Substituted heterocycles and their use in medicaments

A compound of Formula I

• wherein
• is a double bond;
• X is —O— or —S(O)m—;
• R1 and R2, independently of one another, are each hydrogen, halogen, S(O)n—R7, OR7, COOR7, NR7R8, C(═NR7)—NHR8, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or —S—C(═NR7)—NHR8;
• R3 is hydrogen, C1-12 alkyl, phenyl, CO—NR9R10, CSNR9R10, COR9, CSR9, COOR9, OH, or O—C1-6 alkyl;
• R4 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-pentyl, tert-pentyl, neo-pentyl, n-hexyl, sec-hexyl, heptyl, octyl, CO—NR9R10, CSNR9R10, COR9, CSR9, COOR9, OH, or O—C1-6 alkyl;
• R5 is halogen, C1-8 alkoxy, S(O)p—C1-6 alkyl, C1-8 alkylcarbonyl, C1-8 alkyl, C3-10 cycloalkyl, phenyl or a C1-8 alkly radical, which is substituted with phenyl, halogen, hydroxy, S(O)nR11, NO2, OR11, COOR11, NR11R12, cyano, —C(═NR11)—NHR12 or —S—C(═NR11)—NHR12;
• R6 is hydrogen or C1-3 alkyl, which optionally together with R5 forms a 3-, 4- or 5-membered spirocyclic compound;
• R7, R8 and R11, R12, are each, independently, hydrogen, C1-6 alkyl, phenyl or C3-7 cycloalkyl,
• R9 and R10, independently of one another, are each hydrogen, phenyl, benzyl, C3-7 cycloalkyl or C1-6 alkyl;
• and
• m, n, or p is 0, 1 or 2;
• or
• a physiologically compatible salt thereof,
• with the proviso that when R1, R2, R3, R4 and R6 are each H, R5 is not C1-8 alkoxy.

A compound of Formula I

• wherein
• is a double bond;
• X is —S(O)m—;
• R1 and R2, independently of one another, are each hydrogen, halogen, S(O)n—R7, OR7, COOR7, NR7R8, C(═NR7)—NHR8, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or —S—C(═NR7)—NHR8;
• R3 and R4, independently of one another, are hydrogen, C1-12 alkyl, phenyl, CO—NR9R10, CSNR9R10, COR9, CSR9, COOR9, OH, or O—C1-6 alkyl;
• R5 is halogen, C1-8 alkoxy, S(O)p—C1-6 alkyl, C1-8 alkylcarbonyl, C1-8 alkyl, C3-10 cycloalkyl, phenyl or a C1-8 alkly radical, which is substituted with phenyl, halogen, hydroxy, S(O)nR11, NO2, OR11, COOR11, NR11R12, cyano, —C(═NR11)—NHR12 or —S—C(═NR11)—NHR12;
• R6 is hydrogen or C1-3 alkyl, which optionally together with R5 forms a 3-, 4- or 5-membered spirocyclic compound;
• R7, R8 and R11, R12 , are each, independently, hydrogen, C1-6 alkyl, phenyl or C3-7 cycloalkyl;
• R9 and R10, independently of one another, are each hydrogen, phenyl, benzyl, C3-7 cycloalkyl or C1-6 alkyl;
• and
• m, n, or p is 0, 1 or 2;
• or
• a physiologically compatible salt thereof,
• with the proviso that when R1, R2, R3, R4 and R6 are each H, R5 is not C1-8 alkoxy.

A process for the production of compounds of Formula I, comprising:

• a) reacting a compound of Formula IIa or IIb or its salts
• wherein
• R1 and R2, independently of one another, are each hydrogen, halogen, S(O)n—R7, R7, COOR7, NR7R8, C(═NR7)—NHR8, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or —S—C(═NR7)—NHR8;
• R7 and R8, being the same or different, are each hydrogen, C1-6 alkyl, phenyl or C3-7 cycloalkyl;
• X is —O— or —S(O)m—;
• and
• Z is oxygen or sulfur;
• with ammonia or a primary or secondary amine;
• or
• b) cyclizing a compound of Formula III
• wherein
• R1 and R2 independently of one another, are each hydrogen, halogen, S(O)n—R7, R7, COOR7, NR7R8, C(═NR7)—NHR8, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or —S—C(═NR7)—NHR8;
• R5 is halogen, C1-8 alkoxy, S(O)p—C1-6 alkyl, C1-8 alkylcarbonyl, C1-8 alkyl, C3-10 cycloalkyl, phenyl or a C1-8 alkly radical, which is substituted with phenyl, halogen, hydroxy, S(O)nR11, NO2, OR11, COOR11, NR11R12, cyano, —C(═NR11)—NHR12 or —S—C(═NR11)—NHR12;
• R6 is hydrogen or C1-3 alkyl, which optionally together with R5 forms a 3-, 4- or 5-membered spirocyclic compound;
• R7, R8 and R11, R12, being the same or different, are each hydrogen, C1-6 alkyl, phenyl or C3-7 cycloalkyl;
• and
• n or p is 0, 1 or 2
• and optionally then sulfides are oxidized, esters are saponified, acids are esterified, hydroxy groups are etherified or acylated, amines are acylated, alkylated, diazotized, halogenated, NO2 is introduced or reduced, reacted with thiourea derivatives, the isomers are separated or the salts are formed.

A method for treating diseases that are triggered by nitrogen monoxide synthases comprising administering to a patient an effective amount of a compound according to formula (I):

• wherein
• is a double bond;
• X is —O— or —S(O)m—;
• R1 and R2, independently of one another, are each hydrogen, halogen, S(O)n—R7, OR7, COOR7, NR7R8, C(═NR7)—NHR8, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or —S—C(═NR7)—NHR8;
• R3 and R4, independently of one another, are each hydrogen, C1-12 alkyl, phenyl, CO—NR9R10, CSNR9R10, COR9, CSR9, COOR9, OH, or O—C1-6 alkyl;
• R5 is halogen, C1-8 alkoxy, S(O)p—C1-6 alkyl, C1-8 alkylcarbonyl, C1-8 alkyl, C3-10 cycloalkyl, phenyl or a C1-8 alkyl radical, which is substituted with phenyl, halogen, hydroxy, S(O)nR11, NO2, OR11, COOR11, NR11R12, cyano, —C(═NR11)—NHR12 or —S—C(═NR11)—NHR12;
• R6 is hydrogen or C1-3 alkyl, which optionally together with R5 forms a 3-, 4- or 5-membered spirocyclic compound;
• R7, R8 and R11, R12, being the same or different, are each hydrogen, C1-6 alkyl, phenyl or C3-7 cycloalkyl;
• R9 and R10, independently of one another, are each hydrogen, phenyl, benzyl, C3-7 cycloalkyl or C1-6 alkyl;
• and
• m, n, or p is 0, 1 or 2;
• or
• a physiologically compatible salt thereof.