WO1997030072B1

WO1997030072B1 - Peptidomimetic inhibitors of cathepsin d and plasmepsins i and ii

Info

Publication number: WO1997030072B1
Application number: PCT/US1997/002930
Authority: WO
Filing date: 1997-02-20
Publication date: 1997-10-23

Abstract

The present invention relates to the design and synthesis of linear and cyclic inhibitors of cathepsin D and plasmepsins I and II. The present invention also relates to the uses of these inhibitors for inhibiting invasion and metastasis of cancerous cells. The present invention further relates to the use of cathepsin D and plasmepsin I and II inhibitors for the prevention and treatment of Alzheimer's disease and malaria.

Claims

AMENDED CLAIMS

[received by the International Bureau on 17 September 1997 (17.09.97); new claims 31-47 added; remaining claims unchanged (22 pages)]

31 . A compound o f f ormula ( I ) :

in which R, R, = represent hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclyl alkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkyl, alkoxyalkyl, akylthioalkyl, mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;

R_{l r} R₂, R«, R₅, R₆ = optionally substituted lower alkyl, lower cycloalkyl, aryl, aralkyl and heteroaryl;

R₃ = optionally substituted lower alkyl, lower alkoxy, lower alkylthio, mono or dilower alkyl amino, aralkyl, aralkoxy, aralkylthio, aralkylamino, cvcloalkylalkyl, cycloalkylalkoxy, cycloalkylalkylthio, cycloalkylalkylamino; and wherein R₂ and R₅ or R_! and R₃ are connected by an optionally substituted bridging moiety comprised of a stable combination of C, N, 0 or S atoms.

32. A compound selected from the group consisting of ;i) Iva-Val-Val-Sta-Val-Leu-Gly-NH2 (SEQ. ID. NO. 1); (2) Iva-Gln-Val-Sta -Ala-Leu-Gly-NH2 (SEQ. ID. NO. 2) ,

(3) Iva-Lys-Val-Sta -Ala-Leu-Gly-NH2 (SEQ. ID. NO. 3) ,

(4) Tba-Val-Val-Sta -Ala-Leu-Gly-NH2 (SEQ. ID. NO. 4)

(5) Iva-Val-Ile-Sta -Ala-Leu-Gly-NH2 (SEQ. ID. NO. 5)

(6) Iva-Val-Leu-Sta -Ala-Leu-Gly-NH2 (SEQ. ID. NO. 6)

(7) Tba-Val-Val-Pst -Val-Leu-Gly-NH2 (SEQ. ID. NO. 7)

(8) Tba-Val-Cys-Pst -Val-Leu-Gly-NH2 (SEQ. ID. NO. 8)

(9) Tba-Val-Glu-Pst -Val-Leu-Gly-NH2 (SEQ. ID. NO. 9)

(10) Tba-Val-Asp-Ps t-Val-Leu-Gly-NH2 (SEQ . ID . NO . 10) ;

(11) Iva-Val-Val-St a-Ala-Leu-Gly-NH2 (SEQ . ID . NO . 11) ;

(12) Tba-Val-Cys-Ps t-Val-Cys-Gly-NH2 (SEQ . ID . NO . 12) ;

(SEQ ID NO: 17) ;

(SEQ LD NO: 18);

(SEQ ID NO: 19) ;

COValNH

(SEQ ID NO: 20) ;

(SEQ ID NO: 21);

(SEQ ID NO: 21)

COValNH

(SEQ ID NO: 21)

(SEQ

COValL^βuGlyNH_a

:SEQ ID NO: 22) ; and

COValL^βuGlyNH,

ISEQ ID NO: 23)

33. A compound of formula II

in which R, R₇ = represent hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl , heteroaralkoxycarbonyl , heteroaryloxycarbonyl , heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkyl, alkoxyalkyl, akylthioalkyl, mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;

R₂ = optionally substituted lower alkyl, lower cycloalkyl, aryl, aralkyl and heteroaryl;

R₃ = optionally substituted lower alkyl, lower alkoxy, lower alkylthio, mono or dilower alkyl amino, aralkyl, aralkoxy, aralkylthio, aralkylamino, cvcloalkylalkyl, cycloalkylalkoxy, cycloalkylalkylthio, cycloalkylalkylamino; and wherein R and R3 are connected by an optionally substituted bridging moiety comprised of a stable combination of C, N, 0 or S atoms .

34. A compound selected from the group consisting of

COValValNH

COValNH i

OH

OH

and

35. A compound having the formula:

in which R and R ' are given in the following table : R R'

(CH₂),CH, (CH₂)₆CH₃ (CH₂)₂SPr <CH₂)₂SPr (CHj)jSCHjPh (CHj)₂SCH,Ph (CH_:)₂SCH₂Ph (CH₂)₃SCH₂Ph (CH₂),SCH,Ph (CH₂)₃SCH,Ph and wherein : O(CH₂)_r4-Pyr (CH₂),SCH,Ph (CH₂)jSCH₂Ph (CH₂)₆CH, CH =CHbenzodioxolane (CH₂)jSCHjPh (CH₂)₆CH,

Ph = phenyl, pyr = pyπdyl (CH₂)₄CH₃ (CH₂)_}SBn

(CH₂)₂CO₂H n-CjH.j and Bn = benzyl.

(CH₂)jCOHN₂ n-C₇H_I5

(CH,),CO₂H n-C₇H_l5 (CH₂),CO₂Me n-C₇H„

CH₂-p-Ph-Ph n-C₇H_I5 (E)-3- n-C₇H_l5

36 . A compound selected from the group consisting of

i

OH

(SEQ ID NO: 13);

COValNH

(SEQ ED NO: 13);

OH

(SEQ ID NO: 14);

(SEQ DD NO: 13);

OH

(SEQ DD NO: 13);

OValNH

i OH

(SEQ DD NO: 13);

(SEQ DD NO: 15);

OValValNH

(SEQ DD NO: 15); and

(SEQ ID NO: 16) .

37. A compound having the formula IV:

where X, Y = NRCW, NRS(0)_n, NRP(0) (Q); Z = CRR' , NR, 0, S;

A = an optionally substituted bridging group which is saturated or unsaturated and having 2-15 atoms comprised of any stable combination of C, N, 0, or S;

R = represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkyl, alkoxyalkyl, akylthioalkyl, mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;

R', R₂ = H, halo, optionally substituted lower alkyl, lower akoxy, lower alkylthio, mono- or di-lower alkyl amino;

R₃ = optionally substituted lower alkyl, lower alkoxy, lower alkylthio, mono or dilower alkyl amino, aralkyl, aralkoxy, aralkylthio, aralkylamino, cvcloalkylalkyl, cycloalkylalkoxy, cycloalkylalkylthio, cycloalkylalkylamino.

38. The compound of claim 37, wherein X = OCWNR, SCWNR; and Z = CRR' , NR.

39. A compound selected from the group consisting of

OH

OH

OH

40. A compound having the formula:

in which R and R' are given in the following table:

R R^l ra n A

PhCH₂ D-iPr 11

PhCHj Me 11

PhCH₂ Et 11

PhCHj 3-PyrCH₂ ll

PhCH, CH,CH(OCH₂Ph 11 )CH₂

PhCH₂ CH₃CH(OH)CH₂ 11

PhCH₂ tBu 11

PhCH₂ Ph 11

p-(PhCHjO)- iPr 11

PhCH₂

p-(OH)PhCH₂ iPr 11

p- iPr 11

(OMe)PhCH₂

p-(OEt)- iPr li

PhCH₂ R R¹ m

p-(OiPr)- iPr 11

PhCH₂

p-(3PyrCH₂O)- iPr 11

PhCH₂ p- iPr 11

PhCH₂

(F₅-Ph)CH₂ iPr 11

(m,p- iPr 11

Cl₂Ph)CH₂

(mp-F₂Ph)CH₂ iPr 11 p-F-PhCH₂ iPr 11

HSCH₂ iPr 11

MeSCH₂ iPr 11

EtSCHj iPr 11

PrSCH₂ iPr 11

CH₂ = CHCHj iPr 11

BuSCH₂ iPr 11 iBuSCH₂ iPr 11

PhCH₂SCH₂ iPr 11

PhCH₂CH₂ iPr 11

2-naph-CH₂ iPr 11 R R' m n A

l-naph-CH₂ iPr 1 1 - -

4-thiazolyl- iPr 11 - -

CH₂ -indolyl-CH₂ iPr 11 - -

PhCH₂ iPr - 10 O

PhCHj iPr - 12 O

PhCH₂ iPr 2 2 S(CH₂),S

PhCH₂ iPr 2 2 S(CH₂)₄S

PhCH₂ iPr 2 2 S(CH₂)₅S

PhCH₂ iPr 2 2 S(CH₂)_βS

PhCH₂ iPr 2 2 S(CH₂)₇S

PhCH, iPr 2 2 SCHjCH = CH

(cis)

PhCH₇ iPr SCH,CH =CHCH,S

PhCH₂ iPr 2 2 SCHjCCCH₂S

PhCHj iPr 2 2 SCH₃p-Ph-CH₂S

PhCH₂ iPr 2 2 SCH₂m-Ph-CH,S

PhCH, iPr 2 2 SCH,o-Ph-CH₂S

PhCH₂ iPr 2 2 SCH₂p-(Cl)₄Ph- CH₂S

PhCH₂ iPr 11 - replace amide NH by O. 41. A compound of formula V:

where X, Y = NRCW, NRS(0)_n, NRP(0) (Q); Z = CRR', NR, 0, S;

A = an optionally substituted bridging group which is saturated or unsaturated and having 2-15 atoms comprised of any stabl.e combination of C, N, 0, or S;

R = represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl , heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkyl, alkoxyalkyl, akylthioalkyl, mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkylalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical; and

R', R₂ and R₃ = H, halo, optionally substituted lower alkyl, lower akoxy, lower alkylthio, mono- or di-lower alkyl amino.

42. The compound of claim 37, wherein X = OCWNR, SCWNR; and Z = CRR' , NR' .

43. A method of inhibiting the growth of a Plasmodium protozoan in a subject which comprises administering to said subject a growth inhibiting effective amount of at least one compound from any one of claims 31-42. 44. The method of claim 43, wherein the Plasmodium protozoan is Plasmodium falciparum.

45. A method of treating malaria in a subject which comprises administering to said subject an effective amount of at least one compound from any one of claims 31-42.

46. A method of inhibiting the invasion and metastasis of tumor cells in a subject which comprises administering to said subject an effective amount of at least one compound from any one of claims 31-42.

47. The method of claim 46, wherein the tumor cells are breast cancer cells.