Patent EA-003365-B1 (EA)
Title: (benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties
Inventor: WIGERINCK PIET TOM BERT PAUL
IPC: C07D405/14
Filed: 1998-11-27
Abstract: 1. A compound of formula (I) a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, wherein Alk<1> is carbonyl, or C1-4alkanediyl optionally substituted with hydroxy; -Z<1>-Z<2>- is a bivalent radical of formula -CH= (e-6), O-CH2- (e-2), CH2-CH2- (e-4); R<1>, R<2> and R<3> are each independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, hydroxy, C1-6alkyloxycarbonyl,; or when R<1> and R<2> are on adjacent carbon atoms, R<1> and R<2> taken together may form a bivalent radical of formula -CH=CH-CH=CH- (a-4); R<4> is hydrogen, C1-6alkyl, or a direct bond when the bivalent radical -Z<1>-Z<2> has formula (e-6); A is a bivalent radical of formula wherein the nitrogen atom is connected to Alk<1> and, m is 0 or 1; Alk<2> is C1-6alkanediyl; R<6> is hydrogen, C1-6alkyl, C1-4alkylcarbonyl, phenylmethyl; R<5> is a radical of formula X is oxygen, sulfur, NR<9>; R<7> is hydrogen, C1-6alkyl; R<9> is cyano or aminocarbonyl; R<10> is hydrogen or C1-6alkyl; and Q is a bivalent radical of formula -CH2-CH2- (d-1), -CH=CH- (d-4), -CH2-CH2-CH2- (d-2), -CH2-CO- (d-5), wherein optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by C1-4alkyl, hydroxy or phenyl, or Q is a bivalent radical of formula with proviso that when the bivalent radical -Z<1>-Z<2> is represented by formula (e-2), and bivalent radical Q by formulas (d-1) and (d-2), one or two hydrogen atoms on the same or a different carbon atom may be replaced by C1-4alkyl, hydroxy or phenyl. 2. A compound as claimed in claim 1 wherein the bivalent radical A is of formula (b-1). 3. A compound as claimed in claim 1 wherein the bivalent radical A is of formula (b-2). 4. A compound according to claim 1 wherein R<4> is hydrogen; A is a radical of formula (b-1) wherein R<6> is hydrogen or C1-6alkyl, and Alk<2> is C2-4alkanediyl; or A is a radical of formula (b-2); and R<5> is a radical of formula (c-1) wherein X is hydrogen, , and Q is (d-1) or (d-2) wherein optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by C1-4alkyl. 5. A compound according to claim 1 wherein the compound is 1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-propyl]-tetrahydro-2(1H)-pyrimidinone; a stereoisomeric form or a pharmaceutically acceptable acid addition salt thereof. 6. A compound according to claim 5 wherein the compound is (R)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl) methyl]amino]propyl]tetrahydro-2(1H)-pyrimidinone (R-(R*,R*)]-2,3-dihydroxybutanedioate. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any of claims 1 to 6. 8. The use of compound according to claims 1-6 as a treatment for relaxation of muscular system of gastric fundus. 9. The use of compound according to any of claims 1-6 for treatment of conditions attached to the disturbances and troubles with relaxation of muscular system of gastric fundus. 10. A process for preparing a compound of formula (I) wherein an intermediate of formula (II) is alkylated with an intermediate of formula (III) in a reaction-inert solvent and, optionally in the presence of a suitable base, wherein in the above reaction schemes the radicals A, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in claim 1 and W is an appropriate leaving group; and/ or if desired, a obtained compound of formula (I) is converted into another compound of formula (I) following artknown transformation reactions; and/ or if desired; a compound of formula (I) is converted into an acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof. 11. A process for preparing a compound of formula (I) wherein an intermediate of formula (IV), wherein Alk<1> represents a direct bond or C1-5alkanediyl, is reacted with an intermediate of formula (III), wherein the values of radicals A, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in claim 1 and/or, compounds of formula (1) are converted into each other following artknown transformation reactions; or if desired; a compound of formula (I) is converted into an acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof. 12. A process for preparing a compound of formula (I) wherein an intermediate of formula (V), wherein Alk<1> represents a direct bond or C1-5alkanediyl, is subjected to reaction with an intermediate of formula (III), wherein in the above reaction schemes the radicals A, R<1>, R<2>, R<3>, R<4> and R<5> are as defined in claim 1; and/ or if desired, a obtained compound of formula (I) is converted into another compound of formula (I) following artknown transformation reactions; and/ or if desired; a compound of formula (I) is converted into an acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.