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Claims for Patent: 4,472,380

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Claims for Patent: 4,472,380

Title: Amino acid derivatives as antihypertensives
Abstract:There are disclosed processes for preparing carboxyalkyl dipeptide derivatives and related compounds which are useful as angiotension converting enzyme (ACE) inhibitors and as antihypertensives and pharmaceutical compositions containing these carboxyalkyl dipeptide compounds in combination with another antihypertensive and/or diuretic compound.
Inventor(s): Harris; Elbert E. (Westfield, NJ), Patchett; Arthur A. (Westfield, NJ), Tristram; Edward W. (Watchung, NJ), Wyvratt; Matthew J. (Mountainside, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:06/423,916
Patent Claims: 1. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an amino acid compound of the formula: ##STR16## wherein R and R.sup.6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, arloweralkyloxy substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy, amino, loweralkylamino diloweralkylamino, arloweralkylamino or hydroxyamino;

R.sup.1 is hydrogen, alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent is halo, hydroxy, lower alkoxy, aryloxy, amino, loweralkylamino, diloweralkylamino, acylamino, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, carbolower alkoxy, phenyl, substituted phenyl wherein the substituent is lower alkyl, lower alkoxy or halo; arloweralkyl or heteroarloweralkyl, arloweralkenyl or heteroarloweralkenyl, substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, acylamino, diloweralkylamino, loweralkylamino, carboxyl, halo lower alkyl, cyano or, sulfonamido; arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or benzoylamino;

R.sup.2 and R.sup.7 are hydrogen or lower alkyl;

R.sup.3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acetylamino lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl and loweralkylthio lower alkyl;

R.sup.4 is hydrogen or lower alkyl;

R.sup.5 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, quanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or, loweralkyl thio lower alkyl;

R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with hydroxy, lower alkoxy or lower alkyl or the pharmaceutically acceptable salts thereof, and an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine hydrochloride, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, quanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metaprololtartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxide, pargyline hydrochloride, polythiazide, prazosin hydrochloride, propanolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol, trichloromethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, and mixtures and combinations thereof.

2. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an amino acid compound of the formula: ##STR17## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy, aralkyloxy,

R.sup.2 and R.sup.7 are hydrogen,

R.sup.3 is methyl, aminoloweralkyl,

R.sup.4 and R.sup.5 are joined through the carbon and nitrogen atoms to form proline, 4-thiaproline or 4-methoxy-proline, and

R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;

the pharmaceutically acceptable salts thereof; and, an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine hydrochloride, cryptenamine acetates and cryptenamine tennates, deserpidine, diazoxide, quanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metaprololtartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxide, pargyline hydrochloride, polythiazide, prazosin hydrochloride, propanolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, and mixtures and combinations thereof.

3. The composition of claim 2 wherein said amino acid compound is a member selected from the group consisting of:

N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline;

N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline;

N-(1-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L-proline;

N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline;

N-.alpha.-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline;

N-.alpha.-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L-p roline;

N-.alpha.-[1-carboxy-5-aminopentyl]-L-lysyl-L-proline;

N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline;

Ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride;

N-[1-(ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline;

N-[1-carboxy-3-(4-imidazolyl)propyl]-L-lysyl-L-proline;

N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline;

N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline;

N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt;

N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline;

Ethyl N-(1((S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride; and,

N-.alpha.-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

4. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of an amino acid compound of claim 3; a pharmaceutically effective amount of hydrochlorothiazide; and, a pharmaceutically acceptable carrier therefor.

5. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of an amino acid compound of claim 3; a pharmaceutically effective amount of hydrochlorothiazide and timolol; and, a pharmaceutically acceptable carrier therefor.

6. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of an amino acid compound of claim 3; a pharmaceutically effective amount of timolol; and, a pharmaceutically acceptable carrier therefor.

7. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of an amino acid compound of claim 3; a pharmaceutically effective amount of hydrochlorothiazide and amiloride; and, a pharmaceutically acceptable carrier therefor.

8. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of an amino acid compound of claim 3; a pharmaceutically effective amount of furosemide; and, a pharmaceutically acceptable carrier therefor.

9. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline; a pharmaceutically effective amount of hydrochlorthiazide; and, a pharmaceutically acceptable carrier therefor.

10. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; a pharmaceutically effective amount of hydrochlorthiazide; and, a pharmaceutically acceptable carrier therefor.

11. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline; a pharmaceutically effective amount of hydrochlorothiazide and timolol; and, a pharmaceutically acceptable carrier therefor.

12. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; a pharmaceutically effective amount of hydrochlorothiazide and timolol; and, a pharmaceutically acceptable carrier therefor.

13. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline; a pharmaceutically effective amount of timolol; and a pharmaceutically acceptable carrier therefor.

14. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; a pharmaceutically effective amount of timilol; and, a pharmaceutically acceptable carrier therefor.

15. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline; a pharmaceutically effective amount of hydrochlorothiazide and amiloride; and, a pharmaceutically acceptable carrier therefor.

16. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; a pharmaceutically effective amount of hydrochlorothiazide and niloride; and, a pharmaceutically acceptable carrier therefor.

17. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline; a pharmaceutically effective amount of furosemide; and, a pharmaceutically acceptable carrier therefor.

18. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically effective amount of N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; a pharmaceutically effective amount of furosemide; and, a pharmaceutically acceptable carrier therefor.

19. A process for preparing a compound of the formula ##STR18## wherein R and R.sup.6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, phenyl, substituted phenyl wherein the substituent is lower alkyl, lower alkoxy or halo; arloweralkyl or heteroarloweralkyl, arloweralkenyl or heteroarloweralkenyl, substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, acylamino, diloweralkylamino, loweralkylamino, carboxyl, halo loweralkyl, cyano or, arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino;

R.sup.2 and R.sup.7 are hydrogen or lower alkyl;

R.sup.3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acetylamino lower alkyl, acylamino lower alkyl, amino lower alkyl, acyloxy lower alkoxy, aryloxy, arloweralkyloxy, substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy, amino, loweralkylamino, diloweralkylamino, arloweralkylamino or hydroxyamino;

R.sup.1 is hydrogen, alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent is halo, hydroxy, lower alkoxy, aryloxy, amino, loweralkylamino, diloweralkylamino, acylamino, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, carbolower alkoxy, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl and loweralkylthio lower alkyl;

R.sup.4 is hydrogen or lower alkyl;

R.sup.5 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or loweralkyl thio lower alkyl;

R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with hydroxy, lower alkoxy or, lower alkyl, and the pharmaceutically acceptable salts thereof which comprises reacting a ketone of the formula ##STR19## wherein R.sup.1 may include suitable protection of any reactive groups with dipeptide or protected dipeptide of the formula ##STR20## wherein R.sup.3 and R.sup.5 may include suitable protection of any reactive groups and reducing the intermediate(s) so formed by conducting the reaction in the presence of a reducing agent, followed by removal of the protecting groups if necessary to yield the desired product, and, if desired, preparing a salt thereof by conventional means and, if desired, isolating the biologically more active isomer by chromatography or fractional crystallization.

20. A process for preparing a compound of claim 19 which comprises reacting a ketone of the formula ##STR21## wherein R is not hydroxy, and R.sup.1 may include suitable protection of any reactive group with an amino acid or protected amino acid of the formula ##STR22## wherein R.sup.3 may include suitable protection of any reactive group in the presence of a reducing agent to form an intermediate of the formula: ##STR23## then coupling said intermediate with an amino acid or protected amino acid derivative of the formula ##STR24## wherein R.sup.6 is not hydroxy and R.sup.5 may include suitable protection of any reactive group to yield a compound of claim 19 where R and R.sup.6 are not hydroxy, followed by removal of protecting groups and if desired converting R and/or R.sup.6 to hydroxy by hydrolyzing or hydrogenating the appropriate precursor, and, if desired, preparing a salt thereof by conventional means and, if desired, isolating the biologically more active isomer by chromatography or fractional crystallization.

21. A process for preparing a compound of the formula of claim 19 which comprises reacting an amine of the formula ##STR25## wherein R.sup.1 may include suitable protection of any reactive group with a ketone of the formula ##STR26## wherein R.sup.3 and R.sup.5 may include suitable protection of any reactive group, in the presence of a reducing agent followed by removal of the protecting groups if necessary to yield the desired product or if desired performing the reaction in a stepwise fashion by condensing (VII) where R is not hydroxy with a keto acid of the formula ##STR27## wherein R.sup.3 may include suitable protection of any reactive group in the presence of a reducing agent to yield ##STR28## and condensing (X) with an amino acid derivative of the formula ##STR29## wherein R.sup.6 is not hydroxy and R.sup.5 may include suitable protection of any reactive group followed by removal of the protecting groups if necessary to yield a compound of claim 18 where R and R.sup.6 are not hydroxy and if desired converting R and/or R.sup.6 to hydroxy by hydrolyzing or hydrogenating the appropriate precursor and further, if desired, preparing a salt thereof by conventional means and still further, if desired, isolating the biologically more active isomer by chromatography or fractional crystallization.

22. A process for preparing a compound of claim 19 which comprises reacting a dipeptide of the formula ##STR30## wherein R.sup.3 and R.sup.5 may include suitable protection of any reactive group with a compound of the formula ##STR31## wherein R.sup.1 may include suitable protection of any reactive group and where X is chlorine, bromine, iodine, or a sulfonyloxy derivative followed by the removal of protecting groups if necessary to yield the desired product or if desired reacting (XI) in which R is not OH with an amino acid derivative of the formula ##STR32## wherein R.sup.3 may include suitable protection of any reactive group to form an intermediate of the formula ##STR33## and then reacting said intermediate with an amino acid derivative of the formula ##STR34## in which R.sup.6 is not OH and R.sup.5 may include suitable protection of any reactive group followed by removal of the protecting group if necessary, to form a compound of claim 19 and, if desired, preparing a salt thereof by conventional means and, if desired, isolating the biologically more active isomer by chromatography or fractional crystallization.

23. A process for preparing a compound of claim 19 which comprises reacting an amino acid derivative of the formula: ##STR35## wherein R.sup.1 may include suitable production of any reactive group with an .alpha.-substituted acyl amino acid derivative ##STR36## where X is chlorine, bromine, iodine or a sulfonyloxy derivative; preferably where R.sup.6 is not hydroxyl, and where R.sup.3 and R.sup.5 may include suitable protection of any reactive group followed by removal of the protecting group if necessary to form the desired product or if desired reacting an amino acid ester (VII) where R is not hydroxyl with an .alpha.-substituted acid of the formula ##STR37## wherein R.sup.3 may include suitable protection of any reactive group to yield an intermediate ester of the formula ##STR38## and reacting said intermediate with an amino acid ester of the formula ##STR39## wherein R.sup.6 is not hydroxyl and R.sup.5 may include suitable protection of any reactive group followed by removal of the protecting groups if necessary to yield the compound of claim 19 and if desired converting R and/or R.sup.6 to hydroxy by hydrolyzing or hydrogenating the appropriate precursor and further, if desired, preparing a salt thereof by conventional means and still further, if desired, isolating the biologically more active isomer by chromatography or fractional crystallization.

24. A process according to claim 19 for preparing a compound of the formula: ##STR40## wherein R and R.sup.6 can each independently be hydroxy, alkoxy, aralkyloxy,

R.sup.1 is alkyl having from 1-8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl portion has 1-3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1-3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;

R.sup.2 and R.sup.7 are hydrogen;

R.sup.3 is methyl, aminoloweralkyl;

R.sup.4 and R.sup.5 can be joined together through the carbon and nitrogen atoms to which they are attached to form proline, 4-thiaproline or 4-methoxyproline.

25. A process according to claim 19 for preparing a compound of the formula ##STR41## which comprises reacting a ketone of the formula ##STR42## with a dipeptide of the formula ##STR43## in the presence of a reducing agent to obtain the desired product and isolating the biologically more active diastereoisomer by chromatography or fractional crystallization.

26. A process according to claim 25 wherein the maleate salt of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline is obtained by fractional crystallization.

27. A process according to claim 19 for preparing a compound of the formula ##STR44## which comprises reacting a ketone of the formula ##STR45## with a protected dipeptide of the formula ##STR46## wherein t-Boc is the t-butyloxycarbonyl protecting group, in the presence of a reducing agent to yield the protected form of the desired product, then reacting this with a suitable acidic reagent to obtain the desired product, and isolating the biologically more active diastereomer by chromatography or fractional crystallization.

28. A process according to claim 19 for preparing a compound of the formula ##STR47## which comprises reacting a ketone of the formula ##STR48## with a protected dipeptide of the formula ##STR49## wherein t-Boc is the t-butyloxycarbonyl protecting group in the presence of a reducing agent to yield the protected form of the desired product, then reacting this with a suitable acidic reagent to obtain the desired product, and isolating the biologically more active diastereomer by chromatography or fractional crystallization.

29. A process according to claim 19 for preparing a compound of the formula ##STR50## which comprises reacting a ketone of the formula ##STR51## with a protected dipeptide of the formula ##STR52## wherein t-Boc is the t-butyloxycarbonyl protecting group, in the presence of a reducing agent to yield the protected form of the desired product, then reacting this with a suitable acidic reagent to obtain the desired product, and isolating the biologically more active diastereomic by chromatography or fractional crystallization.

30. A process according to claim 19 for preparing the following compounds:

N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline;

N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline;

N-(1-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L-proline;

N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline;

N-.alpha.-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline;

N-.alpha.-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L-p roline;

N-.alpha.-[1-carboxy-5-aminopentyl]-L-lysyl-L-proline;

N-.alpha.-(1-carboxy-3-phenylpropyl)-L-ornithyl-L-proline;

Ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride;

N-[1-(ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline;

N-[1-carboxy-3-(4-imidazolyl)propyl]-L-lysyl-L-proline;

N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline;

N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline;

N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt;

N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline; and, ethyl N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride;

N-.alpha.-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.

31. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an amino acid compound of the formula: ##STR53## wherein R and R.sup.6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, arykoxy, arloweralkyloxy, substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo, or methoxy, amino, loweralkylamino, diloweralkylamino, arloweralkylamino or hydroxyamino;

R.sup.1 is hydrogen, alkyl of from 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl groups; substituted lower alkyl wherein the substituent is halo, hydroxy, lower alkoxy, aryloxy, amino, loweralkylamino, diloweralkylamino, acylamino, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, carbolower alkoxy, phenyl, substituted phenyl wherein the substituent is lower alkyl, lower alkoxy or halo; arloweralkyl or heteroarloweralkyl, arloweralkenyl or heteroarloweralkenyl, substituted arloweralkyl, substituted heteroarloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl, wherein the substituent is halo or dihalo, lower alkyl, hydroxy, loweralkoxy, amino, aminomethyl, acylamino, diloweralkylamino, loweralkylamino, carboxyl, halo lower alkyl, cyano or sulfonamido; arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or benzoylamino;

R.sup.2 and R.sup.7 are hydrogen or lower alkyl;

R.sup.3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acetylamino lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl and loweralkylthio lower alkyl;

R.sup.4 is hydrogen or lower alkyl;

R.sup.5 is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or loweralkyl thio lower alkyl;

R.sup.4 and R.sup.5 may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with hydroxy, lower alkoxy or lower alkyl or the pharmaceutically acceptable salts thereof, and; an antihypertensive and/or diuretic compound and mixtures and combinations thereof.

32. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an amino acid compound of the formula: ##STR54## wherein R and R.sup.6 can each independently be hydroxy, lower alkoxy, aralkyloxy, R.sup.2 and R.sup.7 are hydrogen, R.sup.3 is methyl, aminoloweralkyl, R.sup.4 and R.sup.5 are joined through the carbon and nitrogen atoms to form proline, 4-thiaproline or 4-methoxy-proline, and

R.sup.1 is alkyl having from 1 to 8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1 to 5 carbon atoms and the substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl portion has 1 to 3 carbon atoms, substituted aralkyl or heteroaralkyl wherein the alkyl groups have 1 to 3 carbon atoms and the substituent(s) is halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;

or pharmaceutically acceptable salts thereof; and, an antihypertensive and/or diuretic compound and mixtures and combinations thereof.

33. The composition of claim 32 wherein said amino acid compound is a member selected from the group consisting of:

N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline;

N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline;

N-(1-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L-proline;

N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline;

N-.alpha.-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline;

N-.alpha.-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-2-phenylthioethyl]-L-lysyl-L-proline;

N-.alpha.-[1-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-trans-4-methoxy-L-p roline;

N-.alpha.-[1-carboxy-5-aminopentyl]-L-lysyl-L-proline;

N-.alpha.-(1-carboxy-3-phenypropyl)-L-ornithyl-L-proline;

Ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride;

N-[1-ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline;

N-[1-carboxy-3-(4-imidazolyl)propyl]-L-lysyl-L-proline;

N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline;

N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline;

N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt;

N-.alpha.-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline;

Ethyl N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride; and,

N-.alpha.-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.
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