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Details for Patent: 5,559,233

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Details for Patent: 5,559,233

Title: Methods for preparing n-substituted heterocyclic derivatives
Abstract:The invention relates to processes for preparing N-substituted heterocyclic compounds of formula (I) ##STR1##
Inventor(s): Bernhart; Claude (Saint Gely du Fesc, FR), Breliere; Jean-Claude (Montpellier, FR), Clement; Jacques (Saussan, FR), Nisato; Dino (Saint Georges d'Orques, FR), Perreault; Pierre (Montpellier, FR), Muneaux; Claude (Les Matelles, FR), Muneaux; Yvette (Les Matelles, FR)
Assignee: Sanofi (Paris, FR)
Filing Date:Jun 30, 1994
Application Number:08/269,101
Claims:1. A method of preparing a compound of formula (I) ##STR43## in which R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, aminomethyl, carboxyl, alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N-(4-carboxy-1,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-1-ylcarbonyl and 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen;

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl or phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from the group consisting of C.sub.1 -C.sub.4 perfluoroalkyl, hydroxyl and C.sub.1 -C.sub.4 alkoxy; or

R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is C.sub.1 -C.sub.4 alkyl or a phenyl; or

R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a group N-R.sub.6, in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or

R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11; and

m is an integer between 2 and 5; or

R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

R.sub.5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C.sub.3 -C.sub.7, which is unsubstituted or substituted by one or more halogen atoms; or

R.sub.4 and R.sub.5 are each a cyclopropyl;

X is an oxygen atom; and

z and t are zero or one is zero and the other is one;

and its salts;

which method comprises:

a1) reacting a heterocyclic derivative of the formula ##STR44## in which z, t, R.sub.3, R.sub.4 and R.sub.5 are as defined above, with a (biphenyl-4-yl)methyl derivative of formula (3) ##STR45## in which Hal is halogen atom and R'.sub.1 and R'.sub.2 are respectively either R.sub.1 and R.sub.2 or a precursor group of R.sub.1 and R.sub.2 ; and

b1) reacting the compound obtained in a1), of formula (5) ##STR46## in which X is an oxygen atom, to convert either or both of the groups R'.sub.1 and R'.sub.2 to either or both of the groups R.sub.1 and R.sub.2, wherein

if either or both of R'.sub.1 and R'.sub.2 is an esterified carboxy group, then either or both of R.sub.1 and R.sub.2 is a carboxy group;

if either or both of R'.sub.1 and R'.sub.2 is a protected tetrazolyl group, then either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then either or both of R'.sub.1 and R'.sub.2 are initially converted into a protected tetrazolyl group which is then converted so that either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a carboxy group, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of imidazol-1-ylcarbonyl and N-(4-carboxy-1,3-thiazol-2-yl)acetamide;

if either or both of R'.sub.1 and R'.sub.2 is an acid chloride, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of N-hydroxyacetamide, N-cyanoacetamide, ureido and 2-Cyanoguanidinocarbonyl;

if tither or both of R'.sub.1 and R'.sub.2 is a nitro group, then the nitro group is convened into an amino group, which is then convened so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of methylsulfonylamino, trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then the cyano group is converted into an aminomethyl group, which is then convened so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of 3-cyano-2-methylisothioureidomethyl or a 2-cyanoguanidinomethyl.

2. A method of preparing a compound of formula (I) ##STR47## in which R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, aminomethyl, carboxyl, alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N-(4-carboxy-1,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-1-ylcarbonyl and 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen;

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl or phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from the group consisting of C.sub.1 -C.sub.4 perfluoroalkyl, hydroxyl and C.sub.1 -C.sub.4 alkoxy; or

R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is C.sub.1 -C.sub.4 alkyl or a phenyl; or

R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a group N-R.sub.6, in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or

R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11; and

m is an integer between 2 and 5; or

R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

R.sub.5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C.sub.3 -C.sub.7, which is unsubstituted or substituted by one or more halogen atoms; or

R.sub.4 and R.sub.5 are each a cyclopropyl;

X is an oxygen atom; and

z and t are zero or one is zero and the other is one;

and its pharmaceutically acceptable salts;

which method comprises:

a2) reacting an amino acid of formula (7) ##STR48## in which z, t, R.sub.4 and R.sub.5 are as defined above, and of which the amine group is protected by the Pr group,

with a (biphenyl-4-yl)methylamine derivative of formula (8) ##STR49## in which R'.sub.1 and R'.sub.2 are respectively either R.sub.1 and R.sub.2 or a precursor group of R.sub.1 and R.sub.2 ;

b2) after deprotection of the amine, reacting the resulting compound of formula (9) ##STR50## with an alkyl ortho-ester of the formula R.sub.3 C(OR).sub.3 (10), in which R.sub.3 is as defined above and R is a C.sub.1 -C.sub.4 alkyl; and

c2) reacting the compound thus obtained in b2, of formula (5) ##STR51## to convert either or both of the groups R'.sub.1 and R'.sub.2 to either or both of the groups R.sub.1 and R.sub.2, wherein

if either or both of R'.sub.1 and R'.sub.2 is an esterified carboxy group, then either or both of R.sub.1 and R.sub.2 is a carboxy group;

if either or both of R'.sub.1 and R'.sub.2 is a protected tetrazolyl group, then either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then either or both of R'.sub.1 and R'.sub.2 are initially converted into a protected tetrazolyl group, which is then convened so that either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a carboxy group, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of imidazol-1-ylcarbonyl and N-(4-carboxy-1,3-thiazol-2-yl)acetamide;

if either or both of R'.sub.1 and R'.sub.2 is an acid chloride, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of N-hydroxyacetamide, N-cyanoacetamide, ureido and 2-cyanoguanidinocarbonyl;

if either or both of R'.sub.1 and R'.sub.2 is a nitro group, then the nitro group is converted into an amino group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of methylsulfonylamino, trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then the cyano group is converted into an aminomethyl group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of 3-cyano-2-methylisothioureidomethyl or a 2-cyanoguanidinomethyl.

3. A method of preparing a compound of formula (I) ##STR52## in which R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, aminomethyl, carboxyl, alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N-(4-carboxy-1,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-1-ylcarbonyl and 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen;

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl or phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from the group consisting of C.sub.1 -C.sub.4 perfluoroalkyl, hydroxyl and C.sub.1 -C.sub.4 alkoxy; or

R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is C.sub.1 -C.sub.4 alkyl or a phenyl; or

R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a group N-R.sub.6, in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or

R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11; and

m is an integer between 2 and 5; or

R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

X is an oxygen atom; and

z and t are zero;

and its salts;

which method comprises:

a3) reacting a (biphenyl-4-yl)methyl derivative of formula (3) ##STR53## in which Hal is a halogen atom and R'.sub.1 and R'.sub.2 are respectively either R.sub.1 and R.sub.2 or a precursor group of R.sub.1 and R.sub.2,

with an imidazole derivative of formula (11 ) ##STR54## in which R.sub.3, R.sub.4 and R.sub.5 are as defined above, in the presence of oxygen and UV irradiation and in a basic medium; and

b3) reacting the compound thus obtained in a3, of formula (5') ##STR55## to convert either or both of the groups R'.sub.1 and R'.sub.2 to either or both of the groups R.sub.1 and R.sub.2, wherein

if either or both of R'.sub.1 and R'.sub.2 is an esterified carboxy group, then either or both of R.sub.1 and R.sub.2 is a carboxy group:

if either or both of R'.sub.1, and R'.sub.2 is a protected tetrazolyl group, then either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then either or both of R'.sub.1 and R'.sub.2 are initially convened into a protected tetrazolyl group which is then convened so that either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a carboxy group, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of imidozol-1-ylcarbonyl and N-(4-carboxy-1,3-thiazol-2-yl)acetamide;

if either or both of R'.sub.1 and R'.sub.2 is an acid chloride, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of N-hydroxyacetamide, N-cyanoacetamide, ureido and 2-cyanoguanidinocarbonyl;

if either or both of R'.sub.1 and R'.sub.2 is a nitro group, then the nitro group is converted into an amino group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of methylsulfonylamino, trifluoromethyl sulfonylamino and trifluoromethylsulfonylaminomethyl;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then the cyano group is convened into an aminomethyl group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of 3-cyano-2-methylisothioureidomethyl or a 2-cyanoguanidinomethyl.

4. A process according to claim 1 in which the group R'.sub.1 is a cyano group and R'.sub.2 is hydrogen, and in which the cyano group is converted into the tetrazolyl group R.sub.1 by means of an azide.

5. A process according to claim 2 in which the group R'.sub.1 is a cyano group and R'.sub.2 is hydrogen, and in which the cyano group is converted into the tetrazolyl group R.sub.1 by means of an azide.

6. A process according to claim 3 in which the group R'.sub.1 is a cyano group and R'.sub.2 is hydrogen, and in which the cyano group is converted into the tetrazolyl group R.sub.1 by means of an azide.

7. A process according to claim 4, wherein the azide is tributyltin azide or sodium azide.

8. A process according to claim 5, wherein the azide is tributyltin azide or sodium azide.

9. A process according to claim 6, wherein the azide is tributyltin azide or sodium azide.

10. A process according to claim 1, in which the compound of formula 2 in which z=t=o, R.sub.3 is the n-butyl group, and together are a cyclopentane group, is reacted with a compound of formula 3 in which R'.sub.2 is hydrogen and R'.sub.1 is a cyano group to form a compound of formula 4 in which the substituents are as above defined and in which this compound of formula 4 is treated with an azide to obtain the compound 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)-methyl] -2-imidazolin-5-one.

11. A method of preparing a compound of formula (I) ##STR56## in which R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, aminomethyl, carboxyl, alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N-(4-carboxy-1,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-1-ylcarbonyl and 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen;

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , said alkyl, phenyl or phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from the group consisting of C.sub.1 -C.sub.4 perfluoroalkyl, hydroxyl and C.sub.1 -C.sub.4 alkoxy; or

R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.8 is C.sub.1 -C.sub.4 alkyl or a phenyl; or

R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , or a group N-R6 , in which 1% is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or

R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11; and

m is an integer between 2 and 5; or

R.sub.4 is a C.sub.1 -.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

R.sub.5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C.sub.3 -C.sub.7, which is unsubstituted or substituted by one or more halogen atoms; or

R.sub.4 and R.sub.5 are each a cyclopropyl;

X is a sulfur atom; and

z and t are zero or one is zero and the other is one;

and its salts;

which method comprises:

a1) reacting a heterocyclic derivative of the formula ##STR57## in which z, t, R.sub.3, R.sub.4 and R.sub.5 are as defined above, with a (biphenyl-4-yl)methyl derivative of formula (3) ##STR58## in which Hal is halogen atom and R'.sub.1 and R'.sub.2 are respectively either R.sub.1 and R.sub.2 or a precursor group of R.sub.1 and R.sub.2 ;

b1) reacting the resulting compound of formula (4) ##STR59## with Lawesson's reagent, which is 2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane 2,4-disulfide; and

c1) reacting the compound obtained in b1 of formula (5) ##STR60## in which X is a sulfur atom, to convert either or both of the groups R'.sub.1 and R'.sub.2 to either or both of the groups R.sub.1 and R.sub.2, wherein

if either or both of R'.sub.1 and R'.sub.2 is all esterified carboxy group, then either or both of R.sub.1 and R.sub.2 is a carboxy group;

if either or both of R'.sub.1 and R'.sub.2 is a protected tetrazolyl group, then either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then either or both of R'.sub.1 and R'.sub.2 are initially converted into a protected tetrazolyl group which is then converted so that either or both of R.sub.1 and R.sub.2 is a tetrazolyl group:

if either or both of R'.sub.1 and R'.sub.2 is a carboxy group, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of imidazol-1-ylcarbonyl and N-(4-carboxy-1,3-thiazol-2-yl)acetamide:

if either or both of R'.sub.1 and R'.sub.2 is an acid chloride, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of N-hydroxyacetamide, N-cyanoacetamide, ureido and 2-cyanoguanidinocarbonyl;

if either or both of R'.sub.1 and R'.sub.2 is a nitro group, then the nitro group is convened into an amino group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of methylsulfonylamino. trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then the cyano group is converted into an amino methyl group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of 3-cyano-2-methylisothioureidomethyl or a 2-cyanoguanidinomethyl.

12. A method of preparing a compound of formula (I) ##STR61## in which R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, aminomethyl, carboxyl, alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4 , cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N-(4-carboxy-1,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-1-ylcarbonyl and 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen;

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3 , said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , said alkyl, phenyl or phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from the group consisting of C.sub.1 -C.sub.4 perfluoroalkyl, hydroxyl and C.sub.1 -C.sub.4 alkoxy; or

R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.5 is C.sub.1 -C.sub.4 alkyl or a phenyl; or

R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , or a group N-R.sub.6 , in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or

R.sub.4 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11; and

m is an integer between 2 and 5; or

R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

R.sub.5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C.sub.3 -C.sub.7, which is unsubstituted or substituted by one or more halogen atoms; or

R.sub.4 and R.sub.5 are each a cyclopropyl;

X is a sulfur atom; and

z and t are zero or one is zero and the other is one;

and its pharmaceutically acceptable salts;

which method comprises:

a2) reacting an amino acid of formula (7) ##STR62## in which z, t, R.sub.4 and R.sub.5 are as defined above, and of which the amine group is protected by the Pr group,

with a (biphenyl-4-yl)methylamine derivative of formula (8) ##STR63## in which R'.sub.1 and R'.sub.2 are respectively either R.sub.1 and R2 or a precursor group of R.sub.1 and R.sub.2 ;

b2) after deprotection of the amine, reacting the resulting compound of formula (9) ##STR64## with an alkyl ortho-ester of the formula R.sub.3 C(OR).sub.3 (10), in which R.sub.3 is as defined above and R is a C.sub.1 -C.sub.4 alkyl;

c2) reacting the resulting compound of formula (4) ##STR65## with Lawesson's reagent, which is 2,4-bis(4-methoxy-phenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide; and

d2) reacting the compound thus obtained in c2 of formula (5) ##STR66## to convert either or both of the groups R'.sub.1 and R'.sub.2 to either or both of the groups R.sub.1 and R.sub.2, wherein

if either or both of R'.sub.1 and R'.sub.2 is an esterified carboxy group, then either or both of R.sub.1 and R.sub.2 is a carboxy group;

if either or both of R'.sub.1 and R'.sub.2 is a protected tetrazolyl group, then either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then either or both of R'.sub.1 and R'.sub.2 are initially convened into a protected tetrazolyl group which is then converted so that either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a carboxy group, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of imidazol-1-ylcarbonyl and N-(4-carboxy-1,3-thiazol-2-yl)acetamide;

if either or both of R'.sub.1 and R'.sub.2 is an acid chloride, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of N-hydroxyacetamide, N-cyanoacetamide, ureido and 2-cyanoguanidinocarbonyl;

if either or both of R'.sub.1 and R'.sub.2 is a nitro group, then the nitro group is converted into an amino group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of methylsulfonylamino, trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then the cyano group is converted into an amino methyl group, which is then converted so that either of both of R.sub.1 and R.sub.2 is selected from the group consisting of 3-cyano-2-methylisothioureidomethyl or a 2-canoguanidinomethyl.

13. A method of preparing a compound of formula (I) ##STR67## in which R.sub.1 and R.sub.2 are similar or different and are each independently hydrogen or a group selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.4 alkoxy, amino, aminomethyl, carboxyl, alkoxycarbonyl in which the alkoxy is C.sub.1 -C.sub.4 , cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanoacetamide, N-hydroxyacetamide, N-(4-carboxy-1,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyanoguanidinomethyl, imidazol-1-ylcarbonyl and 3-cyano-2-methylisothioureidomethyl, with the proviso that at least one of the substituents R.sub.1 or R.sub.2 is other than hydrogen;

R.sub.3 is a hydrogen, a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms, a C.sub.2 -C.sub.6 alkenyl, a C.sub.3 -C.sub.7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, or a phenylalkenyl in which the alkenyl is C.sub.2 -C.sub.3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl, a C.sub.1 -C.sub.4 halogenoalkyl, a C.sub.1 -C.sub.4 polyhalogenoalkyl, a hydroxyl or a C.sub.1 -C.sub.4 alkoxy; and

either R.sub.4 and R.sub.5 are each independently a C.sub.1 -C.sub.6 alkyl, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3, said alkyl, phenyl or phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from the group consisting of C.sub.1 -C.sub.4 perfluoroalkyl, hydroxyl and C.sub.1 -C.sub.4 alkoxy; or R.sub.4 and R.sub.5 together form a group of the formula .dbd.CR.sub.7 R.sub.8, in which R.sub.7 is hydrogen, a C.sub.1 -C.sub.4 alkyl or a phenyl and R.sub.5 is C.sub.1 -C.sub.4 alkyl or a phenyl; or R.sub.4 and R.sub.5 together are either a group of the formula (CH.sub.2).sub.n or a group of the formula (CH.sub.2).sub.p Y--(CH.sub.2).sub.q, in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C.sub.1 -C.sub.4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , or a group N-R.sub.6 , in which R.sub.6 is a hydrogen, a C.sub.1 -C.sub.4 alkyl, a phenylalkyl in which the alkyl is C.sub.1 -C.sub.3 , a C.sub.1 -C.sub.4 alkylcarbonyl, a C.sub.1 -C.sub.4 halogenoalkylcarbonyl, a C.sub.1 -C.sub.4 polyhalogenoalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or

R.sub.1 and R.sub.5, together with the carbon atom to which they are bonded, form an indane or an adamantane;

p+q=m;

n is an integer between 2 and 11; and

m is an integer between 2 and 5; or

R.sub.4 is a C.sub.1 -C.sub.6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and

X is an sulfur atom; and

z and t are zero;

and its salts;

which method comprises:

a3) reacting a (biphenyl-4-yl)methyl derivative of formula (3) ##STR68## in which Hal is a halogen atom and R'.sub.1 and R'.sub.2 are respectively either R.sub.1 and R.sub.2 or a precursor group of R.sub.1 and R.sub.2,

with an imidazole derivative of formula (11 ) ##STR69## in which R.sub.3 , R.sub.4 and R.sub.5 are as defined above, in the presence of oxygen and UV irradiation and in a basic medium;

b3) reacting the resulting compound of formula (4') ##STR70## with Lawesson's reagent, which is 2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane 2,4-disulfide; and

c3) reacting the compound thus obtained in b3 of formula (5') ##STR71## to convert either or both of the groups R'.sub.1 and R'.sub.2 to either or both of the groups R.sub.1 and R.sub.2, wherein

if either or both of R'.sub.1 and R'.sub.2 is an esterified carboxy group, then either or both of R.sub.1 and R.sub.2 is a carboxy group;

if either or both of R'.sub.1 and R'.sub.2 is a protected tetrazolyl group, then either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then either or both of R'.sub.1 and R'.sub.2 are initially convened into a protected tetrazolyl group which is then converted so that either or both of R.sub.1 and R.sub.2 is a tetrazolyl group;

if either or both of R'.sub.1 and R'.sub.2 is a carboxy group, then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of imidazol-1-ylcarbonyl and N-(4-carboxy-1,3-thiazol-2-yl)acetamide;

if either or both of R'.sub.1 and R'.sub.2 is an acid chloride, .then either or both of R.sub.1 and R.sub.2 is selected from the group consisting of N-hydroxyacetamide, N-cyanoacetamide, ureido and 2-cyanoguanidinocarbonyl;

if either or both of R'.sub.1 and R'.sub.2 is a nitro group, then the nitro group is converted into an amino group, which is then convened so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of methylsulfonylamino, trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl;

if either or both of R'.sub.1 and R'.sub.2 is a cyano group, then the cyano group is converted into an aminomethyl group, which is then converted so that either or both of R.sub.1 and R.sub.2 is selected from the group consisting of 3-cyano-2-methylisothioureidomethyl or a 2-cyanoguanidinomethyl.
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