O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives

• US 5,258,389 A
• Filed: 11/09/1992
• Issued: 11/02/1993
• Est. Priority Date: 11/09/1992
• Status: Expired due to Term

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Sinclair, Peter J., Parsons, William H., Wyvratt, Matthew J., Wong, Frederick, Goulet, Mark
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US07/973,807
• Time in Patent Office: 358 Days
• Field of Search: 540/456, 514/291
• US Class Current: 514/291
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

O-Aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives of the general structural Formula I: ##STR1## have been prepared from suitable precursors by alkylation and/or arylation at C-42 and/or C-31. These compounds are useful in a mammalian host for the treatment of autoimmune diseases and diseases of inflammation, infectious diseases, the prevention of rejection of foreign organ transplants and the treatment of solid tumors.

Claims

1. A compound of formula I:

##STR12## or a pharmaceutically acceptable salt thereof, wherein;

R¹ and R² are independently selected from;

(1) hydrogen;

(2) phenyl;

(3) substituted phenyl in which the substituents are X, Y and Z;

(4) 1- or 2- naphthyl;

(5) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z;

(6) biphenyl;

(7) substituted biphenyl in which the substituents are X, Y and Z;

(8) C_1-10 alkyl;

(9) substituted C_1-10 alkyl in which one or more substituent(s) is(are) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 -alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) substituted phenyl-C_1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,

(f) --OCO--CL alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from

(i) hydrogen,

(ii) C_1-10 alkyl unsubstituted or substituted with one or more of the substituent(s) selected from;

(a'"'"') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b'"'"') --OH,

(c'"'"') C_1-6 alkoxy,

(d'"'"') --CO₂ H)

(e'"'"') --CO₂ -C_1-6 alkyl,

(f'"'"') --C_3-7 cycloalkyl, and

(g'"'"') --OR¹¹,

(iii)C_3-10 alkenyl unsubstituted or substituted with one or more of the substituent(s) selected from;

(a'"'"') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b'"'"') --OH,

(C'"'"') C_1-6 alkoxy,

(d'"'"') --CO₂ H,

(e'"'"') --CO₂ --C_1-6 alkyl,

(f'"'"') --C_3-7 cycloalkyl, and

(g'"'"') --OR¹¹,

(iv)or where R⁶ and R⁷ and the N to which they are attached can form a 3-7-membered saturated heterocyclic ring, unsubstituted or substituted with C_1-6 alkyl or phenyl, the ring being selected from the group consisting of;

aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperizine,

(h) --NR⁶ CO--C_1-6 alkyl--R⁷, wherein R⁶ is as defined above,

(i) --NR₆ CO₂ --C_1-6 alkyl--R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR₆ R₇,

(l) --COOR₆,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2- naphthyl,

(s) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z,

(t) biphenyl

(u) substituted biphenyl in which the substituents are X, Y and Z;

(v) --OR¹¹, and

(w) --S(O)_p --C_1-6 alkyl;

(10) C_3-10 alkenyl;

(11) substituted C_3-10 alkenyl in which one or more substituent(s) is(are) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) substituted phenyl-C_1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,

(f) --OCO--C_1-6 alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above

(h) --NR⁶ CO--C_1-6 alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O) p--C_1-6 alkyl;

(12) C_3-10 alkynyl;

(13) substituted C_3-10 alkynyl in which one or more substituent(s) is(are) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C alkoxy,

(e) substituted phenyl-C_1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,

(f) --OCO--C_1-6 alkyl,

(g) --NR₆ R , wherein R and R are as defined above,

(h) --NR₆ CO--C_1-6 alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z, and

(q) --OR¹¹ ;

with the proviso that R¹ and R² are not simultaneously hydrogen;

R¹¹ is selected from;

(a) --PO(OH)O^- M⁺, wherein M⁺ is a positively charged inorganic or organic counterion,

(b) --SO₃^- M⁺,

(c) --CO(CH₂)_q CO₂^- M⁺, wherein q is 1-3, and

(d) --CO--C_1-6 alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from;

(i) hydroxy,

(ii) C_1-6 alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from;

(a'"'"') hydrogen, and

(b'"'"') C_1-6 alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C_1-6 alkyl;

X, Y and Z independently are selected from;

(a) hydrogen,

(b) C_1-7 alkyl,

(c) C_2-6 alkenyl,

(d) halogen,

(e) --(CH₂)_m --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and m is 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃)

(i) --SR⁸, wherein R⁸ is hydrogen, C_1-6 alkyl, trifluoromethyl, or phenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_m - wherein R⁹ is hydrogen, C_1-3 alkyl, hydroxy-C_2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C_1-3 alkyl or taken together form an ethyl or propyl bridge,

(o) ##STR13## wherein R⁹ and m are as defined above, and (p) ##STR14## wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of;

dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.

2. The compound of claim 1 wherein:

R¹ and R² are independently selected from;

(1) hydrogen;

(2) methyl;

(3) phenyl;

(4) substituted phenyl in which the substituents are X, Y and Z;

(5) 1- or 2- naphthyl;

(6) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z;

(7) biphenyl; and

(8) substituted and biphenyl in which the substituents are X, Y and Z;

with the proviso that R¹ and R² are not simultaneously hydrogen;

X, Y and Z are independently, selected from;

(a) hydrogen,

(b) C_1- 7 alkyl,

(c) C_2-6 alkenyl,

(d) halogen,

(e) --(CH₂)_m -NR⁶ R⁷, wherein R⁶ and R⁷ are, independently selected from

(i) hydrogen, or

(ii) C_1-6 alkyl unsubstituted or substituted with phenyl, and

m is 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C_1-6 alkyl, trifluoromethyl, or phenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_m - wherein R⁹ is hydrogen, C_1-3 alkyl, hydroxy-C_2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C_1-3 alkyl or taken together form an ethyl or propyl bridge,

(o) ##STR15## wherein R⁹ and m are as defined above, and (p) ##STR16## wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of;

dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl.

3. The compound of claim 1 wherein:

R¹ and R² are independently selected from;

(1) hydrogen;

(2) C_1-10 alkyl;

(3) substituted C_1-10 alkyl in which one or more substituent(s) is(are) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 -alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) substituted phenyl-C_1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,

(f) --OCO--C_1-6 alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from

(i) hydrogen,

(ii) C_1-10 alkyl unsubstituted or substituted with one or more of the substituent(s) selected from;

(a'"'"') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b'"'"') --OH,

(c'"'"') C_1-6 alkoxy,

(d'"'"') --CO₂ H,

(e'"'"') --CO₂ --C_1-6 alkyl,

(f'"'"') --C_3-7 cycloalkyl, and

(g'"'"') --OR¹¹,

(iii)C_3-10 alkenyl unsubstituted or substituted with one or more of the substituent(s) selected from;

(a'"'"') phenyl, which is unsubstituted or substituted with X, Y and Z,

(b'"'"') --OH, alkoxy,

(c'"'"') C_1-6 alkoxy,

(d'"'"') --CO₂ H,

(e'"'"') --CO₂ --C_1-6 alkyl,

(f'"'"') --C_3-7 cycloalkyl, and

(g'"'"') --OR¹¹,

(iv)or where R⁶ and R⁷ and the N to which they are attached can form a 3-7-membered saturated heterocyclic ring, unsubstituted or substituted with C_1-6 alkyl or phenyl, the ring being selected from the group consisting of;

aziridine, morpholine, thiomorpholine, thiomorpholine-oxide, thiomorpholine-dioxide, piperidine, pyrrolidine, and piperazine,

(h) --NR⁶ CO--C_1-6 alkyl-R⁷, wherein R⁶ is as defined above,

(i) --NR⁶ CO₂ --C_1-6 alkyl-R⁷,

(j) --NR⁶ CONR⁶ R⁷,

(k) --OCONR⁶ R⁷,

(l) --COOR⁶,

(m) --CHO,

(n) phenyl,

(o) substituted phenyl in which the substituents are X, Y and Z,

(p) phenyloxy,

(q) substituted phenyloxy in which the substituents are X, Y and Z,

(r) 1- or 2- naphthyl,

(s) substituted 1- or 2- naphthyl in which the substituents are X, Y and Z,

(t) biphenyl

(u) substituted biphenyl in which the substituents are X, Y and Z;

(v) --OR¹¹, and

(w) --S(O)_p --C_1-6 alkyl;

(4) C_3-10 alkenyl;

(5) substituted C_3-10 alkenyl in which one or more substituent(s) is(are) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) substituted phenyl-C_1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,

(f) --OCO--C_1-6 alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above

(h) --NR⁶ CO--C_1-6 alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_p --C_1-6 alkyl;

(6) C_3-10 alkynyl;

(7) substituted C_3-10 alkynyl in which one or more substituent(s) is(are) selected from;

(a) hydroxy,

(b) oxo,

(c) C_1-6 alkoxy,

(d) phenyl-C_1-3 alkoxy,

(e) substituted phenyl-C_1-3 alkoxy, in which the substituents on phenyl are X, Y and Z,

(f) --OCO--C_1-6 alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C_1-6 alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y and Z,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z, and

(q) --OR¹¹ ;

with the proviso that R¹ and R² are not simultaneously hydrogen;

R¹¹ is selected from;

(a) --PO(OH)O^- M⁺, wherein M⁺ is a positively charged inorganic or organic counterion,

(b) --SO₃ ^- M⁺,

(c) --CO(CH₂)_q CO₂^- M⁺, wherein q is 1-3, and

(d) --CO--C_1-6 alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above and the alkyl is unsubstituted or substituted with one or more substituents selected from;

(i) hydroxy,

(ii) C_1-6 alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from;

(a'"'"') hydrogen, and

(b'"'"') C_1-6 alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(vi) substituted phenyl in which the substituents are X, Y and Z,

(vii) --SH, and

(viii) --S--C_1-6 alkyl;

X, Y and Z independently are selected from;

(a) hydrogen,

(b) C_1-7 alkyl,

(c) C_2-6 alkenyl,

(d) halogen,

(e) --(CH₂)_m --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, and m is 0 to 2,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C_1-6 alkyl, trifluoromethyl, or phenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SOR₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_m - wherein R⁹ is hydrogen, C_1-3 alkyl, hydroxy-C_2-3 alkyl, trifluoromethyl, phenyl or naphthyl and m is as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² are C_1-3 alkyl or taken together form an ethyl or propyl bridge,

(o) ##STR17## wherein R⁹ and m are as defined above, and (p) ##STR18## wherein R⁹ and m are as defined above, and (q) --OR¹¹ ;

or any two of adjacent X, Y and Z can be joined to form a ring selected from the group consisting of;

dioxolanyl, dihydro-furanyl, dihydropyranyl, and dioxanyl.

6. The compound of claim 1 which is:

42-O-phenyl rapamycin.

7. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 1.

8. A method for the treatment of immunoregulatory disorders or diseases comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

9. A method for the treatment of resistance to transplantation comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

10. A method for the treatment of inflammatory comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

11. A method for the treatment of autoimmune diseases comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

12. A method for the treatment of fungal infections comprising the administration to a mammalian species in need of such treatment of an effective amount of the compound of claim 1.

4. A compound which is:

##STR19## wherein R¹ and R² are selected from the following combinations of substituents;

space="preserve" listing-type="tabular">______________________________________ R.sup.1 R.sup.2 ______________________________________ a) ##STR20## H b) ##STR21## H c) ##STR22## H d) ##STR23## H e) ##STR24## H f) ##STR25## H g) ##STR26## H h) ##STR27## H i) ##STR28## H j) H ##STR29## k) H ##STR30## l) H ##STR31## m) ##STR32## H n) ##STR33## H o) ##STR34## H p) ##STR35## H q) ##STR36## H r) ##STR37## H. ______________________________________

5. A compound which is:

##STR38## wherein R¹ and R² are selected from the following combinations of substituents;

space="preserve" listing-type="tabular">______________________________________ R.sup.1 R.sup.2 ______________________________________ a) ##STR39## H b) H ##STR40## c) ##STR41## H d) H ##STR42## e) ##STR43## H f) H ##STR44## g) ##STR45## H h) ##STR46## H i) H ##STR47## j) ##STR48## H k) H ##STR49## l) ##STR50## H m) H ##STR51## n) ##STR52## H o) H ##STR53## p) ##STR54## H q) H ##STR55## r) ##STR56## H s) H ##STR57## t) ##STR58## H u) H ##STR59## v) ##STR60## H w) H ##STR61## x) ##STR62## H y) H ##STR63## z) ##STR64## H aa) ##STR65## H bb) ##STR66## H cc) ##STR67## H dd) ##STR68## H ee) ##STR69## H ff) ##STR70## H gg) ##STR71## H hh) H ##STR72## ii) ##STR73## H jj) ##STR74## H kk) H ##STR75## ______________________________________