US 4,291,159 AGranted

9,11-Dideoxy-10-oxa-TXB intermediates

AssigneeThe Upjohn Company

InventorDouglas R. Morton, Jr.

Life of this patent

Estimating the term…

Abstract

The present invention provides novel analogs of the thromboxanes. These thromboxane analogs are useful for a variety of pharmacologically useful purposes, most particularly as antithrombotic agents.

Claims1

Dependent claims

A thromboxane intermediate of formula IX, ##STR2## wherein Y.sub.1 is (1) trans-CH.dbd.CH--,

(2) cis-CH.dbd.CH--,
(3) --CH.sub.2 CH.sub.2 --, or
(4) -C.tbd.C-,
wherein M.sub.1 is .alpha.-R.sub.5 :.beta.-OH, .alpha.-OH:.beta.-R.sub.5, or .alpha.-H:.beta.-H, wherein R.sub.5 is hydrogen or methyl;
wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .beta.-R.sub.3 :.alpha.-R.sub.4, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro;
wherein Z.sub.1 is
(1) cis--CH.dbd.CH-CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --,
(2) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --,
(3) cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --,
(4) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 --,
(5) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2 --,
(6) --CH.sub.2 --O--CH.sub.2 --(CH.sub.2)--.sub.g --CH.sub.2 --,
(7) --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.g --CH.sub.2 --, or
(8) trans-CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --CH.dbd.CH--;
wherein g is one, 2 or 3;
wherein R.sub.7 is
(1) --(CH.sub.2).sub.m --CH.sub.3, wherein m is an integer from one to 5 inclusive;
(2) phenoxy;
(3) phenoxy substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, icnlusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;
(4) phenyl;
(5) phenyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;
(6) phenylmethyl, phenylethyl, or phenylpropyl;
or
(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;
with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;
wherein L.sub.4 is
(a) amino of the formula --NR.sub.21 R.sub.22, wherein R.sub.21 and R.sub.22 are
(i) hydrogen;
(ii) alkyl of one to 12 carbon atoms, inclusive;
(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;
(iv) aralkyl of 7 to 12 carbon atoms, inclusive;
(v) phenyl;
(vi) phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro;
(vii) carboxyalkyl of 2 to 5 carbon atoms, inclusive;
(viii) carbamoylalkyl of 2 to 5 carbon atoms, inclusive;
(ix) cyanoalkyl of 2 to 5 carbon atoms, inclusive;
(x) acetylalkyl of 2 to 5 carbon atoms, inclusive;
(xi) benzoylalkyl of 7 to 11 carbon atoms, inclusive;
(xii) benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro;
(xiii) pyridyl;
(xiv) pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive;
(xv) pyridylalkyl of 6 to 9 carbon atoms, inclusive;
(xvi) pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy or alkoxy of one to 3 carbon atoms, inclusive;
(xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive;
(xviii) dihydroxyalkyl of one to 4 carbon atoms, or
(xix) trihydroxyalkyl of one to 4 carbon atoms;
with the further proviso that not more than one of R.sub.21 and R.sub.22 is other than hydrogen or alkyl;
(b) cycloamino selected from the group consisting of
(i) pyrrolidino,
(ii) piperidino,
(iii) morpholino,
(iv) piperazino,
(v) hexamethyleneimino,
(vi) pyrrolino,
(vii) 3,4-didehydropiperidinyl, or
(viii) pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl substituted by one or two alkyl of one to 12 carbon atoms, inclusive;
(c) carbonylamino of the formula --NR.sub.23 COR.sub.21, wherein R.sub.23 is hydrogen or alkyl of one to 4 carbon atoms and R.sub.21 is other than hydrogen, but otherwise as defined above;
or
(d) sulfonylamino of the formula --NR.sub.23 SO.sub.2 R.sub.21, wherein R.sub.21 and R.sub.23 are as defined in (c).

56 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/116,323Filed 28 Jan 1980 · division
Priority: 12 Mar 1979
Granted: 22 Sep 1981
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 309/16
Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings: having…
C07C 43/178
Unsaturated ethers: containing hydroxy or O-metal groups
C07D 309/10
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,…:…
C07D 319/06
1,3-Dioxanes; Hydrogenated 1,3-dioxanes: not condensed with other rings

Family

Serial19,752Parent of this division · filed 12 Mar 1979
US 4,291,159 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The present invention provides novel analogs of the thromboxanes. These thromboxane analogs are useful for a variety of pharmacologically useful purposes, most particularly as antithrombotic agents.

A thromboxane intermediate of formula IX, ##STR2## wherein Y.sub.1 is (1) trans-CH.dbd.CH--,

(2) cis-CH.dbd.CH--,
(3) --CH.sub.2 CH.sub.2 --, or
(4) -C.tbd.C-,
wherein M.sub.1 is .alpha.-R.sub.5 :.beta.-OH, .alpha.-OH:.beta.-R.sub.5, or .alpha.-H:.beta.-H, wherein R.sub.5 is hydrogen or methyl;
wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .beta.-R.sub.3 :.alpha.-R.sub.4, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro;
wherein Z.sub.1 is
(1) cis--CH.dbd.CH-CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --,
(2) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --,
(3) cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --,
(4) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 --,
(5) --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2 --,
(6) --CH.sub.2 --O--CH.sub.2 --(CH.sub.2)--.sub.g --CH.sub.2 --,
(7) --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.g --CH.sub.2 --, or
(8) trans-CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --CH.dbd.CH--;
wherein g is one, 2 or 3;
wherein R.sub.7 is
(1) --(CH.sub.2).sub.m --CH.sub.3, wherein m is an integer from one to 5 inclusive;
(2) phenoxy;
(3) phenoxy substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, icnlusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;
(4) phenyl;
(5) phenyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;
(6) phenylmethyl, phenylethyl, or phenylpropyl;
or
(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, two, or three chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two substituents are other than alkyl;
with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;
wherein L.sub.4 is
(a) amino of the formula --NR.sub.21 R.sub.22, wherein R.sub.21 and R.sub.22 are
(i) hydrogen;
(ii) alkyl of one to 12 carbon atoms, inclusive;
(iii) cycloalkyl of 3 to 10 carbon atoms, inclusive;
(iv) aralkyl of 7 to 12 carbon atoms, inclusive;
(v) phenyl;
(vi) phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro;
(vii) carboxyalkyl of 2 to 5 carbon atoms, inclusive;
(viii) carbamoylalkyl of 2 to 5 carbon atoms, inclusive;
(ix) cyanoalkyl of 2 to 5 carbon atoms, inclusive;
(x) acetylalkyl of 2 to 5 carbon atoms, inclusive;
(xi) benzoylalkyl of 7 to 11 carbon atoms, inclusive;
(xii) benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro;
(xiii) pyridyl;
(xiv) pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive;
(xv) pyridylalkyl of 6 to 9 carbon atoms, inclusive;
(xvi) pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy or alkoxy of one to 3 carbon atoms, inclusive;
(xvii) hydroxyalkyl of one to 4 carbon atoms, inclusive;
(xviii) dihydroxyalkyl of one to 4 carbon atoms, or
(xix) trihydroxyalkyl of one to 4 carbon atoms;
with the further proviso that not more than one of R.sub.21 and R.sub.22 is other than hydrogen or alkyl;
(b) cycloamino selected from the group consisting of
(i) pyrrolidino,
(ii) piperidino,
(iii) morpholino,
(iv) piperazino,
(v) hexamethyleneimino,
(vi) pyrrolino,
(vii) 3,4-didehydropiperidinyl, or
(viii) pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl substituted by one or two alkyl of one to 12 carbon atoms, inclusive;
(c) carbonylamino of the formula --NR.sub.23 COR.sub.21, wherein R.sub.23 is hydrogen or alkyl of one to 4 carbon atoms and R.sub.21 is other than hydrogen, but otherwise as defined above;
or
(d) sulfonylamino of the formula --NR.sub.23 SO.sub.2 R.sub.21, wherein R.sub.21 and R.sub.23 are as defined in (c).

56 more elements

Facts

Application

06/116,323Filed 28 Jan 1980 · division

Priority

12 Mar 1979

Granted

22 Sep 1981

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 309/16
Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings: having…
C07C 43/178
Unsaturated ethers: containing hydroxy or O-metal groups
C07D 309/10
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,…:…
C07D 319/06
1,3-Dioxanes; Hydrogenated 1,3-dioxanes: not condensed with other rings