Miles Laboratories, Inc.

Miles Inc.

William G Biddlecom

Warren D Woessner

Harold C Kluender

Henry Clifford Arndt

Charles J Sih

George Peter Peruzzotti

Warren D Woesner

A therapeutic method for inhibiting gastric secretion in an individual for whom such therapy is indicated is disclosed. The method comprises administering to such an individual an effective inhibitory amount of certain derivatives of 15-deoxy-16-hydroxy-prostaglandin E.sub.1 esters.

Methods of inhibitng gastric secretion with prostaglandin derivatives

A therapeutic method for producing bronchodilation in an individual for whom such therapy is indicated is disclosed. The method comprises administering to said individual an effective bronchodilation amount of certain derivatives of 15-deoxy-16-hydroxy-prostaglandin E.sub.1 esters.

Therapeutic method for producing bronchodilation by administration of

Analogues of PGE.sub.1 having the structural formula, ##STR1## in which J is R-hydroxymethylene or S-hydroxymethylene; R.sub.1 is hydrogen; R.sub.2 is hydrogen or together with R.sub.4 is a methylene chain of 2 to 3 carbon atoms such that a cycloalkyl of 5 to 6 carbon atoms inclusive is formed; R.sub.3 is hydrogen or methyl, or together with R.sub.4 is a methylene or a lower alkylated methylene chain of 2 to 5 carbon atoms such that a cycloalkyl or a lower alkylated cycloalkyl of 4 to 7 carbon atoms inclusive is formed, or together with R.sub.4 is bicycloalkyl or bicycloalkenyl moiety having the formula: ##STR2## such that a bicycloalkyl or bicycloalkenyl compound is formed, wherein m and n are integers having a value from 0 to 3, p is an integer having a value from 0 to 4 and q is an integer having a value of from 1 to 4 and wherein the double bond of such bicycloalkenyl is in the m, n, p, or q bridge; R.sub.4 is hydrogen or methyl or together with R.sub.2 or R.sub.3 forms a cycloalkyl or bicycloalkyl or bicycloalkenyl as defined above, or together with R.sub.5 is a methylene chain of 3 to 5 carbon atoms such that a cycloalkyl of 4 to 6 carbon atoms inclusive is formed; R.sub.5 is selected from the group consisting of hydrogen, straight-chain alkyl having from 1 to 3 carbon atoms or together with R.sub.4 forms a cycloalkyl as defined above; and R.sub.6 is hydrogen or straight-chain alkyl having from 1 to 3 carbon atoms are disclosed. PGE.sub.1 ester analogues of the above formula, limited to the structures wherein two of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 form a cycloalkyl, lower alkylated cycloalkyl, bicycloalkyl or bicycloalkenyl are also disclosed. The prostaglandin analogues selectively produce bronchodilation and decrease gastric secretion in vivo. Methods of preparing the analogues and starting materials required in the synthesis of the analogues are also disclosed.

15-Deoxy-16-hydroxy prostaglandins for producing bronchodilation

Disclosed are C-9 enol acylate analogs of E.sub.1 and E.sub.2 prostaglandins which are variously useful as bronchodilators, gastric anti-secretory agents and cyto-protective agents.

Enol acylate analogs of E.sub.1 and E.sub.2 prostaglandins

Disclosed are 1-acyloxy-15-deoxy-16-hydroxy prostaglandin E.sub.1 analogs characterized by the formula: ##STR1## Compounds corresponding to the foregoing formula in which R.sub.1 can be H or methyl and R.sub.2 can be C(CH.sub.3).sub.2 (CH.sub.2).sub.2 CH.sub.3 or (CH.sub.2).sub.3 CH.sub.3 are variously useful as inhibitors of gastric secretion and as bronchodilators.

1-Acyloxy-15-deoxy-16-hydroxy-analogs of prostaglandin E.sub.1

Analogues of PGE.sub.1 having the structural formula, ##STR1## in which J is R-hydroxymethylene or S-hydroxymethylene; R.sub.1 is hydrogen; R.sub.2 is hydrogen or together with R.sub.4 is a methylene chain of 2 to 3 carbon atoms such that a cycloalkyl of 5 to 6 carbon atoms inclusive is formed; R.sub.3 is hydrogen or methyl, or together with R.sub.4 is a methylene or a lower alkylated methylene chain of 2 to 5 carbon atoms such that a cycloalkyl or a lower alkylated cycloalkyl of 4 to 7 carbon atoms inclusive is formed, or together with R.sub.4 is bicycloalkyl or bicycloalkenyl moiety having the formula: ##STR2## such that a bicycloalkyl or bicycloalkenyl compound is formed, wherein m and n are integers having a value from 0 to 3, p is an integer having a value from 0 to 4 and q is an integer having a value of from 1 to 4 and wherein the double bond of such bicycloalkenyl is in the m, n, p, or q bridge; R.sub.4 is hydrogen or methyl or together with R.sub.2 or R.sub.3 forms a cycloalkyl or bicycloalkyl or bicycloalkenyl as defined above, or together with R.sub.5 is a methylene chain of 3 to 5 carbon atoms such that a cycloalkyl of 4 to 6 carbon atoms inclusive is formed; R.sub.5 is selected from the group consisting of hydrogen, straight-chain alkyl having from 1 to 3 carbon atoms or together with R.sub.4 forms a cycloalkyl as defined above; and R.sub.6 is hydrogen or straight-chain alkyl having from 1 to 3 carbon atoms are disclosed. PGE.sub.1 ester analogues of the above formula, limited to the structures wherein two of R.sub.2, R.sub.3 R.sub.4 and R.sub.5 form a cycloalkyl, lower alkylated cycloalkyl, bicycloalkyl or bicycloalkenyl are also disclosed. The prostaglandin analogues selectively produce bronchodilation and decrease gastric secretion in vivo. Methods of preparing the analogues and starting materials required in the synthesis of the analogues are also disclosed.

Therapeutic method for inhibiting gastric secretion by administration of

15-Deoxy-16-hydroxy prostaglandins

Disclosed are trans 1 & 2-di(loweralkyl)phosphono; 1 & 2-chloro, bromo and iodo; 1 & 2-thio and 1 & 2-amino analogues of E.sub.1, A.sub.1, F.sub.1.alpha., F.sub.1.beta., 11 deoxy E.sub.1, 11 deoxy F.sub.1.beta., and 11 deoxy F.sub.1.alpha. prostaglandins. The prostaglandins of this invention are variously useful as antithrombic agents, bronchodilators such as in the treatment of asthma, inhibitors of gastric secretion and as antihypertensive agents. Certain of the prostaglandins disclosed herein are useful as precursors for prostaglandins having one or more of the foregoing utilities.

1 And 2-substituted analogues of certain prostaglandins

Useful intermediates in the preparation of bicycloalkyl analogues or derivatives of prostaglandins are represented by the formula ##STR1## wherein: X is an iodo or bromo radical;

Intermediates for the preparation of bicycloalkyl derivatives of

Analogues of prostaglandins A, E, and F in which the C.sub.13 -C.sub.20 chain of the natural prostaglandins is replaced by a cycloalkenyl or a hydroxycycloalkenyl moiety such that vinylene radical and the hydroxyl group of the ring respectively retain their natural sequential positions at C.sub.13 -C.sub.14 and C.sub.15, inhibit aggregation of platelets in vitro and exhibit useful cardiovascular activity in vivo.

Cycloalkenyl analogues of prostaglandin A

Cycloalkenyl analogues of prostaglandin F

Analogues of PGE.sub.1 having the structural formula, ##STR1## in which J is R-hydroxymethylene or S-hydroxymethylene; R.sub.1 is hydrogen; R.sub.2 is hydrogen or together with R.sub.4 is a methylene chain of 2 to 3 carbon atoms such that a cycloalkyl of 5 to 6 carbon atoms inclusive is formed; R.sub.3 is hydrogen or methyl, or together with R.sub.4 is a methylene or a lower alkylated methylene chain of 2 to 5 carbon atoms such that a cycloalkyl or a lower alkylated cycloalkyl of 4 to 7 carbon atoms inclusive is formed, or together with R.sub.4 is bicycloalkyl or bicycloalkenyl moiety having the formula: ##STR2## SUCH THAT A BICYCLOALKYL OR BICYCLOALKENYL COMPOUND IS FORMED, WHEREIN M AND N ARE INTEGERS HAVING A VALUE FROM 0 TO 3, P IS AN INTEGER HAVING A VALUE FROM 0 TO 4 AND Q IS AN INTEGER HAVING A VALUE OF FROM 1 TO 4 AND WHEREIN THE DOUBLE BOND OF SUCH BICYCLOALKENYL IS IN THE M, N, P, OR Q BRIDGE; R.sub.4 is hydrogen or methyl or together with R.sub.2 or R.sub.3 forms a cycloalkyl or bicycloalkyl or bicycloalkenyl as defined above, or together with R.sub.5 is a methylene chain of 3 to 5 carbon atoms such that a cycloalkyl of 4 to 6 carbon atoms inclusive is formed; R.sub.5 is selected from the group consisting of hydrogen, straight-chain alkyl having from 1 to 3 carbon atoms or together with R.sub.4 forms a cycloalkyl as defined above; and R.sub.6 is hydrogen or straight-chain alkyl having from 1 to 3 carbon atoms are disclosed. Pge.sub.1 ester analogues of the above formula, limited to the structures wherein two of R.sub.2, R.sub.3 R.sub.4 and R.sub.5 form a cycloalkyl, lower alkylated cycloalkyl, bicycloalkyl or bicycloalkenyl are also disclosed. The prostaglandin analogues selectively produce bronchodilation and decrease gastric secretion in vivo. Methods of preparing the analogues and starting materials required in the synthesis of the analogues are also disclosed.

Preparation of 15-deoxy-16-hydroxyprostaglandins

Novel bicycloalkyl analogues or derivatives of prostaglandin A, E and F are useful modifiers of smooth muscle activity. The compounds have valuable pharmacological properties as platelet antiaggregating agents and gastric antisecretory agents. The compounds are also valuable pharmacological agents for increasing femoral blood flow and decreasing blood pressure and heart rate.

Bicycloalkyl derivatives of prostaglandins 11-deoxy-PGE.sub.2 acids and

Bicycloalkyl derivatives of prostaglandins PGE.sub.1 alcohols

Novel bicycloalkyl analogues or derivatives of prostaglandin A, E, and F are useful modifiers of smooth muscle activity. The compounds have valuable pharmacological properties as platelet antiaggregating agents and gastric antisecretory agents. The compounds are also valuable pharmacological agents for increasing femoral blood flow and decreasing blood pressure and heart rate.

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Madison, WI, United States of America

William G Biddlecom