N,N-dialkylguanidino dipeptides

Claim 2

A compound of the general formula (A) wherein R' represents hydroxy, C 1-6 alkoxy, benzyloxy or amino optionally substituted with one or two C1 -6 alkyl groups; R 2 and R 3 represent (1) hydrogen or preferably C 1-6 alkyl (optionally omega-substituted with phenyl or naphthyl; less preferred omega-substituted with di(C 1-6 )alkylguanidino); or and one of R 2 and R 3 being (1), the other being (2); and the group - is an amino acid residue selected from imino acid residues, preferably cyclic imino acid residues in which the subgroup forms a heterocyclic radical containing one nitrogen atom and up to 9 ring carbon atoms, in particular where said cyclic imino acid residue is or is derived from proline, hydroxyproline or proline analogs; R 6 is hydroxy, C 1-6 alkoxy, benzyloxy or amino optionally substituted with one or two C 1-6 alkyl groups; R' and R" are independently C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; n is an integer from 3 to 5, preferably 4; and their pharmaceutically acceptable, non-toxic salts.

Claim 3

The compound of claim 1 wherein one of R 2 and R 3 represents C 1 - 6 alkyl, benzyl or 2 - phenylethyl.

Claim 4

The compound according to claim 1 or 2 wherein one of R 2 and R 3 is C 1-6 alkyl or 2-phenylethyl; and the group represents proline (I) or a proline analog in which the pyrrolidine ring is substituted by an oxo group (IV) by hydroxy, mercapto, C 1-6 alkylmercapto or C 1-6 alkoxy (V) or the proline function is replaced with the residues II, III or VI: and R' is hydroxy or benzyloxy; and X is hydrogen, nitro, C 1-6 alkyl, chloro or bromo.

Claim 5

The compound of one of the preceding claims wherein R 2 represents (2).

Claim 6

The compound according to claims 1 to 3 wherein R 2 is phenylethyl.

Claim 7

The compound according to claims 1 to 4 wherein R 3 is lower alkyl with 1 to 4 carbons.

Claim 8

The compound according to claim 6 wherein R 3 is methyl, ethyl, or n-propyl.

Claim 9

The compound according to one of the preceding claims wherein the group forms a proline residue.

Claim 10

The compound of one of claims 1 to 7 wherein the group is a proline residue or a residue selected from the groups II, III or VI and R' is hydroxy.

Claim 11

The compound of one of the claims 1 to 7 and 9 wherein the group is II.

Claim 12

The compound of claim 10 wherein X is hydrogen.

Claim 13

The compound of one of the preceding claims wherein R' and R' are lower alkyl with 1 to 4 carbon atoms.

Claim 14

The compound of claim 12 wherein R 7 and R 8 are methyl, ethyl, 2,2,2-trifluoroethyl, n-propyi or n-butyl.

Claim 15

The compound of claim 13 wherein R 7 and R 8 are ethyl.

Claim 16

A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound of one of the preceding claims and a pharmaceutically acceptable excipient.

Claim 17

The composition of Claim 15 for the treatment of hypertension.

Claim 18

The composition of Claim 15 or 16 including other antihypertensives.

Claim 19

The composition of Claim 15 or 16 including diuretic.

Claim 20

The pharmaceutical composition of Claims 15 or 16 including a calcium blocker.

Claim 21

The composition of Claim 15 or 16 including nicardipine.

Claim 22

The use of a compound of any one of claims 1 to 14 in the manufacture of a medicament for treating hypertension in mammals.

Claim 23

A compound according to any one of claims 1 to 14 for pharmaceutical use.

Claim 25

A process for the preparation of a compound of any one of claims 1 to 14; said process comprising (a) hydrolyzing a compound of the formula wherein R 1 * and R 6 * are hydroxy, C 1-6 alkoxy, benzyloxy or amino optionally substituted with one or two C 1-6 alkyl groups and at least one of R 1 * and R 6 * is C 1-6 alkoxy or benzyloxy to a compound of formula A wherein R 1 and R 6 are hydroxy; (b) hydrogenolyzing (reductively cleaving) a compound of the formula R 1 * ...... R 6 * wherein R 1 * and R 6 * are hydroxy, C 1-6 alkoxy, benzyloxy or amino optionally substituted with one or two C 1-6 alkyl groups and at least one of R 1 * and R 6 * is benzyloxy to a compound of formula A wherein at least one of R' and R 6 is hydroxy; (c) reducing a compound of the formula wherein one of R 2 * or R 3 * is oxo-substituted C 1-6 alkyl optionally ω-substituted with phenyl or naphthyl the other of R 2 * and R 3 * is (2) of claims 1 to 14; (d) reacting a compound of formula A with a base to form a salt of the compound of formula A; (e) reacting a compound of formula A with an acid to form an acid addition salt of the compound of formula A; (f) condensing an amino acid derivative of the formula with an a-ketoacid derivative of the formula under reductive conditions to form a compound of formula - (A); (g) reducing a Schiff base of the formula to a compound of formula A; (h) condensing an a-ketoacid derivative of the formula with a dipeptide of the formula under reductive conditions; (i) condensing an amino acid derivative of the formula with proline or a proline analog derivative of the formula to form a compound of formula A; (j) alkylating a dipeptide of the formula wherein one of R 2 * and R 3 *is -(CH 2 ) n NH 2 and the other of R 2 * and R 3 * is (1) of claims 1 to 14 with an alkylating agent of the formula wherein Z is chloro, bromo or iodo, or a C 1-6 alkyl mercapto group; (k) esterifying a compound of the formula R 1 * ..... R 6 * wherein at least one of R 1 * and R 6 * is hydroxy and the other is hydroxy, C 1-6 alkoxy or benzyloxy with a C 1-6 alkanol or benzyl alcohol; (I) alkylating a compound of the formula wherein one of R 2 * and R 3 * represents an omega-guanidine substituted alkylene group with 3 to 5, preferably 4 , carbon atoms and the other of R 2 * and R 3 * is (1) of claims 1 to 14 with a C 1-6 alkyl alkylating agent optionally substituted with 1 to 5 fluorine atoms; (m) alkylating a dipeptide derivative of the formula with an alkylating agent of the formula wherein P is halo selected from the group of chloro, bromo or iodo, or is a sulfonyloxy group; (n) alkylating an amino acid derivative of the formula with an alkylating agent of the formula wherein P has the meanings of step (m); (o) alkylating a guanidino derivative of the formula with an alkylating agent of the formula wherein one of R 2* and R 3 * is an alkylating group of the formula -(CH 2 )n -P and P has the meanings of step (m), and the other of R 2 * and R 3 * is (1 ) of claims 1 to 14; (p) converting an acid addition salt of the dipeptide of formula A with base to the dipeptide of formula A or a salt thereof with said base; (q) converting a salt of a dipeptide of formula A (derived from a base) with acid to the free dipeptide of formula A or an acid addition salt thereof; (r) converting a salt of a dipeptide of formula A, preferably a soluble salt, to another salt of the dipeptide, preferably less soluble than said soluble salt; (s) acylating ammonia, a C 1 . 6 alkyl amine or a di(C 1 . 6 ) alkyl amine with a dipeptide derivative of the formula R 1 * ...... R 6 * wherein R 1 * and R 6 * are hydroxy, chloro, bromo, C 1-6 alkoxy, benzyloxy, a C 1-6 alkanoyloxy group, or amino optionally substituted with one or two C 1 . 6 alkyl groups, and at least one of R 1 * and R 6 * is hydroxy, chloro, bromo, C 1-6 alkoxy, benzyloxy, or a C 1-6 alkanoyloxy group. 25. A method for preparing a pharmaceutical composition comprising a dipeptide of formula A or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient, said method comprising converting said dipeptide or said salt obtained according to Claim 24 and said excipient into said pharmaceutical composition.

Claim 26

Claim(s) for contracting state : AT

Claim 27

A process for the preparation of a compound having the general formula (A) wherein R 1 represents hydroxy, C 1-6 alkoxy, benzyloxy or amino optionally substituted with one or two C 1-6 alkyl groups; R 2 and R 3 represent (1) hydrogen or preferably C 1-6 alkyl (optionally omega-substituted with phenyl or naphthyl; less preferred omega-substituted with di(C 1-6 )alkylguanidino); or and one of R 2 and R 3 being (1), the other being (2); and the group - is an amino acid residue selected from imino acid residues, preferably cyclic imino acid residues in which the subgroup forms a heterocyclic radical containing one nitrogen atom and up to 9 ring carbon atoms, in particular where said cyclic imino acid residue is or is derived from proline, hydroxyproline or proline analogs; R 5 is hydroxy, C 1-6 alkoxy, benzyioxy or amino optionally substituted with one or two C 1-6 alkyl groups; R 7 and R 8 are independently C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; n is an integer from 3 to 5, preferably 4; and their pharmaceutically acceptable, non-toxic salts, said process comprising (a) hydrolyzing a compound of the formula under reductive conditions; (i) condensing an amino acid derivative of the formula with proline or a proline analog derivative of the formula to form a compound of formula A; (j) alkylating a dipeptide of the formula wherein one of R 2 * and R 3 * is -(CH 2 ) n NH 2 and the other of R 2 * and R 3 * is (1) (above) with an alkylating agent of the formula wherein Z is chloro, bromo or iodo, or a C 1-6 alkyl mercapto group; (k) esterifying a compound of the formula R 1 * ..... R 6 * wherein at least one of R 1 * and R 6 * is hydroxy and the other is hydroxy, C 1-6 alkoxy or benzyloxy with a C 1-6 alkanol or benzyl alcohol; (I) alkylating a compound of the formula wherein one of R 2 * and R 3 * represents an omega-guanidine substituted alkylene group with 3 to 5, preferably 4, carbon atoms and the other of R 2 * and R 3 * is (1) (above) with a C 1-6 alkyl alkylating agent optionally substituted with 1 to 5 fluorine atoms; (m) alkylating a dipeptide derivative of the formula with an alkylating agent of the formula wherein P is halo selected from the group of chloro, bromo or iodo, or is a sulfonyloxy group; '(n) alkylating an amino acid derivative of the formula with an alkylating agent of the formula wherein P has the meanings of step (m); (o) alkylating a guanidino derivative of the formula with an alkylating agent of the formula wherein one of R2* and R 3 * is an alkylating group of the formula -(CH 2 ) n -P and P has the meanings of step (m), and the other of R 2* and R 3 * is (1) (above). (p) converting an acid addition salt of the dipeptide of formula A with base to the dipeptide of formula A or a salt thereof with said base; (q) converting a salt of a dipeptide of formula A (derived from a base) with acid to the free dipeptide of formula A or an acid addition salt thereof; (r) converting a salt of a dipeptide of formula A, preferably a soluble salt, to another salt of the dipeptide, preferably less soluble than said soluble salt (s) acylating ammonia, a C 1-6 alkyl amine or a di(C 1-6 ) alkyl amine with a dipeptide derivate of the formula R 1 * ..... R 6 * wherein R 1 * and R 6 * are hydroxy, chloro, bromo, C 1-6 alkoxy, benzyloxy, a C 1 . 6 alkanoyloxy group, or amino optionally substituted with one or two C 1 - 6 alkyl groups, and at least one of R 1 * and R 6 * is hydroxy, chloro, bromo, C 1-6 alkoxy, benzyloxy, or a C 1-6 alkanoyloxy group.

Claim 28

A process for the preparation of a compound having the general formula (A) wherein R 1 represents hydroxy, C 1-6 alkoxy, benzyloxy or amino optionally substituted with one or two C 1-6 alkyl groups; R 2 and R 3 represent (1) hydrogen or preferably C 1-6 alkyl (optionally omega-substituted with phenyl or naphthyl; less preferred omega-substituted with di(C 1-6 )alkylguanidino); or and one of R 2 and R 3 being (1), the other being (2); and the group - is an amino acid residue selected from imino acid residues, preferably cyclic imino acid residues in which the subgroup forms a heterocyclic radical containing one nitrogen atom and up to 9 ring carbon atoms, in particular where said cyclic imino acid residue is or is derived from proline, hydroxyproline or proline analogs; R 5 is hydroxy, C 1-6 alkoxy, benzyioxy or amino optionally substituted with one or two C 1-6 alkyl groups; R 7 and R 8 are independently C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; n is an integer from 3 to 5, preferably 4; and their pharmaceutically acceptable, non-toxic salts, said process comprising (a) hydrolyzing a compound of the formula under reductive conditions; (i) condensing an amino acid derivative of the formula with proline or a proline analog derivative of the formula to form a compound of formula A; (j) alkylating a dipeptide of the formula wherein one of R 2 * and R 3 * is -(CH 2 ) n NH 2 and the other of R 2 * and R 3 * is (1) (above) with an alkylating agent of the formula wherein Z is chloro, bromo or iodo, or a C 1-6 alkyl mercapto group; (k) esterifying a compound of the formula R 1 * ..... R 6 * wherein at least one of R 1 * and R 6 * is hydroxy and the other is hydroxy, C 1-6 alkoxy or benzyloxy with a C 1-6 alkanol or benzyl alcohol; (I) alkylating a compound of the formula wherein one of R 2 * and R 3 * represents an omega-guanidine substituted alkylene group with 3 to 5, preferably 4, carbon atoms and the other of R 2 * and R 3 * is (1) (above) with a C 1-6 alkyl alkylating agent optionally substituted with 1 to 5 fluorine atoms; (m) alkylating a dipeptide derivative of the formula with an alkylating agent of the formula wherein P is halo selected from the group of chloro, bromo or iodo, or is a sulfonyloxy group; '(n) alkylating an amino acid derivative of the formula with an alkylating agent of the formula wherein P has the meanings of step (m); (o) alkylating a guanidino derivative of the formula with an alkylating agent of the formula wherein one of R2* and R 3 * is an alkylating group of the formula -(CH 2 ) n -P and P has the meanings of step (m), and the other of R 2* and R 3 * is (1) (above). (p) converting an acid addition salt of the dipeptide of formula A with base to the dipeptide of formula A or a salt thereof with said base; (q) converting a salt of a dipeptide of formula A (derived from a base) with acid to the free dipeptide of formula A or an acid addition salt thereof; (r) converting a salt of a dipeptide of formula A, preferably a soluble salt, to another salt of the dipeptide, preferably less soluble than said soluble salt (s) acylating ammonia, a C 1-6 alkyl amine or a di(C 1-6 ) alkyl amine with a dipeptide derivate of the formula R 1 * ..... R 6 * wherein R 1 * and R 6 * are hydroxy, chloro, bromo, C 1-6 alkoxy, benzyloxy, a C 1 . 6 alkanoyloxy group, or amino optionally substituted with one or two C 1 - 6 alkyl groups, and at least one of R 1 * and R 6 * is hydroxy, chloro, bromo, C 1-6 alkoxy, benzyloxy, or a C 1-6 alkanoyloxy group.

Claim 29

The process of claim 1 wherein one of R 2 and R 3 represents C 1-6 alkyl, benzyl or 2-phenylethyl.

Claim 30

The process according to claim 1 or 2 wherein one of R 2 and R 3 is C 1-6 alkyl or 2-phenylethyl; and the group represents proline (I) or a proline analog in which the pyrrolidine ring is substituted by an oxo group (IV) by hydroxy, mercapto, C 1-6 alkylmercapto or C 1-6 alkoxy (V) or the proline function is replaced with the residues II, III or VI: and R 6 is hydroxy or benzyloxy; and X is hydrogen, nitro, C 1-6 alkyl, chloro or bromo.

Claim 31

The process of one of the preceding claims wherein R 2 represents (2).

Claim 32

The process according to claims 1 to 3 wherein R 2 is phenylethyl.

Claim 33

The process according to claims 1 to 4 wherein R 3 is lower alkyl with 1 to 4 carbons.

Claim 34

The process according to claim 6 wherein R 3 is methyl, ethyl, or n-propyl.

Claim 35

The process according to one of the preceding claims wherein the group forms a proline residue.

Claim 36

The process of one of claims 1 to 7 wherein the group is a proline residue or a residue selected from the groups II, III or VI and R 6 is hydroxy.

Claim 37

The process of one of the claims 1 to 7 and 9 wherein the group is II.

Claim 38

The process of claim 10 wherein X is hydrogen.

Claim 39

The process of one of the preceding claims wherein R' and R' are lower alkyl with 1 to 4 carbon atoms.

Claim 40

The process of claim 12 wherein R 7 and R 8 are methyl, ethyl, 2,2,2-trifluoroethyl, n-propyl or n-butyl.

Claim 41

The process of claim 13 wherein R 7 and R 8 are ethyl.

Claim 42

Use of a compound of any one of the preceding claims in the manufacture of a medicament

Claim 43

The method of claim 15 wherein the medicament is for the treatment of hypertension.

Claim 44

The method of claim 15 or 16 wherein the medicament includes other antihypertensives.

Claim 45

The method of claim 15 or 16 wherein the medicament includes a diuretic.

Claim 46

The method of claim 15 or 16 wherein the medicament includes a calcium blocker.

Claim 47

The method of claim 15 or 16 wherein the medicament includes nicardipine.