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Claims  |
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What is claimed is:
1. A compound of the formula:
##STR47##
wherein R is carboxy, a carboxy salt, a carboxy ester of the formula
COOR.sup.5 wherein R.sup.5 is C.sub.1-10 alkyl, or CONHR.sup.6 wherein
R.sup.6 is amino or methylsulfonyl;
A is a p-phenylene or a m-phenylene or substituted phenylene derivative in
which one or two of the phenylene hydrogens is replaced by a methyl or a
halo substituent, or 2,5-thienylene or 2,5-furylene;
n is 3 or 4;
m is 0, 1, or 2;
R.sup.1 is hydrogen, deuterium, or methyl;
Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms;
R.sup.2 is hydrogen or lower alkanoyl;
R.sup.3 is hydrogen or straight chain C.sub.1-3 alkyl; and
R.sup.4 is lower straight chain or branched alkyl having from 3-7 carbon
atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted
lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and
lower alkoxy methylene; or
R.sup.3 and R.sup.4 taken together with the carbon atom connecting R.sup.3
and R.sup.4 is a cyclic substituent selected from a bridged or unbridged
alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing
sulfur or oxygen and from 5-7 ring-forming carbon atoms.
2. The compound of claim 1 wherein R is carboxy or carboxy salt having the
formula --COO.sup.- M.sup.+ wherein M.sup.+ is a pharmaceutically
acceptable cation derived from a metal or an amine.
3. The compound of claim 2 having the formula:
##STR48##
wherein X is chlorine or methyl;
r is 0, 1, or 2;
n is 3 or 4;
R.sup.1 is hydrogen, deuterium, or methyl;
Z is ethylene, trimethylene, cis or trans-propenylene, or propynylene;
R.sup.3 is hydrogen or lower alkyl of 1-3 carbon atoms; and
R.sup.4 is 4-pentenyl, 5,5,5-trifluoropentyl, or lower straight or branched
chain alkyl of 3-7 carbon atoms.
4. The compound of claim 3 wherein r is 0, n is 3, and R.sup.1 is hydrogen.
5. The compound of claim 4 wherein Z is ethylene.
6. 4-{3-[3-(3-Hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the
compound of claim 5 wherein R.sup.3 is hydrogen and R.sup.4 is pentyl.
7. 4-{3-[3-(3-Hydroxydecyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the
compound of claim 5 where R.sup.3 is hydrogen and R.sup.4 is heptyl.
8. 4-{3-[3-(3-Hydroxy-4,4-dimethyloctyl)-4-oxo-2-thiazolidinyl]propyl
}benzoic acid, the compound of claim 5 where R.sup.3 is hydrogen and
R.sup.4 is 1,1-dimethylpentyl.
9. 4-{3-[3-(3-Hydroxy-7-octenyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid,
the compound of claim 5 where R.sup.3 is hydrogen and R.sup.4 is
4-pentenyl.
10. 4-{3-[3-
(3-Hydroxy-8,8,8-trifluorooctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid,
the compound of claim 5 where R.sup.3 is hydrogen and R.sup.4 is
5,5,5-trifluoropentyl.
11. 4-{3-[3-(3-Hydroxy-3-methyloctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic
acid, the compound of claim 5 where R.sup.3 is methyl and R.sup.4 is
pentyl.
12. The compound of claim 2 having the formula:
##STR49##
wherein X is chlorine or methyl;
r is 0, 1, or 2;
n is 3 or 4;
R.sup.1 is hydrogen, deuterium, or methyl;
Z is ethylene, trimethylene, cis or trans-propenylene, or propynylene; and
R.sup.4 is CH.sub.2 OR.sup.7 wherein R.sup.7 is lower straight or branched
chain alkyl of 2-5 carbon atoms.
13. The compound of claim 12 wherein r is 0, n is 3, and R.sup.1 is
hydrogen.
14. The compound of claim 13 wherein Z is ethylene.
15. 4-{3-[3-(3-Hydroxy-4-propoxybutyl)-4-oxo-2-thiazolidinyl]propyl}benzoic
acid, the compound of claim 14 where R.sup.7 is propyl.
16. The compound of claim 2 having the formula:
##STR50##
wherein X is chlorine or methyl;
r is 0, 1, or 2;
n is 3 or 4;
m is 0, 1, or 2;
R.sup.1 is hydrogen, deuterium, or methyl;
Z is ethylene, trimethylene, propenylene, or propynylene;
y is 0, 2, or 3; and
W is polymethylene of 2-6 carbon atoms.
17. The compound of claim 16 where r is 0, m is 0, and R.sup.1 is hydrogen.
18. The compound of claim 17 where Z is ethylene.
19. 4-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-
2-thiazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3,
y is 0, and W is trimethylene.
20. 4-{3-[3-[2-(1-Hydroxycyclop
entyl)ethyl]-4-oxo-2-triazolidinyl]propyl}benzoic acid, the compound of
claim 18 where n is 3, y is 0, and W is ethylene.
21. 4-{3-[3-[2-(1-Hydroxycycloheptyl)ethyl]-4-oxo-
2-thiazolidinyl]propyl}benzoic acid, the compound of claim 18 where n is 3,
y is 0, and W is tetramethylene.
22. 4-{3-[3-[2-(1-Hydroxy-4,4-dim
ethylcyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the
compound of claim 18 where n is 3, y is 0, and W is
2,2-dimethyltrimethylene.
23. 4-{3-[3-[2-(9-Hydroxy-
9-bicyclo[3.3.1]nonyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the
compound of claim 18 where n is 3, y is 3, and W is trimethylene.
24. 4-{4-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]b
utyl}benzoic acid, the compound of claim 18 where n is 4, y is 0, and W is
trimethylene.
25. The compound of claim 17 where Z is trimethylene.
26. 4-{3-[3-[3-(1-Hydroxycyclohexyl)propyl]-4-oxo-2-t
hiazolidinyl]propyl}benzoic acid, the compound of claim 25 where n is 3, y
is 0, and W is trimethylene.
27. The compound of claim 17 where Z is cis-propenylene.
28. 4-{3-[3-[3-(1-Hydroxycyclohexyl)-(Z)-2-propenyl]-4-o
xo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 27 where n is
3, y is 0, and W is trimethylene.
29. The compound of claim 17 where Z is trans-propenylene.
30. 4-{3-[3-[3-(1-Hydroxycyclohexyl)-(E)-2-propenyl]-4-oxo
-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 29 where n is
3, y is 0, and W is trimethylene.
31. The compound of claim 17 where Z is propynylene.
32. 4-{3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-o
xo-2-thiazolidinyl]propyl}benzoic acid, the compound of claim 31 where n is
3, y is 0, and W is trimethylene.
33. The compound of claim 16 where X is chlorine, r is 1, m is 0, R.sup.1
is hydrogen, and Z is ethylene.
34. 4-{3-[3-[2-(1-Hydroxycyclohe
xyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-3-chlorobenzoic acid, the compound
of claim 33 where n is 3, y is 0, W is trimethylene, with chlorine in the
3-position of the phenylene group.
35. 4-{3-[3-[2-(1-Hydroxycyclohexyl
)ethyl]-4-oxo-2-thiazolidinyl]propyl}-2-chlorobenzoic acid, the compound of
claim 33 where n is 3, y is 0, W is trimethylene with chlorine in the
2-position of the phenylene group.
36. The compound of claim 16 where X is methyl, r is 1, m is 0, R.sup.1 is
hydrogen, and Z is ethylene.
37. 4-{3-[3-[2-(1-Hydroxycycl
ohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-3-methylbenzoic acid, the
compound of claim 36 where n is 3, y is 0, W is trimethylene with methyl
in the 3-position of the phenylene group.
38. The compound of claim 16 where m is 1, r is 0, R.sup.1 is hydrogen, and
Z is ethylene.
39. 4-{3-[3-[2-
(1-Hydroxycyclohexyl)ethyl]-1,4-dioxo-2-thiazolidinyl]propyl}benzoic acid,
the compound of claim 38 where n is 3, y is 0, and W is trimethylene.
40. The compound of claim 16 where m is 2, r is 0, R.sup.1 is hydrogen, and
Z is ethylene.
41. 4-{3-[3-[2-
(1-Hydroxycyclohexyl)ethyl]-1,1,4-trioxo-2-thiazolidinyl]propyl}benzoic
acid, the compound of claim 40 where n is 3, y is 0, and W is
trimethylene.
42. The compound of claim 16 where m is 0, r is 0, R.sup.1 is methyl, and Z
is ethylene.
43. 4-{3-[3-[
2-(1-Hydroxycyclohexyl)ethyl]-5,5-dimethyl-4-oxo-2-thiazolidinyl]propyl}ben
zoic acid, the compound of claim 42 where n is 3, y is 0, and W is
trimethylene.
44. The compound of claim 16 where m is 0, r is 0, R.sup.1 is deuterium,
and Z is ethylene.
45. 4-{3-[3-[2-(1-H
ydroxycyclohexyl)ethyl]-5,5-dideuterio-4-oxo-2-thiazolidinyl]propyl}benzoic
acid, the compound of claim 44 where n is 3, y is 0, and W is
trimethylene.
46. The compound of claim 2 having the formula:
##STR51##
wherein X is chlorine or methyl;
r is 0, 1, or 2;
n is 3 or 4;
m is 0, 1, or 2;
R.sup.1 is hydrogen or methyl;
Z is ethylene, trimethylene, propenylene, or propynylene; and
y is 4 to 8.
47. The compound of claim 46 where r is 0, m is 0, R.sup.1 is hydrogen, and
Z is ethylene.
48. 3-{3-[3-[2-
(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the
compound of claim 47 where n is 3, and y is 5.
49. The compound of claim 2 having the formula:
##STR52##
wherein n is 3 or 4;
R.sup.1 is hydrogen or methyl;
Z is ethylene, trimethylene, propenylene, or propynylene; and
y is 4 to 8.
50. 5-{3-[3-
[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}thiophene-2-car
boxylic acid, the compound of claim 49 where n is 3, R.sup.1 is hydrogen, Z
is ethylene, and y is 5.
51. The compound of claim 2 having the formula:
##STR53##
wherein n is 3 or 4;
R.sup.1 is hydrogen or methyl;
Z is ethylene, trimethylene, propenylene, or propynylene; and
y is 4 to 8.
52. 5-{3-[3-
[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}furan-2-carboxy
lic acid, the compound of claim 51 where n is 3, R.sup.1 is hydrogen, Z is
ethylene, and y is 5.
53. The compound of claim 2 having the formula:
##STR54##
wherein n is 3 or 4;
R.sup.1 is hydrogen or methyl;
Z is ethylene, trimethylene, propenylene, or propynylene;
w and y are each 1 to 5 with the sum of w and y being from 4 to 6; and
A is oxygen or sulfur.
54. 4-{3-[3-[2-(4-Hydr
oxytetrahydro-4-pyranyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid,
the compound of claim 53 where n is 3, R.sup.1 is hydrogen, Z is ethylene,
w and y are each 2, and A is oxygen.
55. 44-{3-[3-[2-(4-Hydroxytetrahydro-
4-thiopyranyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid, the
compound of claim 53 where n is 3, R.sup.1 is hydrogen, Z is ethylene, w
and y are each 2, and A is sulfur.
56. The compound of claim 1 wherein R is COOR.sup.5 where R.sup.5 is
C.sub.1-10 alkyl.
57. Methyl
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoa
te, the compound of claim 56 where A is unsubstituted p-phenylene (r=0), n
is 3, m is 0, R.sup.1 is hydrogen, R.sup.2 is hydrogen, R.sup.3 and
R.sup.4 are lower alkyl, joined to form a cyclohexane ring together with
the carbon atom joining R.sup.3 and R.sup.4.
58. The compound of claim 1 wherein R is CONHR.sup.6 where R.sup.6 is amino
and R.sup.2 is hydrogen.
59. 4-{3-[3-[2-(1-Hydroxy
cyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid hydrazide, the
compound of claim 58 where A is unsubstituted p-phenylene (r=0), n is 3, m
is 0, R.sup.1 is hydrogen, and R.sup.3 and R.sup.4 are lower alkyl joined
to form a cyclohexane ring together with the carbon atom joining R.sup.3
and R.sup.4.
60. The compound of claim 1 wherein R is CONHR.sup.6 where R.sup.6 is
methylsulfonyl.
61. N-Methylsulf
onyl-4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}be
nzamide, the compound of claim 60 where A is unsubstituted p-phenylene
(r=0), n is 3, m is 0, R.sup.1 and R.sup.2 are hydrogen, and R.sup.3 and
R.sup.4 are lower alkyl joined to form a cyclohexane ring together with
the carbon atom joining R.sup.3 and R.sup.4.
62. The compound of claim 1 wherein R is carboxy, carboxy salt, or
COOR.sup.5 where R.sup.5 is C.sub.1-10 alkyl; and R.sup.2 is acetyl.
63. 4-{3-[3-[2-(1-Acetoxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]prop
yl}benzoic acid, the compound of claim 62 where R is carboxy, A is
unsubstituted p-phenylene (r=0), n is 3, m is 0, R.sup.1 is hydrogen, and
R.sup.3 and R.sup.4 are lower alkyl joined to form a cyclohexane ring
together with the carbon atom joining R.sup.3 and R.sup.4.
64. A pharmaceutical composition for improving renal function in patients
with renal impairment comprising an aqueous, oily, or enteric-coated
pharmaceutical carrier and an effective renal vasodilator amount of a
compound of the formula:
##STR55##
wherein R is carboxy, a carboxy salt, a carboxy ester of the formula
COOR.sup.5 wherein R.sup.5 is C.sub.1-10 alkyl, or CONHR.sup.6 wherein
R.sup.6 is amino or methylsulfonyl;
A is a p-phenylene or a m-phenylene or substituted phenylene derivative in
which one or two of the phenylene hydrogens is replaced by a methyl or a
halo substituent, or 2,5-thienyl or 2,5-furylene;
n is 3 or 4;
m is 0, 1, or 2;
R.sup.1 is hydrogen, deuterium, or methyl;
Z is alkylene or unsaturated alkylene having from 2-3 carbon atoms;
R.sup.2 is hydrogen or lower alkanoyl;
R.sup.3 is hydrogen or straight chain C.sub.1-3 alkyl; and
R.sup.4 is a lower straight chain or branched alkyl having from 3-7 carbon
atoms, an unsaturated alkyl having from 3-7 carbon atoms, or a substituted
lower alkyl selected from polyfluoro alkyl of from 3-7 carbon atoms and
lower alkoxy methylene; or
R.sup.3 and R.sup.4 taken together with the carbon atom connecting R.sup.3
and R.sup.4 is a cyclic substituent selected from a bridged or unbridged
alicyclic ring of from 5-9 carbon atoms or a heterocyclic ring containing
sulfur or oxygen and from 5-7 ring-forming carbon atoms.
65. A composition of claim 64 wherein R is carboxy, A is phenyl, n is 3, m
is 0, R.sup.1 is hydrogen, Z is ethylene, R.sup.2 is hydrogen, and R.sup.3
and R.sup.4 taken together with the carbon atom connecting R.sup.3 and
R.sup.4 is cyclohexyl. |
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Claims |
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Description |
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DESCRIPTION OF THE INVENTION
This invention relates to novel interphenylene
9-thia-11-oxo-12-azaprostanoic acids, salts, and derivatives which are
represented by the following formula:
##STR1##
wherein R is selected from the group consisting of carboxy and a carboxy
salt which incorporates a pharmaceutically acceptable cation, such as
metal cations derived from alkali metals, alkaline earth metals, and
amines such as ammonia, primary and secondary amines and quaternary
ammonium hydroxides. Especially preferred metal cations are those derived
from alkali metals, e.g., sodium, potassium, lithium, and the like, and
alkaline earth metals, e.g., calcium, magnesium, and the like, and other
metals, i.e., aluminum, iron, and zinc.
Pharmaceutically acceptable cations derived from primary, secondary, or
tertiary amines, or quaternary ammonium hydroxides are methylamine,
dimethylamine, 1-methylpiperazine, trimethylamine, ethylamine,
N-methylhexylamine, benzylamine, .alpha.-phenethylamine, ethylenediamine,
piperidine, morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanolamine,
diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane,
N-methylglucamine, N-methylglucosamine, ephedrine, procaine,
tetramethylammonium hydroxide, tetraethylammonium hydroxide,
benzyltrimethylammonium hydroxide, and the like.
R is also selected from alkoxycarbonyl, e.g., a carboxy ester of the
formula --COOR.sup.5 wherein R.sup.5 is alkyl having 1-10 carbon atoms.
R is further selected from the group
##STR2##
wherein R.sup.6 is amino (NH.sub.2) or methylsulfonyl (CH.sub.3 SO.sub.2).
A is a divalent monocyclic aromatic or a 5-membered sulfur or oxygen
containing heterocyclic ring preferably a p-phenylene or a m-phenylene or
substituted phenylene derivatives in which one or two of the phenylene
hydrogens is replaced by a methyl or a halo, preferably chloro,
substitutent or 2,5-thienylene or 2,5-furylene. Examples of such
substituents are p-phenylene
##STR3##
or m-phenylene
##STR4##
where X is either hydrogen or chloro or methyl, and r is 0, 1, or 2, or
2,5-thienylene
##STR5##
or 2,5-furylene
##STR6##
n is 3 or 4.
m is 0, 1, or 2.
R.sup.1 is hydrogen, an isotope thereof especially deuterium, or methyl.
Z is alkylene or unsaturated alkylene of from 2-3 carbon atoms preferably
ethylene (--CH.sub.2 CH.sub.2 --), trimethylene (--CH.sub.2 CH.sub.2
CH.sub.2 --), cis-propenylene
##STR7##
trans-propenylene
##STR8##
or propynylene (--CH.sub.2 C.tbd.C--).
R.sup.2 is hydrogen or lower alkanoyl especially acetyl.
R.sup.3 is hydrogen or a straight chain lower alkyl of one to three carbon
atoms.
R.sup.4 is lower straight chain or branched alkyl having from 3 to 7 carbon
atoms (especially propyl, butyl, amyl, isoamyl, heptyl, and
1,1-dimethylpentyl), unsaturated lower alkyl including 4-pentenyl,
substituted lower alkyl such as polyfluoroalkyl, as for example
5,5,5-trifluoropentyl, and lower alkoxy methylene such as --CH.sub.2
--O--R.sup.7 preferably where R.sup.7 is selected from the group
consisting of lower alkyl, straight or branched, with from 2 to 5 carbon
atoms; or R.sup.3 and R.sup.4 taken together with the carbon atom
connecting R.sup.3 and R.sup.4 is a cyclic substituent comprising an
alicyclic ring, bridged or unbridged, of from 5 to 9 carbon atoms such as
cyclopentyl, cyclohexyl, cyclooctyl, or bicyclo [3.3.1] nonyl, or a
heterocyclic ring containing sulfur or oxygen and with from 5 to 7
ring-forming carbon atoms such as tetrahydropyranyl or
tetrahydrothiopyranyl.
A preferred sub-group of the compounds of this invention are compounds of
the formula:
##STR9##
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; R.sup.1 is
hydrogen, deuterium, or methyl; Z is ethylene, trimethylene, cis or
trans-propenylene, or propynylene; R.sup.3 is hydrogen or lower alkyl of
1-3 carbon atoms; and R.sup.4 is 4-pentenyl, 5,5,5-trifluoropentyl, or
lower straight or branched chain alkyl of 3-7 carbon atoms. Examples of
compounds included within this group are:
4-{3-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid;
4-{3-[3-(3-hydroxydecyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid;
4-{3-[3-(3-hydroxy-4,4-dimethyloctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic
acid;
4-{3-[3-(3-hydroxy-7-octenyl)-4-oxo-2-thiazolidinyl]propyl}benzoic acid;
4-{3-[3-(3-hydroxy-8,8,8-trifluorooctyl)-4-oxo-2-thiazolidinyl]propyl}benzo
ic acid; and
4-{3-[3-(3-hydroxy-3-methyloctyl)-4-oxo-2-thiazolidinyl]propyl}benzoic
acid.
Another preferred sub-group of the compounds of this invention are selected
from the group consisting of a compound of the formula:
##STR10##
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; R.sup.1 is
hydrogen, deuterium, or methyl; Z is ethylene, trimethylene, cis or
trans-propenylene, or propynylene; and R.sup.4 is CH.sub.2 OR.sup.7
wherein R.sup.7 is lower straight or branched chain alkyl of 2-5 carbon
atoms. An example of such a compound is
4-{3-[3-(3-hydroxy-4-propoxybutyl)-4-oxo-2-thiazolidinyl]propyl}benzoic
acid.
Another preferred sub-group of the compounds of this invention is selected
from the group consisting of a compound of the formula:
##STR11##
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; m is 0, 1,
or 2; R.sup.1 is hydrogen, deuterium, or methyl; Z is ethylene,
trimethylene, propenylene, or propynylene; y is 0, 2, or 3; and W is
polymethylene of 2-6 carbon atoms. Examples of such compounds are:
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic
acid
4-{3-[3-[2-(1-hydroxycyclopentyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoi
c acid
4-{3-[3-[2-(1-hydroxycycloheptyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoi
c acid
4-{3-[3-[2-(1-hydroxy-4,4-dimethylcyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]p
ropyl}benzoic acid
4-{3-[3-[2-(9-hydroxy-9-bicyclo[3.3.1]nonyl)ethyl]-4-oxo-2-thiazolidinyl]pr
opyl}benzoic acid
4-{4-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]butyl}benzoic
acid
4-{3-[3-[3-(1-hydroxycyclohexyl)propyl]-4-oxo-2-thiazolidinyl]propyl}benzoi
c acid
4-{3-[3-[3-(1-hydroxycyclohexyl)-(Z)-2-propenyl]-4-oxo-2-thiazolidinyl]prop
yl}benzoic acid
4-{3-[3-[3-(1-hydroxycyclohexyl)-(E)-2-propenyl]-4-oxo-2-thiazolidinyl]prop
yl}benzoic acid
4-{3-[3-[3-(1-hydroxycyclohexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl}b
enzoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-3-chlo
robenzoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-2-chlo
robenzoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}-3-meth
ylbenzoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-1,4-dioxo-2-thiazolidinyl]propyl}ben
zoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-1,1,4-trioxo-2-thiazolidinyl]propyl}
benzoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-5,5-dimethyl-4-oxo-2-thiazolidinyl]p
ropyl}benzoic acid
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-5,5-dideuterio-4-oxo-2-thiazolidinyl
]propyl}benzoic acid
A still further preferred sub-group of this invention is selected from the
group consisting of a compound of the formula:
##STR12##
wherein X is chlorine or methyl; r is 0, 1, or 2; n is 3 or 4; m is 0, 1,
or 2; R.sup.1 is hydrogen or methyl; Z is ethylene, trimethylene,
propenylene, or propynylene; and y is 4 to 8. An example of a compound of
this sub-group is
3-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoi
c acid.
Still further sub-groups of preferred compounds of this invention are
represented by the formulas:
##STR13##
wherein n is 3 or 4; R.sup.1 is hydrogen or methyl; Z is ethylene,
trimethylene, propenylene, or propynylene; and y is 4 to 8;
##STR14##
wherein n is 3 or 4; R.sup.1 is hydrogen or methyl; Z is ethylene,
trimethylene, propenylene, or propynylene; and y is 4 to 8; and
##STR15##
wherein n is 3 or 4; R.sup.1 is hydrogen or methyl; Z is ethylene,
trimethylene, propenylene, or propynylene; w and y are each 1 to 5 with
the sum of w and y being from 4 to 6; and A is oxygen or sulfur.
The carbon atom in the thiazolidinone ring marked by an asterisk (*) is
asymmetric in all compounds of this invention. In compounds wherein
R.sup.3 and R.sup.4 are dissimilar, the carbon atom bearing these groups
is asymmetric. Thus, the compounds of this invention are obtained as
racemates when only the former carbon is asymmetric and they are obtained
as mixtures of diastereomers when both carbon atoms are asymmetric. This
invention includes the separate stereoisomers which are components of
these mixtures of isomers. The separate stereoisomers have biological
activity similar to those of the racemates and diastereomeric mixtures,
which biological activity varies from compound to compound.
BACKGROUND OF THE INVENTION
The compounds of formula I are described as interphenylene
9-thia-11-oxo-12-azaprostanoic acids and derivatives as a means of
describing the structural relationship to prostanoic acid, which has the
carbon skeleton of the natural prostaglandins as shown in the following
formula:
##STR16##
The prostaglandins constitute a class of highly functionalized C.sub.20
fatty acids. They have been shown to occur extensively in low
concentrations in mammalian tissues where they are both rapidly anabolized
and catabolized and to exhibit a broad spectrum of pharmacological
activities including prominent roles in (a) functional hyperemia, (b) the
inflammatory response, (c) the central nervous system, (d) transport of
water and electrolytes, and (e) regulation of cyclic AMP. Further details
concerning the prostaglandins can be found in recent reviews of their
chemistry [J. E. Pike, FORTSCHR. CHEM ORG. NATURST., 28, 313 (1970) and G.
F. Bundy, A. REP. IN MED. CHEM., 7, 157 (1972)]; biochemistry [J. W.
Hinman, A. REV. BIOCHEM., 41, 161 (1972)]; pharmacology [J. R. Weeks, A.
REV. PHARM., 12, 317 (1972)]; physiological significance [E. W. Horton,
PHYSIOL. REV. 49, 122 (1969)]; and general clinical application [J. E.
Hinman, POSTGRAD MED. J. 46, 562 (1970)].
The potential application of natural prostaglandins as medicinally useful
therapeutic agents in various mammalian disease states is obvious but
suffers from three formidable major disadvantages, namely, (a)
prostaglandins are known to be rapidly metabolized in vivo in various
mammalian tissues to a variety of metabolites which are devoid of the
desired original biological activities, (b) the natural prostaglandins are
inherently devoid of biological specificity which is requisite for a
successful drug (since this property is responsible for intolerable side
effects), and (c) although limited quantities of prostaglandins are
presently produced by both chemical and biochemical processes, their
production cost is extremely high; and consequently, the availability is
quite restricted.
Our interest has, therefore, been to synthesize novel compounds with the
following unique advantages: (a) simplicity of synthesis leading to low
cost of production; (b) specificity of biological activity; and (c)
metabolic stability so that activity can be obtained on oral as well as
parenteral administration.
In accordance with the present invention, there is provided a novel group
of aza-prostanoic acids of formula I hereinabove. Surprisingly, the
compounds of the present invention have a specific range of biological
activities and do not possess the broad spectrum of biological activity
possessed by the natural prostaglandins and their analogs. The compounds
of the present invention, for example, are completely inactive in the
mouse ovary prostaglandin assay which measures increases in cellular
cyclic adenosine monophosphate levels ordinarily caused by prostaglandins
and related compounds.
The compounds of the present invention, in addition, are highly potent,
orally effective renal vasodilators having a sustained biological action
but with reduced side effects and, therefore, are useful for the treatment
of patients with renal impairment. Included in this group are patients
with hypertension, renal failure, congestive heart failure,
glomerulonephritis, uremia, and chronic renal insufficiency. The compounds
of this invention by virtue of their renal vasodilatory activity improve
renal function both when used alone or in conjunction with other renal
agents. An example of a compound with high renal vasodilatory activity is
4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoi
c acid.
The compounds of the present invention are also orally effective
antihypertensive agents and as such are useful in reducing blood pressure
in individuals affected by this problem. The compounds of the present
invention are surprisingly potent in their antihypertensive effect when
compared with structurally related compounds.
The compounds of this invention have adjunctive properties which give them
added utility for the treatment of renal disease. Such properties include
antiasthmatic (bronchorelaxant), cardiotonic, and immunoregulant
activities.
A further area of usefulness of the compounds of this invention is in the
prevention of organ transplant rejection.
The compounds of this invention can be administered intravenously,
subcutaneously, intramuscularly, orally, rectally, or by aerosolization in
the form of sterile implants for long action. They can be formulated in
any of a number of pharmaceutical compositions and nontoxic carriers to
this end.
The pharmaceutical compositions can be sterile, injectable suspensions or
solutions, or solid, orally administrable, pharmaceutically acceptable
tablets or capsules; the compositions can also be intended for sublingual
administration, or for suppository use. It is especially advantageous to
formulate compositions in dosage unit forms for ease and economy of
administration and uniformity of dosage. "Dosage unit form" as a term used
herein refers to physically discrete units suitable as unitary dosages for
animal and human subjects, each unit containing a predetermined quantity
of active material calculated to produce the desired biological effect in
association with the required pharmaceutical means.
Illustratively, a sterile injectable composition can be in the form of
aqueous or oleagenous suspensions or solutions.
The sterile, injectable composition can be aqueous or oleagenous suspension
or solution. Suspensions can be formulated according to the known art
using suitable dispersing and wetting agents and suspending agents.
Solutions are similarly prepared from the salt form of the compound. For
the laboratory animals, we prefer to use incomplete Freund's adjuvant or
sterile saline (9%) as carrier. For human parenteral use, such as
intramuscularly, intravenously, or by regional perfusion, the diluent can
be a sterile aqueous vehicle containing a preservative, for example,
methylparaben, propylparaben, phenol, and chlorobutanol. The aqueous
vehicle can also contain sodium chloride, preferably in an amount to be
isotonic, as well as a suspending agent, for example, gum arabic,
polyvinyl pyrrolidone, methyl cellulose, acetylated monoglyceride
(available commercially as Myvacet from Distillation Products Industry, a
division of Eastman Kodak Company), monomethyl glyceride, dimethyl
glyceride, or a moderately high molecular weight polysorbitan
(commercially available under the tradenames Tween or Span from Atlas
Powder Company, Wilmington, Delaware). Other materials employed in the
preparation of chemotherapeutic compositions containing the compound may
include glutathione, 1,2-propanediol, glycerol, and glucose. In addition,
the pH of the composition is adjusted by use of an aqueous solution such
as tris(hydroxymethyl)aminomethane (tris buffer).
Oily pharmaceutical carriers can also be used, since they dissolve the
compound and permit high doses. Many oily carriers are commonly employed
in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed
oil, peanut oil, sesame oil, or the like.
It is preferred to prepare the compositions, whether aqueous or oils, in a
concentration in the range of from 2-50 mg./ml. Lower concentrations
require needless quantities of liquid. Higher concentrations than 50
mg./ml. are difficult to maintain and are preferably avoided.
Oral administration forms of the drug can also be prepared for laboratory
animals or human patients provided that they are encapsulated for delivery
in the gut. The drug is subject to enzymatic breakdown in the acid
environment of the stomach. The same dosage levels can be used as for
injectable forms; however, even higher levels can be used to compensate
for biodegradation in the transport. Generally, a solid unit dosage form
can be prepared containing from 0.05 mg. to 10 mg. active ingredient and
preferably from 0.1 mg. to 1 mg. of active ingredient.
Whatever the mode of administration, doses in the range of about 0.05 to 10
milligrams per kilogram of body weight, preferably 0.1 to 1 mg.,
administered one to four times per day are used, the exact dose depending
on the age, weight, and condition of the patient, and the frequency and
route of administration.
The low cost and ready accessibility of the compounds of this invention
make them particularly promising for applications in veterinary medicine
in which field their utilities are comparable to those in human medicine.
Processes for the Synthesis of the Compounds of this Invention
One of the preferred groups of compounds of the present invention are the
carboxylic acids represented by formula II:
##STR17##
wherein A, n, R.sup.1, Z, R.sup.3, and R.sup.4 are as previously defined.
These acids can be synthesized by any of three processes which will now be
described.
PROCESS 1
Step 1
An aldehyde of formula III:
OCH--(CH.sub.2).sub.n --A--CO.sub.2 R.sup.8 III
wherein A and n are as previously defined and R.sup.8 is straight chain
lower alkyl (preferably methyl or ethyl), is condensed with a primary
amine of formula IV:
##STR18##
wherein Z, R.sup.3, and R.sup.4 are as previously defined and THP is the
tetrahydro-2H-pyran-2-yl group. The product of this condensation is the
imine of formula V:
##STR19##
wherein all groups are as defined previously.
According to the preferred practice, aldehyde III is added to amine IV
while maintaining a temperature preferably at 0.degree.-5.degree. C.
Anhydrous sodium sulfate is then added, and the mixture stirred at room
temperature for a period of 0.5 to 4 hours. The solid is removed by
filtration. The filtrate consists of the crude imine V which is used in
the next step.
Step 2
A mercaptoacetic acid of formula VI:
##STR20##
wherein R.sup.1 is as defined previously, is condensed with imine V to
yield the thiazolidinone of formula VII:
##STR21##
This condensation is most advantageously conducted by dissolving
mercaptoacetic acid VI and imine V in a solvent such as benzene or toluene
and boiling the solution under reflux in a Dean-Stark or similar apparatus
for removal of the water formed in the condensation.
Alternately, mercaptoacetic acid VI may be replaced by its methyl or ethyl
ester. In this case, the ester of mercaptoacetic acid VI and imine V are
dissolved in benzene or toluene and the solution boiled under reflux for a
period of 3 to 12 hours.
Step 3
Thiazolidinone VII is treated with a trace of strong acid such as
concentrated hydrochloric acid in a protic solvent, preferably methanol or
ethanol, at room temperature for a period of 1 to 24 hours. This treatment
hydrolyzes the protecting tetrahydropyranyl (THP) group and produces the
thiazolidinone of formula VIII:
##STR22##
wherein all groups are as defined previously.
Step 4
Thiazolidinone ester VIII is subjected to basic hydrolysis (dilute aqueous
NaOH, LiOH, or KOH in methanol, ethanol, or tetahydrofuran) at room
temperature to remove the protecting ester function and produce the
thiazolidinone carboxylic acid of formula II, one of the products of this
invention.
PROCESS 2
This process is particularly useful for the preparation of those products
of formula II wherein Z is trimethylene, cis and trans-propenylene, and
propynylene, i.e., wherein a three-carbon chain joins the nitrogen atom of
the thiazolidinone ring and the carbon bearing OH.
Step 1
An aldehyde of formula III above is condensed with a mercaptoacetamide of
formula XI:
##STR23##
wherein R.sup.1 is as defined previously to yield a thiazolidinone ester
of formula XII:
##STR24##
wherein all groups are as defined previously.
The condensation is advantageously conducted by dissolving amide XI and
aldehyde III along with a trace of a strong acid catalyst such as
p-toluenesulfonic acid in a suitable solvent such as benzene or toluene
and boiling the solution under reflux in a Dean-Stark apparatus for
removal of the water formed in the condensation.
Step 2
Thiazolidinone ester XII is converted to its anion by treatment with a
strong base, preferably sodium hydride, in an aprotic solvent such as
dimethylformamide (DMF) or solvent combination such as DMF-benzene or
DMF-toluene. The anion is alkylated by reaction at 35.degree.-75.degree.
C. for a period of 3 to 10 hours with a halide of formula XIII:
##STR25##
wherein X is chlorine, bromine, or iodine, P is an acetyl or
tetrahydropyranyl protecting group, and R.sup.3 and R.sup.4 are as defined
previously. The product of this alkylation is the thiazolidinone ester of
formula XIV:
##STR26##
Step 3
This step is necessary only when protecting group P in thiazolidinone XIV
is tetrahydropyranyl. In this case, XIV (P=tetrahydropyranyl) is treated
with a trace of an acid catalyst (concentrated hydrochloric acid,
p-toluenesulfonic acid, pyridinium tosylate) in a protic solvent,
preferably methanol or ethanol, at room temperature for a period of 1 to
24 hours. This treatment produces the thiazolidinone ester of formula VIII
above.
Step 4
The thiazolidinone esters XIV (P=acetyl) or VIII are subjected to basic
hydrolysis as described in Step 4 of Process 1. The thiazolidinone
carboxylic acid of formula II is thereby produced.
PROCESS 3
This process is useful for the preparation of only those compounds of
formula II in which the alcohol function (C--OH) is tertiary. Thus,
R.sup.3 is limited to lower alkyl and may be joined with R.sup.4 to form
alicyclic or heterocyclic rings as described in the specification. This
process is further limited to the preparation of those compounds of
formula II in which Z is saturated, i.e., is ethylene or trimethylene.
Step 1
Thiazolidinone ester XII above is converted to its anion as described in
Step 2 of Process 2. The anion in solution is alkylated by reaction a
35.degree.-75.degree. C. for a period of 3 to 10 hours with an olefinic
halide of formula XV:
##STR27##
wherein X is bromine or iodine, Z.sup.1 is ethylene or trimethylene,
R.sup.3 is lower alkyl, and R.sup.9 is alkyl with from 2 to 6 carbon
atoms, 3-butenyl, or 4,4,4-trifluorobutyl. Further, when R.sup.9 is alkyl,
R.sup.3 and R.sup.9 can be joined either directly or through an oxygen or
sulfur atom to form, along with C.dbd.CH, an alicyclic ring of from 5 to 9
carbon atoms or a heterocyclic ring containing oxygen or sulfur and with
from 5 to 7 ring-forming carbon atoms. The product of this alkylation of
compound XII is the olefinic thiazolidinone ester of formula XVI:
##STR28##
Step 2
Olefinic thiazolidinone ester XVI is treated with an excess of
trifluoroacetic acid at temperatures from 10.degree. to 25.degree. C. and
for a period of two to six hours. Trifluoroacetic acid adds to the
olefinic bond in the Markownikoff manner to yield the thiazolidinone ester
of formula XVII:
##STR29##
wherein all groups are as defined previously.
Step 3
Thiazolidinone ester XVII is subjected to basic hydrolysis as described in
Step 4 of Process 1. A thiazolidinone carboxylic acid of formula IIa:
##STR30##
wherein all groups are as defined previously are produced. The acids IIa
are seen to be a sub-class of the products of this invention of formula
II.
Alternatively, the order of reactions in Steps 2 and 3 can be reversed.
Thus, under analogous reaction conditions, olefinic thiazolidinone ester
XVI can be hydrolyzed to the acid of formula XVIII:
##STR31##
Acid XVIII can be treated with trifluoroacetic acid as described above to
give the trifluoroacetoxy acid of formula XIX:
##STR32##
Compound XIX can then be subjected to hydrolysis, preferably basis
hydrolysis, to remove the trifluoroacetyl group and yield the products of
this invention of formula IIa.
DERIVATIZATION OF PRODUCTS OF FORMULA II FROM THE PRINCIPAL PROCESSES
The processes described hereinabove lead to the production of carboxylic
acids of formula II. Often these are produced by a process which requires
hydrolysis of a carboxy ester at the final stage or at some intermediate
stage of the process. The hydrolysis of the esters of the acids of formula
II or of the intermediate carboxy esters may be carried out under acid or
basic conditions. Basic hydrolysis is preferred using dilute aqueous
solutions of NaOH, LiOH, or KOH in methanol, ethanol, or tetrahydrofuran
at room temperature, but, if desired, acid hydrolysis using a solution of
a small amount of a mineral acid in aqueous acetone.
The principal processes described in the preceeding sections produce
carboxylic acids (see Formula II). To obtain carboxy salts, the acid
products are dissolved in a solvent such as ethanol, methanol, glyme, and
the like, and the solution treated with an appropriate alkali or alkaline
earth hydroxide or alkoxide to yield the metal salt, or with an equivalent
quantity of ammonia, amine, or quarternary ammonium hydroxide to yield the
amine salt. In each instance, the salt either separates from the solution
and may be separated by filtration, or, when the salt is soluble, it may
be recovered by evaporation of the solvent. Aqueous solutions of the
carboxylic acid salts can be prepared by treating an aqueous suspension of
the carboxylic acid with an equivalent amount of an alkaline earth
hydroxide or oxide, alkali metal hydroxide, carbonate or bicarbonate,
ammonia, an amine, or a quarternary ammonium hydroxide.
To obtain carboxy esters (i.e., compounds where R is alkoxycarbonyl), the
acid products are treated in ether with an ethereal solution of the
appropriate diazoalkane. For example, methyl esters are produced by
reaction of the acid products with diazomethane.
To obtain carboxy hydrazides (i.e., compounds wherein R is --CONHNH.sub.2),
the carboxy esters of formula I where R is --COOR.sup.5 and R.sup.2 is
restricted to hydrogen are treated, preferably in methanol or ethanol
solution, with hydrazine, advantageously in the form of hydrazine hydrate.
The reactions are allowed to proceed at temperatures from 25.degree. to
55.degree. C. and for periods of 16 to 48 hours.
To obtain the methylsulfonylamides (e.g., compounds of formula I wherein R
is --CONHSO.sub.2 CH.sub.3), the carboxylic acids of formula I
(R=--CO.sub.2 H) are treated with one equivalent of
methanesulfonylisocyanate and one equivalent of a base such as
triethylamine in a suitable aprotic solvent, preferably acetonitrile, The
reaction is conducted at 25.degree.-50.degree. C. and for periods of 4 to
24 hours.
To obtain the sulfoxides (compounds of formula I wherein m is 1), the
compounds of formula I (wherein m is 0 and R=CONHNH.sub.2 is excluded) are
oxidized with sodium metaperiodate in a suitable solvent such as
methanol/water. The oxidations are conducted at 0.degree.-10.degree. C.
for periods of 12 to 48 hours.
To obtain the sulfones (compounds of formula I wherein m is 2), the
compounds of formula I (wherein m is 0 and R=CONHNH.sub.2 is excluded) are
oxidized with a peroxy acid such as m-chloroperbenzoic acid in chloroform.
The oxidations are conducted at 25.degree.-70.degree. C. for periods of 30
minutes to 16 hours.
To obtain the acetyl derivatives (compounds of formula I wherein R.sup.2 is
acetyl), the compounds of formula I wherein R.sup.2 is H and
R=CONHNH.sub.2 is again excluded are treated with acetic anhydride in
pyridine solution at temperatures of 5.degree. to 25.degree. C. and for
periods of 2 to 5 days.
Compounds of formula I wherein Z is unsaturated (i.e., is propynylene or
propenylene) may be hydrogenated over palladium or platinum catalysts to
yield more highly saturated compounds of formula I. Thus, the compounds
wherein Z is propynylene, may be hydrogenated to compounds where Z is
cis-propenylene or, with longer reaction times, to compounds where Z is
trimethylene. Similarly, compounds where Z is cis- or trans-propenylene
may be hydrogenated to compounds where Z is trimethylene.
Compounds of formula I wherein R.sup.1 is deuterium may be obtained from
compounds of formula I wherein R.sup.1 is H by dissolving the latter in
deuterium oxide with an excess of sodium or potassium hydroxide and
allowing the exchange reaction to proceed at 20.degree.-30.degree. C. for
16 to 36 hours. Workup with ordinary water removes rapidly exchangeable
deuterium atoms and affords the compounds of formula I wherein R.sup.1 is
deuterium.
Preparation of Intermediates
I. The aldehyde intermediates III which have the following general formula:
OHC--(CH.sub.2).sub.n --A--CO.sub.2 R.sup.8 III
wherein R.sup.8, A, and n are as described previously, are a broad group of
compounds, some of which have been described in the chemical literature.
No single general method of synthesis can be prescribed for these
compounds; a variety of known organic reactions can be selected for their
preparation depending on the length of the chain (CH.sub.2).sub.n and the
nature of the aromatic ring system represented by A. The following
examples are chosen to illustrate the procedures that are most generally
useful in the preparation of the intermediate of formula III.
(a) A synthetic scheme that is broadly applicable when n is 3 and A is
p-phenylene or substituted p-phenylene is illustrated by the synthetic
method used for ethyl 4-(4-oxobutyl)benzoate (XX):
##STR33##
an aldehyde of formula III wherein R.sup.8 is ethyl, A is p-phenylene, and
n is 3.
In the preparation of XX, the dianion prepared by the action of lithium
diisopropylamide on p-toluic acid is alkylated with
2-(2-bromoethyl)-1,3-dioxolane. The resulting
4-{3-[2-(1,3-dioxolanyl)]propyl}benzoic acid is esterified with ethyl
iodide in the presence of potassium carbonate. Acid hydrolysis of the
protecting cyclic acetal function gives the aldehyde intermediate XX.
(b) A synthetic method that is applicable when n is 3 or 4 and A is
p-phenylene or substituted p-phenylene is illustrated by the preparative
method for ethyl 4-(5-oxopentyl)benzoate (XXI):
##STR34##
In this case, 4-bromobutylbenzene is acylated with acetyl chloride and
aluminum chloride; the resulting acetophenone is oxidized with sodium | | |
