH₂ butyl CH₂-1,4, CH-3, isopropyl CH); 4.2 6.4 (m, 5H, asn CH, butyl CH-2, NH, POH); 6.5 - 8.4 (m, 14H, aromatic, NH); 8.78 (m, 2H, NH); P³¹NMR (CDCIj) 9.6 (s).

AP/P/ 94 / 0 0 6 67

AP. Ο Ο 5 9 7

Example 6 cis-1,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane

When cis-1,6-3-t-butoxycarbonyl-4-[(2S, 3S)-2-hydroxy-3-(N-quinaldyl-Lasparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.Ojdecane is substituted for t-butyl

3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutylcarbazate in Example 4, the identical process affords the title compound in 89% yield, as a colourless solid; Rf(B) = 0.64; H'NMR (CDCI3): 1.1 - 1.8 (m, 19H, t-butyl CH3, 10 decane CH₂-7,8,9,10, CH-1,6); 2.12 (m, 1H, butyl CH-3); 2.6 - 5.1 (m, 19H, asn CH₂, CH, butyl CH₂-1,4, CH-2, decane CH₂-2,5, ΡΟΗ x 2.5 H₂O); 6.1 - 8.4 (m, 15H, amide

NH, PH, aromatic); 9.08 (m, 1H, asn NH); P³¹NMR (CDC1₃) 16.43 (J_PH = 700 Hz).

Example 7 cis-1,6-3-t-ButoxycarbonyI-4-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldyl-L-

AP/P/ 94 / 0 0 6 67

When the product of Example 6 is substituted for t-butyl 3-isopropyl-3-[(2S, 3S)-2phosphitooxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl carbazate in Example 5, the identical process affords the title compound in 83% yield, as a colourless solid; Rf(B) 20 = 0.12; H‘NMR (CDCI3): 1.1-2.4 (m, 20H, t-butyl CH₃, decane CH₂-7,8,9,10, CH1,6, butyl CH-3); 2.7 - 3.9 (m, 9H, asn CH₂, butyl CH₂-1,4, CH-2, decane CH₂-5); 5.1

AP . Ο Ο 5 9 Ί (m, IH, asn CH); 6.1 - 8.3 (m, 21H, amide NH, aromatic, POH x 2.5 H₂0); 9.05 (m,

IH, asn NH); P^lNMR (CDC1₃) 10.5 (s).

Other representative compounds in accordance with the invention are described in Tables 1 to 5. Other compounds in accordance with the invention are substances in 5 which a hydroxyl, amino or mercapto group is any of the compounds described in the

Examples and disclosures of the following, has been derivatised with a solubilising group

Px as defined herein:

US Patent Nos. 5,116,835, 5,126,326; 5,132,400; 5.145,951; 5.198.426; 5,212,157;

5,215,968: 5.221,667; 5*250563; 5,268,361; 5,294,720; and 5,296,604; International ic Patent Application Nos. 90/09191; 91/08221; 91/10442; 92/15319 and 92/21696;

European Patent Application Nos. 0574135; 0528242; 0519433 and 0432595 and

Australian Patent Application Nos. 35700/89; 42308/89; 45665/89; 46115/89; 53716/90;

63221/90; 66334/90; 71319/91; 71320/91; 71323/91; 77326/91

88900/91; 82313/91; 83234/91; 83206/91; 85877/91: 87309/91 is 88900/91: 89941/91; 90531/91; 90851/91; 90925/91; 91223/91

91790/92: 10812/92; 18355/92; 19373/92; 21944/92; 22889/92

26424/92; 31628/93; 35165/93; 35621/93; 37160/93; 38808/93

81910/91; 82054/91; 87409/91; 87594/91; 91251/91; 91332/91; 24129/92; 24690/92; 41230/93; 41659/93;

44930/93 and 49072/93, the disclosures of each of which are incorporated herein by reference.

Example 8

In Vivo Removal of Phosphono Group

Solutions; The product of Example 5 was converted quantitatively into the corresponding disodium salt by treatment of the free acid with 2 equiv. of 0.2 M sodium bicarbonate and lyophilization of the resulting solution. The stock solutions of the disodium salt of the product of Example 5, for blood and animal experiments, were prepared in sterile water.

Analyses: Reverse phase analyses (HPLC) were performed on Waters ternary gradient liquid chromatograph equipped with 996 diode array detector set at 238 nm. Separations were achieved on Alltima RP-18 (250 x 4.6 mm, i.d., 5 μ particles), with the flow rate of 1 ml/min. The isocratic mobile phase composition used for analyses consisted of 40% of

0.1% aqueous trifluoroacetic acid (TFA) and 60% of acetonitrile containing 0.1% TFA and 10% water. The retention time of the product of Example 5 (referred to below as Prodrug) was in the range of 3.6 - 3.9 minutes and the retention time of t-butyl 3-isopropyl-3-[(2S, 3S)-2-hydroxy-3-(N-quinaldyl-L-asparaginyl)amino-4-phenylbutyl -carbazate (referred to below as ’’Drug) was about 6.2 minutes. Detector response was linear from 0.5 to 120 μΜ for Prodrug and 0.05 to 50 μΜ for Drug.

AP/P/ 94/ 0 0667

AP. Ο Ο 5 9 7

Standards and Sample Processing: The standards were prepared by serial dilution of Prodrug or Drug in rabbit blood collected into heparinised tubes. Blood samples were transferred into vials containing 150 units of heparin and stored on ice until processed. The blood samples were then separated by centrifuging at 6000 rpm for 10 min. The plasma samples were frozen and stored at -20°C until they were analysed.

Plasma preparation for HPLC analysis: An equal volume (100 pL) of thawed plasma z

and acetonitrile was stirred with a vortex mixer and allowed to stand at room temperature for 5 minutes, then centrifuged at 14000 rpm for 10 minutes. Samples of the supemantant (50 pL) were injected into the chromatograph.

io Transformation of Prodrug into Drug by Blood was established by measurement of prodrug and drug concentrations in plasma following the prodrug incubation in whole rabbit's blood (100 pM) at 36°C for 19 hours. Fig. 1 shows the concentrations of prodrug and drug under these conditions over 19 hours.

Transformation of Prodrug into Drug after intravenous (IV) administration of is prodrug (9.2 mg/kg) to rabbit was established by measurement of prodrug/drug concentrations in plasma over 120 min. The formulated product, containing 30 mg/ml of prodrug, was well tolerated by the rabbit. The plasma profiles of prodrug and drug disappearance are shown in Fig. 2.

Transformation of Prodrug into Drug after Intramuscular (IM) administration of prodrug (7.9 mg/kg) to rabbit was established by measurement of drug concentrations in plasma over 330 min. The formulated product, containing 30 mg/ml of prodrug was well tolerated by the rabbit. The time dependence of the plasma concentration of the drug are shown in Fig. 3.

When prodrug was administered to a dog orally at a dose of 20mg/kg, the blood plasma concentration of drug was found to be 0.044, 0.141, 0.189, 0.172, 0.164, 0.132, 0.089 and 0.060 pM, respectively, after 5, 15, 30, 47, 63, 93, 124 and 155 minutes. When prodrug was administered to a second dog orally at a dose of lOmg/kg, the blood plasma concentration of drug was found to be 0.137, 0.371, 0.297, 0.242, 0.176, 0.11, 0.071, and 0.050 pM, respectively, after 5, 15, 30, 45, 60, 94, 123 and 154 minutes.

AP/P/ 94 / 0 0 6 67

AP· Ο Ο 5 9 Ί

ο

U /9 9 0 0 /76 /d/dV

AP. 0 0 5 9 7

TABLE 1 (CONT.)

AP/P/ 9 4 / 0 0 6 67

AP. Ο Ο 5 9 7

Λ ΰ

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ο

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AP. 0 0 5 9 7

TABLE 1 (CONT.)

AP/P/ 94/ 0 0 6 67

AP.00597

ο

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AP.00597

υ

AP/P/ 9 4 / 0 0 6 67

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AP/P/ 94 / 0 Ο 6 67

AP . 0 0 5 9 7

TABLE 1 (CONT.)

AP/P/ 94/ 0 0 6 67

AP.0 0 5 9 7

TABLE 1 (CONT.)

/ 00667

AP.00597

TABLE 1 (CONT.)

ό

C oi ro r- r-~

AP.00597

AP/P/ 94 / 00 6 67

AP . 0 0 5 9 7

TABLE 1 (CONT.)

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AP/P/ 9 4/ 0 0 6 67

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AP/P/ 94/ 00 6 67

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AP. Ο Ο 5 9 7

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141

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Table 3

Examples of Other Compounds of Formula (I)

142 r

\ ,

143

144 ο

ο

OH

N N

O ,x

OMe

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145

146.

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149.

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Table 3 (cont.)

AP/P/ 94/00667

150

151.

152.

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154

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Table 3 (cont.)

AP/P/ 94 / 0 0 6 67

155

156.

157.

158.

159.

AP. Ο Ο 5 9 7

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AP/P/ 94/00667

160.

161.

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AP. Ο Ο 5 9 7

162.

Table 3 (cont.)

165.

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AP/P/ 94/00667

OCH₂Z

AP. Ο Ο 5 9 7

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Table 3 (cont.)

169.

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ΑΡ/Ρ/ 94/00667

AP. Ο Ο 5 9 7

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ΟΡ(ΟΧΟΗ)2

AP/P/ 94/00667

AP.00597

Table 3 (cont.)

176.

AP/F/ 9 4 / 0 0 6 67

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AP .00597 tr,

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AP/P/ 94 / 0 0 6 67

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Claims (16)

1. A compound having the structure represented by formula (IA):

Ri · R-| o R-t o*

R,₀-N-c-B--c-Y, (IA) ^13 Rl3* wherein R_t* is selected from the group consisting of Rj, P(O)(OR₇)Rg, S(O)_zOR₇ and S(O)_ZNR₇R₈, wherein z is 1 or 2 and R₇ and Rg independently have the meaning of R₂₀ as defined below, or R₇ and Rg together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, wherein:

R[ is selected from the group consisting of Rg and a solubilising group Px which is labile in vivo, wherein Rg is selected from the group consisting of hydrogen, R₂q as defined below, C(D)OR₂₁, C(D)SR₂₁,

C(D)NR_2JR₂₂, C(NR₂₁)R₂₂, C(NR₂₁)OR₂₂, and C(NR₂j)NR₂₂R₂₃, wherein R₂₁, R₂₂ and R₂₃ independently are selected from hydrogen and R_2o, or R₂₁ and R₂₂ together, or R₂₂ and R₂₃ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, wherein D is O or S;

o

Px is selected from the group consisting of Px*, /Px* o

'Px' ^R , and wherein D is O or S, R is H or Cj-C4 alkyl, and wherein Px* is selected from:

(CH2)₄NH₂

AP/P/ 94 / 0 0667

AP . 0 0 5 9 7

H c ¹⁰ f, c

R₂₀ is selected from the group consisting of optionally substituted (C_rC₁₈)alkyl, optionally substituted (C₂-Ci₈)alkenyl, optionally substituted (C₂-C₁₈)alkynyl, optionally substituted (C3-Cjg)cycloalkyl, optionally substituted (C₃-Cig)cycloalkyl(Ci-Ci₈)alkyl, optionally substituted (C₃-C[₈)cycloalkyl(C₂-Cig)alkenyl, optionally substituted (C₃-Cig)cycloalkyl(C₂-Cig)alkynyl, optionally substituted (Cg-C₂₄)aryl, optionally substituted (C6-C₂₄)aryl(Ci-Cig)alkyl, optionally substituted (C6-C₂4)aryl(C₂-C₁₈)alkenyl, optionally substituted (Cg-C^jaryl(C₂-Ci₈)alkynyl, optionally substituted (Cj-Cjgjacyl, optionally substituted heterocyclic, optionally substituted heterocyclic(Cj-Cigjalkyl, optionally substituted heterocyclic(C₂-C₁g)alkenyl, and optionally substituted heterocyclic(C₂-C₁g)alkynyl;

2. A compound according to claim 1 of the general formula (IB):

R512 R542 R551 ,c

R543

R501\ /θ'

B' I Ν' R₅₀₂

R506

R513

R550 wherein B is selected from the group consisting of / \

-c-c— ι I

Rl4*\^yRl4’

O i|

-C—

OR15 —οι

Rl4*

OR18

-οι

ORig and (IB)

OR15

C(Rs60)2 —Οι

Rl4*

Rl4*R-|4**

S ?

wherein R14*, R14**, R15, Rjg and R^ are as defined in claim 1 and each R550 is independently hydrogen or (Cj-C4)alkyl,

R502 and R₅₀₆ are independently a group R^oo, wherein R^qq is selected from the group consisting of hydrogen, C(O)OR₆₂i, C(O)SR₆₂i, C(O)NR₆₂iR622> (Cj-C^alkyl, (C₂-C₆)alkenyl, (C₅-C₁₀)cycloalkyl, (C₅-Ci₀)cycloalkyl(C_rC₆)alkyl, (C₅-C₁₀)cycloalkyl(C₂-C₆)alkenyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C_rC₆)alkyl, (C₆-C₁₀)aryl(C₂-C₆)alkenyl, (C_rC₆)acyl, heterocyclic, heterocycliciCi-Cgjalkyl and heterocyclic(C2-C₆)alkenyl, each of which may be substituted by up to three substituents selected from the substituents defined herein for optionally substituted (Ci-Cig)alkyl and R^2i ^and Ra?? have the meaning of R21 and R22 respectively, as defined in claim 1, or R521 and R^2 together form a saturated or unsaturated cyclic, bicydic or fused ring system as defined herein, is selected from the group consisting of R500 as previously defined, S(O)OR<532, S(O)2R<j32> S(O)NR^32R^33, S(O)2R632R633’ NH2, NHR^i and

501

AP/P/ 94 / 0 0 6 67

AP.00597

120

NR₆₃iR632’ wherein R^i has the meaning of as defined in claim 1 and R<532 and R$33 independently have the meaning of R₂q as defined in claim 1, or R₅₀₁ and R506 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system, or R^₃₁ and R^, or R^₃₂ and R-633 together

3. A compound according to claim 1 or claim 2 wherein said solubilising group Px is

25 selected from

-P-OH

OH and

O xP-OH

H

ΛΡ. Ρ/ 94/ 0 0 6 67

4. A compound according to claim 1 of formula (IQ), wherein R_b to Rj independently are -(CH₂)_a-6OPy ^0Γ wherein a can be 0, 1, 2, 3, 4 or 5, and wherein Py is a solubilising group Px as defined in claim 1, and R5 is as defined in claim 1:

OPy (CH2)o-2

Ra

Rb

Re Rd Rg

Ri (IQ)

30 wherein R_a' and Rj' are independently selected from Rj and Rj*, as defined in claim 1.

5 t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-L-asparaginyl)amino-4-phenylbutylcarbazate and t-Butyl 3-isopropyl-3-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutylcarbazate.

5. A compound according to claim 1 selected from the group consisting of

Γ' c

c

AP . θ θ 5 9 7

121 (i) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (ii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lvalyl)amino-4-phenylbutyl]carbazate, (iii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]carbazate, (iv) t-butyl 3-(l-methyl-3-phenylpropen-3-yl)-3-[(2R or S,3S)-2-hydroxy-3(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (v) t-butyl 3-(l-methyl-3-phenylpropyl)-3-[(2R or S,3S)-2-hydroxv-3-(Nquinaldoy 1-L-asparaginy 1 )amino-4-phenylbuty 1] carbazate, (vi) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-amino-4phenylbutyl]-3,4-diazabicyclo[4.4.OJdecane, (vii) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbony l)amino-4-pheny lbuty 1J -diazabicyclo[4.4. OJdecane, (viii) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lvalyl)amino-4-phenylbutyl]-3,4-diazabicyclo[4.4.OJdecane (ix) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-[N-(2-pyridyl)methoxycarbonyl)-L-valyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.OJdecane (x) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutylJ-3,4-diazabicyclo[4.4.OJdecane, (xi) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaldovl-Lglutaminyl)amino-4-phenylbutylJ-3,4-diazabicyclo[4.4.OJdecane, (xii) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S,3S)-2-hydroxy-3-(N-quinaIdovl-Lthreonyl)amino-4-phenylbutylJ-3,4-diazabicyclo[4.4. OJdecane, (xiii) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-pheny lbuty 1J-2,3-diazabicyclo(2.2.1J hept-5-ene, (xiv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-pheny lbuty 1J-2, 3-diaza-bicyclo[2.2.1 Jheptane, (xv) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2-pyridyl)methoxy-Lvalyl)amino-4-phenylbutyl]-2,3-diaza-bicyclo[2.2.1]heptane, (xvi) 2-[N-(lS)(2-methyl-l-methoxycarbonylpropyl)carbamoylJ-3-[(2R or S,3S)2-hydroxy-3-[N-(2-pyridyl)methoxy-L-valylJamino-4-phenylbutylJ-2,3diazabicyclo [2.2.1 ] heptane, (xvii) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginy l)amino-4-phenylbutylJ-2,3-diazabicyclo[2.2.1 Jheptane, (xviii) l-[2-(2-pyridyl)methoxycarbonylamino-Jbenzoyl-2-[(2R or S,3S)-2hydroxy-3-(N-quinaldoyl-L-asparaginyI)amino-4-phenylbuty!J-2-isopropylhydrazine,

ΑΓ/ΓΖ 94 / 0 0 6 67

AP . 0 0 5 9 7 r

c c

122 (xix) 2-t-butoxycarbonyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]-l,2,3,4-tetrahydrophthalazine, (xx) l-trimethylacetyl-2-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phyenylbutyl]-2-isopropylhydrazine, (xxi) l-trimethylacetyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyI-Lasparaginyl) amino-4-phenylbutyl]-2-isopropylhydrazine, (xxii) l-(t-butylamino)carbonyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-LasparaginyI)amino-4-phenylbutyl]-2-isopropylhydrazine, (xxiii) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-picolinoyl-Lasparaginyl)amino-4-phenylbutyl]carbazate, (xxiv) t-butyl 3-isopropyl-3-[(2R or S.3S)-2-hydroxy-3-(N-(2-pyridyl)-methoxycarbonylanthraniloyl)amino-4-phenylbutyl]carbazate.

(xxv) t-butyl 3-benzyl-3-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]carbazate, (xxvi) t-butyl 3-benzyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldovl-L-asparaginyl)amino-4-pheny I bu ty l ] ca rbaza te, (xxvii) t-butyl 3-cyclohexyl-3-[(2R or S, 3S)-2-hydroxy-3-(phenyl-methoxycarbonyl)amino-4-phenyIbutyl]carbazate, (xxviii) t-butyl 3-cyclohexyl-3-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]carbazate, (xxix) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(l-carbamoyl-methyl)acryloyl)amino-4-phenylbutyl]carbazate.

(xxx) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(2(RS)-3-tert-butylthio2-carbamoyl-methylpropionyl)amino-4-phenylbutyl]carbazate.

(xxxi) t-butyl 3-isopropyl-3-[(2R or S,3S)-2-hydroxy-3-(N-(l-benzovl-Lasparaginyl)amino-4-phenylbutyl]carbazate, (xxxii) l-t-butyloxycarbonyl-2-[(2R or S,3S)-2-hydroxy-3-(phenylmethoxycarbonyl)amino-4-phenylbutyl]hexahydropyridazine, (xxxiii) l-t-butyloxycarbonyl-2-[(2R or S,3S)-2-hydroxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]hexahydropyridazine, and (xxxiv) cis-l,6-3-t-butoxycarbonyl-4-[(2R or S, 3S)-2-hydroxy-3-(N-quinaldoyl-3cyano-L-alanyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4,4,0]decane, wherein the 2-hydroxy group has been derivatised with a solubilising group Px as defined in claim 1.

5 form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

R₅₁₂ and R₅₄₂ independently have the meaning of as previously defined,

R513 and R543 are independently selected from the group consisting of as previously defined and R₂₀q as defined in claim 1, ¹⁰ ^550 has the meaning of as defined in claim 1 and R551 is selected from the group consisting of R^so- hydrogen, S(O)OR^₂₂, S(O)₂R63₂. S(O)NR63₂R633 and S(O)₂R₆3₂R^33, wherein R₆₅₀ has the meaning of R<s as defined in claim 1 and R<532 and R533 are as previously defined, or R₆₃₂ and R₆₃₃ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined is herein, or R_55O and one of R₅₅₁ and R_5O2 together form a diazaheterocycle wherein R₅₅₀, R551 or R502 ^an^ the two nitrogen atoms to which they are bonded are part of a stable 5 to 10-membered ring which may comprise up to two further heteroatoms selected from 0, S and N and to which may be fused one or more cycloalkyl, cycloalkenyl, aryl or heterocyclic residues, which

20 diazaheterocycle may be substituted by one or more of the substituents defined herein for optionally substituted (Cj-C₁₈)alkyl, and wherein two substituents may together form pan of a ring, or one pair selected from R5j₂ and R₅₁3 and R5₄₂ and R₅₄3, together are =0.

5 R15 and R₁₇ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

M and M* are independently selected from the group consisting of Mi as previously defined, OCN, SCN, YR₂, Y* and N = CR₃oR₃i, wherein Y, Y* and R₂ are as defined below, and R₃₀ and R₃₁ independently have io the meaning of R₂q as previously defined,

M₂ is selected from the group consisting of Rj₄* as previously defined, -CR₃q* = Y** and -CR₃q* = NRi₇*, where Y** is as defined below, R₃₀* has the meaning of R₂q as previously defined, and Rp* has the meaning of Rg as previously defined, is Rjg and Rj₉ independently have the meaning of R₂q as previously defined or

R₁₈ and R₁₉ together form part of a saturated or unsarurated cyclic, bicyclic or fused ring system as defined herein,

Y is absent or is selected from the group consisting of;

O O

II II

Ο- ι 0- j II —S-N — Ii —S-N— — N=N— 4 —N=N — + ί —N=N— + ♦ I R50 II 1 0 R₅₀ » 4 0 II —N-S — I R50 4 0 II —N-S — I II R50O 0 II —o-s— II 0 0 II —o-s— 4 0 11 -s-o— 4 0 II —s-o— II 0 4 0 II —s-s— II 0 4 0 II —s-s— II O 4 —s-s— 0 II —P-N — 1 1 ^Κ51θ R50 4 0 II —O-P-N— I I 0 II Μ. Γ4 0 II —N-P-O— 0 II 0 II —O-P— I IN Γ I | —p—0— R51O R50 R50OR51 4 Rso0r₅i OR_S1 OR51 4 4 O II —ρ—N— | j 0 II —Ν—P— - I | O ( II -Ρ—O— —O-l I 3 II □— 1 and 0 II —0—P—0— j R51O R50 4 ^R50O^R51 ί D’ ~r₅₂ I 4 3R₅₂ 4 d~r₅₁ 4

wherein D** is selected from the group consisting of a bond, O, S and NR50, R50 has the meaning of Rg as previously defined, R₅₁ has the meaning of R15 as previously defined and R5₂ has the meaning of R₂q as previously defined, or R₅q and R51, when present,

AP/P/ 9 4 / 0 0 6 67

AP . Ο Ο 5 9 7

118 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and

R₂ has the meaning of R$ as previously defined,

Y* is selected from the group consisting of

_z ^R33 — N-N-R₂. — N—N=c — ! 1 ¹ R ^R50^R51 ^R50 ³⁴ -n-o-r₂. 1 ^R50 —o-n-r₂. I R50 —N=O » ί » 0 0 —S=O Η II — S=O —S=NR₁₁₇« I I D**Rii₅ I R-114* j j ^R114* I I Rl14* Pl14* — P=D* ι — P=D* and I ^R114 ^R114” wherein D* and D** independently have the meaning of D as previously defined; Rii4*, R114**, R115 And R _li7* have the meaning of R₁₄«, R14**,

R₁₅ and Rp* respectively, as previously defined; R₅q and R₅₁ are as previously defined or R50 and R51 together form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein; R₂* is selected from the group consisting of R₂ as previously defined, Px as previously defined, S(O)_zOR[₂₀ and S(O)_zNRi₂qR₁₂i, wherein z is 1 or 2; R₃₃ and R34 are independently selected from the group consisting of hydrogen and R₂₀ as previously defined, or R₃₃ and R₃₄ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein, and R₁₂₀ and R₁₂₁ independently have the meaning of R₂o as previously defined, or R_]20 and R₁₂₁ together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

R30 is as previously defined, and

Y** is selected from = N-NRu5R₁₁₇ and =N-ORu5, wherein R_ll5 and Rn₇ have the meaning of R₁₅ and R5 respectively, as previously defined, or R₁₁₅ and Ri₁₇ together form a saturated or unsaturated cyclic, bicyclic or fused ring svstem as defined herein,

AP/P/ 94 / 0 0 6 67 and

Yj is selected from the group consisting of -R_Z

-Ν—NI I ^R50 ^R51 —n-o-r₂. — o—n-r₂.

I I ^R50 ^R50 and wherein R₅q, R51 and R₂* are as previously defined;

and wherein any group selected from Rj, Rj*, R₂, R₂*, R9, Rj 1, Rj₂, R^. R50 and R51 30 may. together with any other group selected from Rj, Rj*, R₂, R₂*. R9-, Rjq, Rjj, Rl₂, Rj3, R50 and R51 form one or more saturated or unsaturated cyclic, bicyclic or fused ring system(s) as defined herein, and wherein any tertiary amino nitrogen atom may be replaced by the group -^N—O ,

ΑΡ.00597

119 and, wherein any hydroxyl, mercapto or amino group may be protected by a protecting group which is labile in vivo·, provided that the compound of formula (IA) comprises at least one solubilising group Px, as previously defined or, wherein the compound of formula (IA) includes two functional groups capable of being derivatised by a solubilising group Px, said two functional groups being in sufficiently close proximity to one another, comprising a cyclic structure including a structural unit selected from:

O

-»OH —X₂ o OH

C> OH Ο, H O_x 0 %>' V V /\

-xf X₂— —Xi X₂— — Xl X₂and wherein Xj and X₂ are independently selected from O, S and NRg wherein is as 10 previously defined.

5 B* is selected from the group consisting of

ZM Mt M₂ —N— —N— —N0 / \

-C-C —

I I

Rl4*Ri4~

R14'_/Rl4 ¹ /0 .cf

M ZM m₂ D* —c— —C — I —c— ll —c- r₁₄· r₁₄ R14 ORis SR18 Rl4* \ 7*M I A -c— 1 I —c— I cC ί ^OR19 and sr₁₉

wherein:

Rj4* and Rj4«* are independently selected from the group consisting of hydrogen, R20 as previously defined, CF₃, C(D*)OR4q, C(D*)SR4q and C(D*)NR4₀R4i, wherein R4₀ and R41 independently have the meaning of R₂₁ and R₂₂ as previously defined or R40 and R4J form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein,

Rj4 is selected from the group consisting of F, Cl, Br, I, R₁₄* as previously defined and R₂oo as previously defined,

Z is a saturated or unsaturated (C₂-C₄)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br, I and R[₄* as previously defined,

Z* is a saturated or unsaturated (Ci-C₃)alkylidene radical which is optionally substituted with one or more groups selected from F, Cl, Br. I and R₁₄* as previously defined,

Mj is selected from the group consisting of OR_]5, SR^ and NR₁₅R₁₇, wherein Rj5 is selected from the group consisting of:

Px as previously defined,

Rg as previously defined,

P/P/ 94/ 0 0 6 67

Px .Px ^D , ^R , wherein Px and D are as previously defined and R is H or C_rC₄ alkyl, and

AP . 0 0 5 9 7

117 a glycosyl radical which is derived from a synthetic or naturally occurring aldose, ketose, deoxyaldose, deoxyketose, aminoaldose, aminoketose or an oligosaccharide thereof, and

R₁₇ has the meaning of Rg as previously defined, or

6. A compound acording to claim 5, wherein said solubilising group is selected from

O 0

II II /P-OH .P-OH ^0H and ^H .

7. A compound according to claim 6, which compound is selected from the group consisting of:

AP/P/ 94 / 00 667

AP. Ο Ο 5 9 7

123 cis-l,6-3-t-Butoxycarbonyl-4-[(2S, 3S)-2-phosphonooxy-3-(N-quinaldoyl-Lasparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4.0]decane;

cis-1,6-3-t-Butoxycarbony 1-4-[(2S, 3S)-2-phosphitooxy-3-(N-quinaldoy 1-Lasparaginyl)amino-4-phenylbutyl]-3,4-diaza-bicyclo[4.4. Ojdecane;

8. A process for enhancing the water-solubility of a pharmaceutical or veterinary io substance, comprising derivatising a functional group of said substance with a solubilising o group Px, wherein Px is selected from the group consisting of Px*, ^u 'Px* ' ^R , and Px* is selected from:

-Px* wherein D is O or S, R is H or C1-C4 alkyl, and wherein

0 ^P_:OH OH s 0 II II p__0H P-OH OH H * , 0 0 II II ^Λό^οη OH OH > —NO₂ 0 0 /V^X^_0H 15 » X = 0, S, S(O), S(O) 2 0

OH

-OH

-B-OH

OH 'OH

ΊΡΙ 94/00667 and said functional group being capable of being derivatised with said solubilising group Px.

9. A process according to claim 8 wherein said substance is an HIV protease inhibitor.

Ar . Ο Ο 5 9 7

124

10. A process according to claim 8 wherein said solubilising group Px is selected from

O il a ,P-OH and o

II

10 and R_i2 independently have the meaning of R^ as previously defined;

11. A process according to claim 8 comprising reacting a hydroxyl group of said substance with phosphorous acid and optionally oxidising the product so obtained.

5

12. The product of the process of claim 8.

12* and R13* are independently selected from the group consisting of F, Cl, Br, I and R5 wherein R₅ is selected from the group consisting of H, CF₃, C(D)ORio₃, C(D)SRi₀₃ C(D)NRi_O3Rio4 and R₂₀ as previously defined, wherein D is as previously defined, and wherein Riq₃ and R104 have the meaning of R$ as previously defined, or Rjo₃ and R104 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein;

13. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 7 or 12 together with at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

13 is selected from the group consisting of

F, Cl, Br, I, as previously defined, and R₂qq, wherein R₂₀₀ is selected from the group consisting of CN, NCO, NCS, OCN, SCN, N₃, OR^q, SR$q, NR6oR<j1’ DiC(D₂)RgQ, DjCiD^R^, DiCCD^NR^qR^, NR^CCDpR^i, NR₆₀C(Di)D₂R₆i, NR₆₀C(Di)NR₆iR₆₂, NR₆₀OR₆₁, amidino, guanidino, S(O)R60, SfOlnDiR^o, SONR^qR^i, S(O)₂NR₆₀R₆i, DiS(0)R^o, DiS(0)₂OR^o, DiSONR^qR^i, D[S(O)₂NR₆₀R₆i . P(Di)(D₂R₆₀)R₆i,

P(D i)(D₂R_6O)D₃R^i, P(Dj)(D₂R₆₀)NR₆iR₆₂, PfDpR^oR^i,

D iP(D₂)(D₃R$o)R$i, DiP(D₂)(D₃R₆q)D₄R₆i, DiP(D₂)(D₃R5q)NR₆iR₆₂, ^DlP(D₂)R6oR6i, NR₆₀NR₆iR₆₂ and ONR^R^, wherein D_b D₂. D₃ and D₄ independently have the meaning of D as previously defined, and R^q, R^i and R$₂ independently have the meaning of R₆ as previously defined or any two or more of R$q, R^j and R^₂ form part of a saturated or unsaturated cyclic, bicyclic or fused ring system as defined herein;

AP/P/ 94/ 0 0 6 67

AP.00597

116 or Rj2 and R₁₃ together are selected from the group consisting of =0, =S, _zReo = C

D ¹ =NORgQ, =NRgQ, -OQO-, -SQS- and -SQO-, wherein Q is optionally substituted (Cj-C^jalkylidene as defined herein and Rg₀ and Rgj are as previously defined;

14. A process for preparing a pharmaceutical composition according to claim 13, io comprising mixing a compound according to any one of claims 1 to 7 or 12, with at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

15. A compound according to any one of claims 1 to 7 or 12, or a composition according to claim 13 for use in a method for the treatment or prophylaxis of a retroviral infection.

is

16. A compound according to claim 15, wherein said retroviral infection is AIDS.