Derivatives of mercaptoacyl prolines and pipecolic acids

Claim 2

A compound of the formula ##STR145## or a pharmaceutically acceptable salt thereof wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR146## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR147## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one or two; n is one, two or three; p and q are each one or two provided that both are not two; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR148## R 5 is hydrogen, ##STR149## p-methoxybenzyloxycarbonyl, trityl, t-butoxycarbonyl, or provided neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR150## and R 8 is lower alkyl, halo substituted lower alkyl, --(CH 2 ) r -cycloalkyl, ##STR151## wherein r is zero, one, two or three and R 7 and X 3 are as defined above.

Claim 3

The compound of claim 1 wherein p is two and q is one.

Claim 4

The compound of claim 1 wherein p is one and q is two.

Claim 5

The compound of claim 1 wherein p and q are both one.

Claim 6

The compound of claim 4 wherein X 1 and X 2 are independently selected from the group consisting of oxygen or sulfur; R is hydrogen or lower alkyl; R 1 and R 2 each is lower alkyl of 1 to 4 carbons or form two joined methylene groups; R 3 and R 4 each is hydrogen or lower alkyl of 1 to 4 carbons; R 5 is hydrogen, lower alkanoyl of 1 to 4 carbons, or benzoyl; R 6 is hydrogen, and m is zero or one.

Claim 7

The compound of claim 4 wherein X 1 and X 2 each is oxygen; R, R 4 , R 5 and R 6 each is hydrogen; R 1 and R 2 each is lower alkyl of 1 to 4 carbons or R 1 and R 2 each is methylene and join to complete the ethylenedioxy ring; R 3 is methyl; and m is one.

Claim 8

The compound of claim 4 wherein X 1 -R 1 and X 2 -R 2 complete an ethylenedioxy ring.

Claim 9

A compound of the formula ##STR152## or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl ##STR153## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR154## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one or two; n is one, two, or three; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR155## R 5 is hydrogen, ##STR156## p-methoxybenzyloxycarbonyl, trityl, t-butoxycarbonyl, or provided that neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR157## and R 8 is lower alkyl, halo substituted lower alkyl, --(CH 2 ) r -cycloalkyl, ##STR158## wherein r is zero, one, two or three and R 7 and X 3 are as defined above.

Claim 10

A compound of the formula ##STR152## or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl ##STR153## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR154## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one or two; n is one, two, or three; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR155## R 5 is hydrogen, ##STR156## p-methoxybenzyloxycarbonyl, trityl, t-butoxycarbonyl, or provided that neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR157## and R 8 is lower alkyl, halo substituted lower alkyl, --(CH 2 ) r -cycloalkyl, ##STR158## wherein r is zero, one, two or three and R 7 and X 3 are as defined above.

Claim 11

The compound of claim 8 wherein R is hydrogen; R 4 is hydrogen; R 3 and R 6 are both lower alkyl of 1 to 4 carbons or R 6 is hydrogen and R 3 is hydrogen, lower alkyl of 1 to 4 carbons, trifluoromethyl, methylthio, or mercaptomethyl; R 5 is hydrogen, lower alkanoyl of 1 to 4 carbons, or benzoyl; X 1 and X 2 are oxygen or sulfur; R 1 and R 2 are lower alkyl of 1 to 4 carbons, ##STR159## m is zero or one; and R 7 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, trifluoromethyl, or hydroxy.

Claim 12

The compound of claim 9 wherein R is hydrogen; R 4 is hydrogen; R 3 and R 6 are both methyl or R 6 is hydrogen and R 3 is hydrogen, methyl, trifluoromethyl, methylthio, or mercaptomethyl; R 5 is hydrogen, acetyl, or benzoyl; X 1 and X 2 are the same; R 1 and R 2 are methyl, ethyl, ##STR160## m is zero or one; and R 7 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, trifluoromethyl, or hydroxy.

Claim 13

The compound of claim 10 wherein R, R 4 , R 5 , and R 6 are hydrogen; R 3 is methyl; m is one; and R 1 and R 2 are both methyl or ethyl.

Claim 14

The compound of claim 11 wherein X 1 and X 2 are both oxygen.

Claim 15

The compound of claim 12, (S)-1-(3-mercapto-2-methyl-1-oxopropyl)-4,4-dimethoxy-L-proline.

Claim 16

The compound of claim 12, (S)-1-(3-mercapto-2-methyl-1-oxopropyl)-4,4-diethoxy-L-proline.

Claim 17

The compound of claim 8 wherein R is hydrogen; R 4 is hydrogen; R 3 and R 6 are both lower alkyl of 1 to 4 carbons or R 6 is hydrogen and R 3 is hydrogen, lower alkyl of 1 to 4 carbons, trifluoromethyl, methylthio, or mercaptomethyl; R 5 is hydrogen, lower alkanoyl of 1 to 4 carbons, or benzoyl; X 1 -R 1 and X 2 -R 2 join to form ##STR161## R 9 and R 10 are both hydrogen or both lower alkyl of 1 to 4 carbons; or R 9 is hydrogen and R 10 is lower alkyl of 1 to 4 carbons, hydroxy substituted lower alkyl of 1 to 4 carbons, or halogen substituted lower alkyl of 1 to 4 carbons; m is zero or one.

Claim 18

The compound of claim 15 wherein R 9 and R 10 are both hydrogen or R 9 is hydrogen and R 10 is methyl, hydroxymethyl, or trifluoromethyl.

Claim 19

The compound of claim 16 wherein R is hydrogen; R 4 is hydrogen; R 3 and R 6 are both methyl or R 6 is hydrogen and R 3 is hydrogen, methyl, trifluoromethyl, methylthio or mercaptomethyl; R 5 is hydrogen, acetyl, or benzoyl; and X 1 -R 1 and X 2 -R 2 join to form ##STR162##

Claim 20

The compound of claim 17 wherein R, R 4 , R 5 and R 6 are hydrogen, R 3 is methyl; and m is one.

Claim 21

The compound of claim 18, [7(S),8S]-7-(3-mercapto-2-methyl-1-oxopropyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid.

Claim 22

The compound of claim 18, [2(S),3S]-2-(3-mercapto-2-methyl-1-oxopropyl)-6,10-dioxo-2-azaspiro[4.5]decane-3-carboxylic acid.

Claim 23

The compound of claim 18, [7(S),8S]-7-(3-mercapto-2-methyl-1-oxopropyl)-7-aza-1,4-dithiaspiro[4.4]nonane-8-carboxylic acid.

Claim 24

The compound of claim 18, [7(S),8S]-7-(3-mercapto-2-methyl-1-oxopropyl)-1,4-dioxo-7-azaspiro[4.4]nonane-2-methyl-8-carboxylic acid.

Claim 25

The compound of claim 17 wherein R, R 4 ,R 5 and R 6 are hydrogen, R 3 is trifluoromethyl; and m is one.

Claim 26

The compound of claim 23, (8S)-7-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid.

Claim 27

The compound of claim 8 wherein R 3 and R 4 are other than --(CH 2 ) n --SH and R 5 is ##STR163##

Claim 28

The compound of claim 25, (S,S,S,S)-7,7'-[dithiobis(2-methyl-1-oxo-3,1-propanediyl)]-bis[1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid].

Claim 29

A composition for treating hypertension containing a pharmaceutically acceptable carrier and from 10 to 500 mg. of a compound or mixture of compounds or pharmaceutically acceptable salts thereof of the formula ##STR164## wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR165## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR166## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one, or two; n is one, two, or three; p and q are each one or two provided that both are not two; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR167## R 5 is hydrogen, ##STR168## or provided that neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR169## and R 8 is lower alkyl, halo substituted lower alkyl, --(CH 2 ) r -cycloalkyl, ##STR170## wherein r is zero, one, two, or three and R 7 and X 3 are as defined above.

Claim 30

A composition for treating hypertension containing a pharmaceutically acceptable carrier and from 10 to 500 mg. of a compound or mixture of compounds or pharmaceutically acceptable salts thereof of the formula ##STR164## wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR165## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR166## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one, or two; n is one, two, or three; p and q are each one or two provided that both are not two; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR167## R 5 is hydrogen, ##STR168## or provided that neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR169## and R 8 is lower alkyl, halo substituted lower alkyl, --(CH 2 ) r -cycloalkyl, ##STR170## wherein r is zero, one, two, or three and R 7 and X 3 are as defined above.

Claim 31

The method of alleviating hypertension by administering an effective amount of the composition of claim 27.

Claim 32

A composition for treating hypertension containing a pharmaceutically acceptable carrier, 15 to 300 mg. of a diuretic selected from the group consisting of chlorthiazide, hydrochlorothiazide, flumethiazide, hydroglumethiazide, benzdoflumethiazide, methchlothiazide, trichlormethiazide, polythiazide, benzthiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone and pharmaceutically acceptable salts thereof, and 30 to 600 mg. of a compound or mixture of compounds or pharmaceutically acceptable salts thereof of the formula ##STR171## wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR172## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR173## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one or two; n is one, two, or three; p and q are each one or two provided that both are not two; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR174## R 5 is hydrogen, ##STR175## or provided that neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR176## and R 8 is lower alkyl, halo substituted lower alkyl, ##STR177## wherein r is zero, one, two or three and R 7 and X 3 are as defined above.

Claim 33

A composition for treating hypertension containing a pharmaceutically acceptable carrier, 15 to 300 mg. of a diuretic selected from the group consisting of chlorthiazide, hydrochlorothiazide, flumethiazide, hydroglumethiazide, benzdoflumethiazide, methchlothiazide, trichlormethiazide, polythiazide, benzthiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone and pharmaceutically acceptable salts thereof, and 30 to 600 mg. of a compound or mixture of compounds or pharmaceutically acceptable salts thereof of the formula ##STR171## wherein R is hydrogen or lower alkyl; R 1 and R 2 are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR172## or R 1 and R 2 join together in a polymethylene chain of the formula ##STR173## X 1 , X 2 and X 3 are independently selected from the group consisting of oxygen and sulfur; R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, --(CH 2 ) n --SH, and halo substituted lower alkyl; R 6 is hydrogen or lower alkyl provided that R 6 is lower alkyl only when R 3 is lower alkyl; m is zero, one or two; n is one, two, or three; p and q are each one or two provided that both are not two; t is two or three; R 7 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy; R 9 and R 10 are both hydrogen, both lower alkyl, or one is hydrogen and the other is lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, ##STR174## R 5 is hydrogen, ##STR175## or provided that neither R 3 nor R 4 is --(CH 2 ) n --SH ##STR176## and R 8 is lower alkyl, halo substituted lower alkyl, ##STR177## wherein r is zero, one, two or three and R 7 and X 3 are as defined above.

Claim 34

The method of alleviating hypertension by administering an effective amount of the composition of claim 29.