4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine derivatives and analogs having antihypertensive activity

Claim 2

A compound having the formula (I) and their pharmaceutically acceptable base or acid addition salts; wherein (1) - - - is a single or double bond; (2) one of R 1 is present and is (a) alkyl of from four to twenty carbons, inclusive, wherein y is zero, one, two, three, four or five, R' is cycloalkyl, naphthyl, heteroaryl, phenyl unsubstituted or substituted with of from one through five, preferably one through three, substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro or wherein R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR 11 wherein R 11 is hydrogen or lower alkyl, and R" is hydrogen, lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substi- tuents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; (3) R 2 is (a) hydrogen, (b) halo, (c) lower alkyl, (d) R'-(CH 2 ) x - wherein x is one, two, three, four, or five and R' is independently as defined above, wherein R' is independently as defined above, or (f) R'-CH(OH)- wherein R' is independently as defined above; (4) R 3 is (a) R'-(CH 2 ) x - wherein x and R' are independently as defined above, wherein R' and y are independently as defined above, and R'" is lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; wherein R 5 is (i) alkyl of from one to fifteen carbons, inclusive, wherein R', R" and y are independently as defined above, (iv) -(CH=CR 6 )-R 1 , wherein R 6 is hydrogen or lower alkyl and R 1 is as defined above, wherein y, R' and R 6 are independently as defined above, (vi) R'-(CH 2 ) y -O- wherein y and R' are independently as defined above, wherein R', R", and y are independently as defined above, I wherein R 5 is independently as defined above, preferably R'-(CH 2 ) y - wherein R' and y are independently as defined above; (5) R 4 is (a) -CH 2 OR 7 wherein R 7 is hydrogen, lower acyl, a lower alkyl, wherein R 7 is independently as defined above and R 8 is hydrogen, lower alkyl, or benzyl, (d) -C≡N, wherein R 9 is hydrogen, lower alkyl or benzyl; and (6) n is zero, one, two, or three; with the overall proviso that R 9 cannot be hydrogen when R 2 is R'-(CH 2 ) x - or wherein R is R'-(CH 2 ) y -O- or wherein each of R', R", x and y are as defined above.

Claim 3

A compound of claim 1 wherein R 2 is H, n is one or two, and R 3 is wherein R 5 is as defined above and R 4 is as defined above.

Claim 4

A compound of claim 2 wherein R is wherein R 5 is as defined above.

Claim 5

A compound having the formula (II) and the nontoxic, pharmaceutically acceptable base or acid addition salts thereof, wherein - - - is a single or double bond; (1) one of R a is present and is (a) hydrogen, (b) alkyl of from one to twenty carbons, inclusive, wherein y is zero, one, two, three, four or five and R' is cycloalkyl, naphthyl, heteroaryl, phenyl unsubstituted or substituted with of from one through five, preferably one through three, substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro or wherein R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR 11 wherein R 11 is hydrogen or lower alkyl, and R" is hydrogen, lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, anino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; (2) Z is oxygen or sulfur; and (3) R 2 is (a) hydrogen, (b) halo, (c) lower alkyl, (d) R'-(CH 2 ) x - wherein x is one, two, three, four, or five and R' is independently as defined above, wherein R' is independently as defined above, or (f) R'-CH(OH)- wherein R' is independently as defined above; (4) R is selected from the group consisting of lower alkyl, heteroryl, and phenyl or benzyl each unsubstituted or substituted with of from one through five substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy,lower acyloxy, amino, N-lower monoamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro.

Claim 6

A compound having the formula (II) and the nontoxic, pharmaceutically acceptable base or acid addition salts thereof, wherein - - - is a single or double bond; (1) one of R a is present and is (a) hydrogen, (b) alkyl of from one to twenty carbons, inclusive, wherein y is zero, one, two, three, four or five and R' is cycloalkyl, naphthyl, heteroaryl, phenyl unsubstituted or substituted with of from one through five, preferably one through three, substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro or wherein R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR 11 wherein R 11 is hydrogen or lower alkyl, and R" is hydrogen, lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, anino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; (2) Z is oxygen or sulfur; and (3) R 2 is (a) hydrogen, (b) halo, (c) lower alkyl, (d) R'-(CH 2 ) x - wherein x is one, two, three, four, or five and R' is independently as defined above, wherein R' is independently as defined above, or (f) R'-CH(OH)- wherein R' is independently as defined above; (4) R is selected from the group consisting of lower alkyl, heteroryl, and phenyl or benzyl each unsubstituted or substituted with of from one through five substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy,lower acyloxy, amino, N-lower monoamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro.

Claim 7

A compound according to claim 4 wherein Z is as defined above and R is branched alkyl of from three to five carbons, inclusive, or phenyl substituted by one, two or three methoxy groups.

Claim 8

A pharmaceutical composition for treating hypertension in mammals comprising an antihypertensive effective amount of the compound of formula (I') and their pharmaceutically acceptable base or acid addition salts; wherein (1) - - - is a single or double bond; (2) one of R 1 is present and is (a) alkyl of from four to twenty carbons, inclusive, wherein y is zero, one, two, three, four or five, R' is cycloalkyl, naphthyl, heteroaryl, phenyl unsubstituted or substituted with of from one through five, preferably one through three, substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro or wherein R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR 11 wherein R 11 is hydrogen or lower alkyl, and R" is hydrogen, lower alkyl, cycloalky, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; (3) R 2 is (a) hydrogen, (b) halo, (c) lower alkyl, (d) R'-(CH 2 ) x - wherein x is one, two, three, four, or five and R' is independently as defined above, wherein R' is independently as defined above, or (f) R'-CH(OH)- wherein R' is independently as defined above; (4) R 3 is (a) R'-(CH 2 ) x - wherein x and R' are independently as defined above, ' wherein R' and y are independently as defined above, and R'" is lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; wherein R 5 is (i) alkyl of from one to fifteen carbons, inclusive, wherein R', R" and y are independently as defined above, (iv) -(CH=CR 6 )- R 1 , wherein R 6 is hydrogen or lower alkyl and R 1 is as defined above, wherein y, R' and R 6 are independently as defined above, (vi) R'-(CH 2 ) y -O- wherein y and R' are independently as defined above, wherein R', R", and y are independently as defined above, wherein R 5 is independently as defined above, preferably R'(̵CH 2 wherein R' and y are independently as defined above; (5) R 4 is (a) -CH 2 OR 7 wherein R 7 is hydrogen, lower acyl, a lower alkyl, wherein R 7 is independently as defined above and R 8 is hydrogen, lower alkyl, or benzyl, (d) -C≡N, wherein R' 9 is hydrogen, lower alkyl or benzyl; and (6) n is zero, one, two, or three; together . with a pharmaceutically acceptable carrier.

Claim 9

A pharmaceutical composition for treating hypertension in mammals comprising an antihypertensive effective amount of the compound of formula (I') and their pharmaceutically acceptable base or acid addition salts; wherein (1) - - - is a single or double bond; (2) one of R 1 is present and is (a) alkyl of from four to twenty carbons, inclusive, wherein y is zero, one, two, three, four or five, R' is cycloalkyl, naphthyl, heteroaryl, phenyl unsubstituted or substituted with of from one through five, preferably one through three, substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro or wherein R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR 11 wherein R 11 is hydrogen or lower alkyl, and R" is hydrogen, lower alkyl, cycloalky, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; (3) R 2 is (a) hydrogen, (b) halo, (c) lower alkyl, (d) R'-(CH 2 ) x - wherein x is one, two, three, four, or five and R' is independently as defined above, wherein R' is independently as defined above, or (f) R'-CH(OH)- wherein R' is independently as defined above; (4) R 3 is (a) R'-(CH 2 ) x - wherein x and R' are independently as defined above, ' wherein R' and y are independently as defined above, and R'" is lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; wherein R 5 is (i) alkyl of from one to fifteen carbons, inclusive, wherein R', R" and y are independently as defined above, (iv) -(CH=CR 6 )- R 1 , wherein R 6 is hydrogen or lower alkyl and R 1 is as defined above, wherein y, R' and R 6 are independently as defined above, (vi) R'-(CH 2 ) y -O- wherein y and R' are independently as defined above, wherein R', R", and y are independently as defined above, wherein R 5 is independently as defined above, preferably R'(̵CH 2 wherein R' and y are independently as defined above; (5) R 4 is (a) -CH 2 OR 7 wherein R 7 is hydrogen, lower acyl, a lower alkyl, wherein R 7 is independently as defined above and R 8 is hydrogen, lower alkyl, or benzyl, (d) -C≡N, wherein R' 9 is hydrogen, lower alkyl or benzyl; and (6) n is zero, one, two, or three; together . with a pharmaceutically acceptable carrier.

Claim 10

A pharmaceutical composition for treating hypertension in mammals comprising an antihypertensive effective amount of the compound of formula (IIa) wherein Z is oxygen or sulfur and R 11 is branched alkyl of from three to five carbons, inclusive, and substituted phenyl, and a pharmaceutically acceptable carrier.

Claim 11

A pharmaceutical composition for treating hypertension in mammals comprising an antihypertensive effective amount of the compound of formula (IIa) wherein Z is oxygen or sulfur and R 11 is branched alkyl of from three to five carbons, inclusive, and substituted phenyl, and a pharmaceutically acceptable carrier.

Claim 12

A composition of claim 7 wherein R 11 is branched alkyl of from three to five carbons, inclusive and phenyl substituted by one to three methoxy groups.

Claim 13

) Use of a compound of formula I' according to claim 6 for the manufacture of a medicament for treating hypertension in mammals suffering therefrom.

Claim 14

) Use of a compound of formula IIa according to claim 7 for the manufacture of a medicament for treating hypertension in mammals suffering therefrom.

Claim 15

) A process for preparing a compound having the formula (I) in accordance with claims 1 to 3, wherein R 1 , R 2 , R 31 R4 and n have the above mentioned meaning, and their pharmaceutically acceptable base or acid addition salts. comprising (A) contacting a compound of the formula wherein R 1 and n are as defined above, with formaldehyde or a formaldehyde equivalent such as dimethoxymethane in the presence of a strong acid such as hydrochloric acid to give a compound of the formula III wherein R 1 n and R 4 are as defined above, (B) and further a compound of the formula III is contacted with an activated acylating derivative of R 5 CO 2 H or R 5 S0 3 H or a compound of formula III wherein R 4 is -CO 2 H, is acylated in aqueous basic solution with selected compounds of the formula wherein Hal is halo and R 5 is as defined above to give a compound of formula I wherein R 1 , R 4 and n are as defined above and R 3 is wherein R 5 is as defined above or (C) contacting a compound of the formula wherein n is as defined above with acidic formaldehyde to give a compound of the formula VI wherein R 4 and n are as defined above and Ph is a phenyl radical. (D) and further the compound of the formula VI is contacted with an activated acylating derivative such as described above to give a compound of the formula IV wherein R 4 , R 5 and n are as defined above, (E) a) and further the compound of the formula IV is contacted with R 1 -Q wherein Q may be halo or sulfonate and trifluorosulfonate ester of R 1 -OH wherein R 1 is as defined above to give the intermediate salt of formula V wherein R 1 , R 4 , R 5 and n are as defined above, (b) and further deprotecting and optionally reacting the product of step (c) to obtain the compound of formula I wherein R 3 is as defined above. (F) contacting (a) a compound of the formula with an RN=C=O or RN=C=S, wherein R is selected from the group consisting of lower alkyl, heteroaryl, and phenyl or benzyl each unsubstituted or substituted with of from one through five substituents comprising lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower acyloxy, amino, N-lower monoamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro and Alk is a lower alkyl group to give a compound of the formula VII wherein Z is oxygen or sulfur and R is as defined above, (b) and further the compound of formula VII is contacted with R 1 -Q as defined above in the presence of a strong base such as sodium or potassium hydride or sodium alkylate to give a mixture having the compound of formula VIII wherein Z, R and R 1 are as defined above and a compound of formula IX wherein Z, R and R 1 are as defined above which is optionally separated by crystallisation or chromatography. (c) and further the compounds of formula VIII or IX and hydrolyzed under moderate basic conditions such as alkali hydride to give a compound of formula I wherein R5 is wherein R 1 and Y are as defined above and R 6 is H, or under more rigorous basic conditions such as concentrated alkali hydroxide to give intermediate of formula III wherein R 4 is C0 2 H. (G) Additionally a compound of the formula I wherein R 2 is H, R 4 is as defined above, R 4 is CH 2 O-R 1 and R 3 is COR 5 wherein R 4 , R 3 and R 5 are as defined above, a compound of the formula VIII or IX as defined above is contacted with a brominating agent such as bromine or N-bromo-succinimide to give an intermediate of the formula or (H) (a) and further this intermediate is contacted with an alkyllithium reagent such as n-butyllithium to form a lithio-derivative which is further contacted with an alkylating agent R 2 -Q, where R 2 and Q are as described above, an aldehyde or ketone or an appropriate carboxylic acid derivative to give an intermediate of the formula wherein R 2 and Ph is as described above, (b) and further processing of the intermediate as described above gives a compound of formula I wherein R 1 , R 2 , R 4 , and R 5 have the above mentioned meaning.

Claim 16

) A process for preparing a compound having the formula II according to claims 4 and 5, wherein R a , R 2 , Z and R have the above mentioned meaning and the nontoxic, pharmaceutically acceptable base or acid addition salts thereof, comprising (A) contacting a compound of the formula wherein alk is a lower alkyl group with an RN=C=O or RN=C=S, wherein R is-as defined above to give a compound of the formula VII wherein Z and R are as defined above (B) and further compound of formula VII is contacted with R a -Q as defined above in the presence of a strong base such as sodium or potassium hydride or sodium alkylate to give a mixture of a compound of formula VIII wherein Z, R and R a are as defined above and a compound of formula IX wherein Z, R and R a are as defined above, which is optionally separated by crystallization or chromatography; or (C) and further compounds of formula VIII or IX both as defined above when Z is O, may be contacted with an aroylhalide in the presence of a tertiary organic base such as triethylamine to give compounds of formula II where R 2 is wherein R' is as defined above and where this group may further be reduced and deoxygenated using methods known in the art to produce other R 2 substituents as.defined above.