AP597A - Retroviral protease inhibitors. - Google Patents

Retroviral protease inhibitors. Download PDF

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Publication number
AP597A
AP597A APAP/P/1994/000667A AP9400667A AP597A AP 597 A AP597 A AP 597A AP 9400667 A AP9400667 A AP 9400667A AP 597 A AP597 A AP 597A
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AP
ARIPO
Prior art keywords
group
amino
previously defined
hydroxy
meaning
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APAP/P/1994/000667A
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AP9400667A0 (en
Inventor
Damian Wojciech Grobelny
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Narhex Ltd
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Priority claimed from AUPM6446A external-priority patent/AUPM644694A0/en
Application filed by Narhex Ltd filed Critical Narhex Ltd
Publication of AP9400667A0 publication Critical patent/AP9400667A0/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
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    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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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 Rb 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 CrC4 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(CrC18)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, DlS(O)2NR60R61, P(D1)(D2R60)R61,
P(D1)(D2R6o)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 Rl4* 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 CrC4 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 R50
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 R50OR51
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**, Rl5 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°xH
-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 (CrC18)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, (CrC18)alkyl, (C2'C18)alkenyl, (C2-C18)alkynyl, (C3-C18)cycloalkyl (C3-C18)cycloalkyl(CrC18)alkyl, (C3-C18)cycloalkyl(C2-C18)alkenyl, (C3-C 18)cycloalkyl(C2-C18)aikynyl, (C6-C24)aryl, (C6-C24)aryl(CrC18)alkyl, (C6-C24)aryl(C2-Clg)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(CrC18)alkyl, typically (C3-C12)cycloalkyl(CrC6)alkyl; (C6-C24)aryl, typically is (C6-C16)aryl; (C6-C24)aryl(CrC18)alkyl, typically (C6-C10)aryl(CrC6)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, (CrC6)alkoxy, (CrC6)aryloxy, (CrC6)thioalkoxy, (C1-C6)thioaryloxy, (Ci-C6)alkoxy(CrC6)alkoxy, amino, (CrC6)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 (CrC18)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 RIV and T as previously defined, wherein RIV is selected from (Ci-C18)alkyl, (C2-Cig)alkenyl, (C2-C18)alkynyl, (C3-CI8)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 RIV 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 Rv 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 Rv is selected from (CrC18)alkyl, (C2-C18)alkenyl. (C2-C18)alkynyl, (C3-C18)cycloalkyl, (C3-C18)cycloalkyl(CrC18)alkyl, (C3-C18)cycloalkyl(C2-C18)alkenyl, (C3-Ci8)cycloalkyl(C2-C18)alkynyl, (C2-C18)acyl, (C6-C24)aryl(C2.C18)acyl, heterocyclic, heterocyclic(CrC18)alkyl, heterocyclic(C2-C18)alkenyl, and heterocycIic(C2-C18)alkynyl, and wherein Rv may be substituted with up to six groups independently selected from hydroxy, amino, (CrC6)alkoxy, (CrC6)aryloxy, (CrC6)thioalkoxy, (C1-C6)thioaryloxy, (CrC6)alkoxy(CrC6)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 (CrCi8) 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 (CrC6)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 (CrC18)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
Vz Vz 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 Rig 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> (CrC6)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(CrC6)aIkyI, (C6-C10)aryI(C2-C6)alkenyl, (Cr
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-Cl8)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(CrC6)alkyl, heterocyclic(C2-C6)alkenyl, heterocyclic(C(5-C10)aryl, C(D*)OR21*, C(D*)SR2i* and C(D*)NR21*R22*, wherein D*, R2J* 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 (CrC6)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(CrC6)alkyl, heterocyclic(C2-C6)alkenyl, heterocyclic(C6-Cl0)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$32 and ^33 are as previously defined, (vii) R502 is selected from the group consisting of R^ as previously defined,
C(D*)SR2i* and C(D*)NR21*R22+, wherein D*, R21* and R22* are as previously defined, <
(viii) R502 and R551 are both hydrogen or are both (Cj-C^acyl, (ix) R[4* is selected from the group consisting of C(D*)OR40, C(D*)SR4q and C(D*)NR40R41, wherein R40 and R41 are as previously defined, (x) R501 is selected from the group consisting of R^g as previously defined, S(O)OR632, 5(0)^32, S(O)NR632R633, S(O)2R632R633, nh2, nhr631 and NR63iRg32, wherein R^32 and R^33 are as previously defined, (xi) R50i and R5O6 are both (CrC6)acyl,
AP/P/ 94 / 0 0 6 67
AP.00597
OH
I and wherein when B is | or H
O
II c— then at least one of the following conditions also applies:
(xii) x + y > 0, (xiii) x + y = 0 and at least one of R532 and R533 is other than hydrogen, (xiv) R50 and R51 together form a diazaheterocycle as previously defined, (xv) at least one of R501, R502. R506 and R551 >s optionally substituted heterocyclic(Ci-Cig)alkyl, and (xvi) at least one of R5i2, R542, Rs22> ^532> ^513- ^543> ^523 an<l R533 is selected from the group consisting of C(O)OR62i, C(O)SR62i and C(O)NR^2iR^22’ wherein R^i and R622 are as previously defined.
Examples of typical unsubstituted diazaheterocycles are:
/9900,06 /d/dV
Another form of the first embodiment of the invention has the structure represented by formula (IQ) below, in which Rj, to Rj independently are -(CH2)a^OPy, or R<p wherein a can be 0, 1, 2, 3, 4 or 5, Py is a solubilising group Px as defined herein, R$ is as previously defined and Ra' 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
RaNHNH2 (RO)2C(O) base
RaNHNHC(O)OR
RbHal base
Ra—N—NH2 Rb
Ra—N—NHC(O)OR Rb
RcHal base
Ra—N— NHRC 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 Ra, 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 Ra represents R2.
z^33
When V is Y* where Y* is — n-n=cs , 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*)mZa with a synthon Zb, where Za includes one of the heteroatoms of Y, and Zb 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)R2 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
0R115
MeO-P
R114.. 0R115
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 RtX 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 Rc /I'k
RaRbN N Rd
L 9 9 0 0 / ‘z 6 /d/dV
H
AP. Ο Ο 5 9 7 where Ra and Rp have the meaning of R5qi and R506 as previously defined and Rc 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)
RaRbN'
OCH2O(CH2)2OCH3 2 S'io^3 OBz * 3. RaRt,NH/DMF
AP/P/ 94 7 ΦΟ'6 67
OH
RaRbN
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''~ACN 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) RaRbN
OCH2O(CH2)2OCH3 -A RNH2 hAd
OCH2O(CH2)2OCH3
OCH2O(CH2)2OCH3
RaRbN^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 cbc''°
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 NMez 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 R5q 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
RIZ (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,
Rlb R12, R50 and R51, together with another group selected from R1? R^, R2, R2*, R9*, R10, Rn, 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
Me2ButSi • '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
Me2ButSi
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 CrC4 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 CrC6 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 Rf (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; Rf (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); Rf (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; HJNMR (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 (JP.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 (JPH = 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
ΑΡ/Ρ/ 94/ 0 0 6 67
AP . Ο Ο 5 9 7
ο
U
ΑΡ/Ρ/ 94/ 00667
AP. 0 0 5 9 7
TABLE 1 (CONT.)
AP/P/ 94/ 0 0 6 67
AP.00597
ο
U
ΑΡ/Ρ/ 94 7 0 0 6 67
AP.00597
υ
AP/P/ 9 4 / 0 0 6 67
AP.00597
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.)
© υ
AP/P/ 9 4/ 0 0 6 67
105
AP.00597
AP/P/ 9 4/ 0 0 6 67
AP . 0 0 5 9 7
AP/P/ 94/ 00 6 67
Ο
U
ΑΡ/Ρ/ 94/00667
AP. Ο Ο 5 9 7
94/ 0 0 6 67
AP. Ο Ο 5 9 7
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AP .0 0 5 9 7
ο
U
AP/P/ 94 / 0 0 6 67
AP . Ο Ο 5 9 7
/9 9 0 0 /76 .'d/dV
AP. Ο Ο 5 9 7
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ο
U
ΑΡ/Ρ/ 94/00667
AP. Ο Ο 5 9 7
ΑΡ/Ρ/ 94/ 0 0 6 67
AP. Ο Ο 5 9 7
AP/P/ 94 / 00 667
AP. 00597
MVP/ 94/00667
141
AP. Ο Ο 5 9 7
Table 3
Examples of Other Compounds of Formula (I)
142 r
\ ,
143
144 ο
ο
OH
N N
O ,x
OMe
HO
ΛΡ/Ρ/ 94/ 0 0 6 67
145
146.
147.
c
148.
149.
AP. 0 0 5 9 7
Table 3 (cont.)
AP/P/ 94/00667
150
151.
152.
AP. Ο Ο 5 9 7
153.
154
Λ
Table 3 (cont.)
AP/P/ 94 / 0 0 6 67
155
156.
157.
158.
159.
AP. Ο Ο 5 9 7
Table 3 (cont.)
AP/P/ 94/00667
160.
161.
EtO
AP. Ο Ο 5 9 7
162.
Table 3 (cont.)
165.
ί j
i
I
AP/P/ 94/00667
OCH2Z
AP. Ο Ο 5 9 7
Γ
Table 3 (cont.)
169.
ΝΗΒζ
Ο
ΑΡ/Ρ/ 94/00667
AP. Ο Ο 5 9 7
Table 3 (cont.)
171
Ο
ΟΡ(ΟΧΟΗ)2
AP/P/ 94/00667
AP.00597
Table 3 (cont.)
176.
AP/F/ 9 4 / 0 0 6 67
AP.00597
AP/P/ 94/00667
AP .00597 tr,
ΙΛ
o CJ o CJ 1—^ <J o
o o o O o o
X >-o S3 CQ o X X
υ ί
CJ !n / ,y-. ' s'.—'Z.
\ £
Z—ci _ A _ =—υ—o £! / oi—U-” Λ \ 05 z—Oi
CO σι
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k.
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tn
Ό c
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Q.
E o
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rj £
N
CQ
N
S3
ΓΜ
CQ
N Si N M
CQ CQ CQ CQ
ΙΛ
S3 S3
S3
S3 S3 S3 S3
Γ*Ί
OO
Tt
OC ι/Ί
OO <0
ΓΟΟ oo
189. Ζ H Bz P(O)(O1I)2 (CII2)4- Boc
AP.00597 rq o
ΙΛ ai
tt w u >
> > O 1 O
N N U-j o ca
C3 >
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>.
δ ύ
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ca
TABLE 4 (cont.)
AP/P/ 94 / 0 0 6 67
AP. Ο Ο 5 9 7
/ Ο Ο 6 67
Ar . 0 0 5 9 7
AP/P/ 94 / 0 0 6 67
AP . 0 0 5 9 7
CM ©
»z>
>
I ύ
CJ O > CJ o JJ a δ
ca CM ca N CM
CJ o
ca
CJ a
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ir, ir.
© tz>
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N
CS
Γτ
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c.
s
CS
N
CQ
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Q,
S3
CS
TABLE 4 (cont.)
04 S' CM CM |U_ CM CM =i CM s 04 s o o CM E
o o o o g / g o X X O
§ g g o S Λ g o g g ST O
£U cT Sm ca -J if M X X λ
N
CM C2
Τ’ Ν Ν N & CS CS CS cN ca rc ca
SJ Ν N ca ca ca
N ca sO
IZ, κ a = x x x
N aa
AP/P/ 94/00667 ©
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c c c
X o> CZ3
> < < <
CM N N CM
a £ Λ > C cn < e cn <
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σ σ ο θ' σ
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u σ
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a ζ 04 04 04 ΟΙ 04 ΓΜ
5
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04 04 04 04 04
AP .0 0 5 9 7
73 u o u Q Th CQ 3 2 S Z u o o o
co u ca co co /**>s CQ CQ
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TABLE 4 (cont.)
CM c?
N N CQ CQ
CQ
N
CQ
N
CQ
N N CQ CQ
CQ
AP/P/ 94 / 0 0 6 67 o
£
X X 33 X
c ίΛ < e !Λ < c Vl < c !Λ < & < C cn < C Ζ! < e (Λ < C ΙΛ < C X <
ύ ύ ύ ύ ό ύ ό ό ύ ύ
Ο ο ο ο & ο Ο ο ο ο
Τ3 3 3
9 CL ~ m -ί Ό Ό
*7 Ο 1 ζ CM CM CM CM
CM CM CM CM
oo Ο © «—4 CM
CM CM o ΓΠ Cl
CM CM CM CM CM
AP .00597
TABLE 4 (cont.)
AP/P/ 9 4/ 0 0 6 67
AP.00591
CM ©
tn a
ca x
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x
rt Λ rt > > >
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- X X X Ξ
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TABLE 4 (cont.)
cm C4 CM CM CM CJ CM CM CJ O CJ
X X MM 2 X X X X X X
o '-v*' o x o z-s o X g g Λ g g X g g Λ wM g g X o -ν' g X g δ -ν' X g g X g g X g g X
δ <M g
vi <o
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S3
CQ
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S3 a
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N ca
S3 ca
S3 ca
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S3 ca
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AP.00597
λ σ3 53
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u Q CO CJ o co U 2 CQ N
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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 Rt* 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)NR2JR22, C(NR21)R22, C(NR21)OR22, and C(NR2j)NR22R23, wherein R21, R22 and R23 independently are selected from hydrogen and R2o, 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 (CrC18)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(CrC6)alkyl, (C5-C10)cycloalkyl(C2-C6)alkenyl, (C6-C10)aryl, (C6-C10)aryl(CrC6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, (CrC6)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 Rb 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 Ra' 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 R55O and one of R551 and R5O2 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 ORS1 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 R50OR51 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 R50R51 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 Rll5 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 -RZ
-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 Ox 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 CrC4 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 /VX^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 Ri2 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)NRiO3Rio4 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$q, NR6oR<j1’ DiC(D2)RgQ, DjCiD^R^, DiCCD^NR^qR^, NR^CCDpR^i, NR60C(Di)D2R6i, NR60C(Di)NR6iR62, NR60OR61, amidino, guanidino, S(O)R60, SfOlnDiR^o, SONR^qR^i, S(O)2NR60R6i, DiS(0)R^o, DiS(0)2OR^o, DiSONR^qR^i, D[S(O)2NR60R6i . P(Di)(D2R60)R6i,
P(D i)(D2R6O)D3R^i, P(Dj)(D2R60)NR6iR62, PfDpR^oR^i,
D iP(D2)(D3R$o)R$i, DiP(D2)(D3R6q)D4R6i, DiP(D2)(D3R5q)NR6iR62, DlP(D2)R6oR6i, NR60NR6iR62 and ONR^R^, wherein Db 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.
APAP/P/1994/000667A 1993-09-10 1994-09-09 Retroviral protease inhibitors. AP597A (en)

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