Prodrugs of bicyclic substituted pyrimidine type PDE-5 inhibitors
Provided are prodrugs of a bicyclic substituted pyrimidine type PDE-5 inhibitors, pharmaceutically acceptable salts or stereoisomers thereof. Also provided are methods for preparing these prodrug compounds, pharmaceutical preparations, and pharmaceutical compositions, as well as a use of these compounds, pharmaceutical preparations and pharmaceutical compositions in the manufacture of medicaments for treatment and/or prophylaxis of sexual dysfunction and lower urinary tract symptoms.
1. A compound of Formula (I), pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 1 represents 6- or 7-membered nitrogen-containing fused heterocyclyl, 7- to 12-membered nitrogen-containing spiral heterocyclyl, or 7- to 12-membered nitrogen-containing bridged heterocyclyl, any of which is optionally substituted with 1-4 substituent groups, and R 1 links to pyrimidine ring of Formula (I) via N atom,
the substituent groups are selected from halogen atoms, cyano, amino, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl or C 1-6 alkoxycarbonyl;
R 2 represents hydrogen atom, hydroxyl, amino, cyano, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl or C 1-6 alkoxy;
R 3 and R 4 each independently represent hydrogen, or C 1-6 alkyl optionally substituted with 1-3 halogen atoms, hydroxyl, carboxyl;
m is 0 to 3;
Z is hydrogen, or a cation of inorganic base or organic base capable of forming a salt with phosphoric acid;
R 5 and R 6 each independently represent hydrogen atom or -Q-R 7 ,
Q represents a bond, or optionally substituted C 1-6 alkylidene, the substituent groups are selected from halogen atoms, hydroxyl, C 1-6 alkyl, amino, cyano, nitro or C 1-6 alkoxy;
R 7 is selected from 6- to 14-membered aryl, 5- to 7-membered heterocyclyl or 8- to 10-membered fused cyclyl, any of which is optionally substituted with 1-4 substituent groups,
the substituent groups are selected from halogen atoms, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, carboxyl C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, nitro, C 1-6 alkylcarbonyl, sulfonylamino or C 1-6 alkylsulfonylamino.
2. The compound according to claim 1 , pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 2 is hydrogen atom, hydroxyl or methyl;
R 6 represents hydrogen atom.
3. The compound according to claim 2 , pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 3 and R 4 are independently selected from hydrogen;
m is 0, 1 or 2;
Z is hydrogen, or sodium ion.
4. The compound according to claim 3 , pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 5 represents -Q-R 7 ,
Q is selected from C 1-6 alkylidene,
R 7 is selected from 6- to 10-membered aryl, 5- to 7-membered heterocyclyl or 8- to 10-membered fused cyclyl, any of which is optionally substituted with 1-4 substituent groups,
the substituent groups are selected from halogen atoms, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, carboxyl C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, nitro, C 1-6 alkylcarbonyl, sulfonylamino or C 1-6 alkylsulfonylamino.
5. The compound according to claim 4 , pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 1 represents 6- or 7-membered nitrogen-containing fused heterocyclyl, 7- to 12-membered nitrogen-containing spiral heterocyclyl, or 7- to 12-membered nitrogen-containing bridged heterocyclyl, any of which is optionally substituted with 1-4 substituent groups, and R 1 links to pyrimidine ring of Formula (I) via N atom,
the substituent groups are selected from halogen atoms, cyano, amino, hydroxyl, C 1-6 alkyl, halo C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl or C 1-6 alkoxycarbonyl.
6. The compound according to claim 5 , pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 1 is selected from 6- or 7-membered nitrogen-containing fused heterocyclyl, 7- to 10-membered nitrogen-containing spiral heterocyclyl, or 7- to 8-membered nitrogen-containing bridged heterocyclyl, any of which is optionally substituted with 1-3 substituent groups, and R 1 links to pyrimidine ring of Formula (I) via N atom,
the substituent groups are selected from halogen atoms, cyano, amino, hydroxyl, C 1-4 alkyl, halo C 1-4 alkyl, hydroxyl C 1-4 alkyl, or C 1-4 alkoxy;
R 3 and R 4 each independently are hydrogen;
m is 0, 1 or 2;
Z is hydrogen, or sodium ion;
R 5 represents -Q-R 7 ,
Q is selected from C 1-4 alkylidene,
R 7 is selected from phenyl, 5- to 7-membered heterocyclyl or 8- to 10-membered fused cyclyl, any of which is optionally substituted with 1-3 substituent groups,
the substituent groups are selected from halogen atoms, methyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, dimethylamino or carboxymethyl;
R 2 is selected from hydrogen atom;
R 6 is selected from hydrogen atom.
7. The compound according to claim 6 , pharmaceutically acceptable salts or stereoisomers thereof:
wherein R 1 is selected from 6- or 7-membered nitrogen-containing fused heterocyclyl, or 7- to 10-membered nitrogen-containing spiral heterocyclyl, any of which is optionally substituted with 1-3 substituent groups, and R 1 links to pyrimidine ring of Formula (I) via N atom,
the substituent groups are selected from halogen atoms, cyano, amino, hydroxyl, C 1-4 alkyl, halo C 1-4 alkyl, hydroxyl C 1-4 alkyl, or C 1-4 alkoxy;
R 3 and R 4 are independently selected from hydrogen;
m is 0, 1 or 2;
Z is hydrogen, or sodium ion;
R 5 represents -Q-R 7 ,
Q is selected from methylene or ethylene,
R 7 is selected from phenyl, pyrrolyl, furyl, pyridyl, thiazolyl, naphthyl, benzopyrrolyl, indenyl, quinolyl or indolyl, any of which is optionally substituted with 1-3 substituent groups,
the substituent groups are selected from fluorine atom, chlorine atom, cyano, amino, hydroxyl, C 1-4 alkyl, halo C 1-4 alkyl, hydroxyl C 1-4 alkyl, or C 1-4 alkoxy.
8. The compound according to claim 7 , pharmaceutically acceptable salts or stereoisomers thereof:
R 1 is selected from the following groups:
R 3 and R 4 are independently selected from hydrogen;
m is 0 or 1;
Z is sodium ion;
R 5 is selected from the following groups:
9. The compound according to claim 1 , pharmaceutically acceptable salts or stereoisomers thereof, the compound being selected from:
10. A pharmaceutical preparation comprising the compound of claim 1 , pharmaceutically acceptable salts or stereoisomers thereof, and one or more pharmaceutically acceptable carriers and/or diluents.
11. A pharmaceutical composition comprising the compound of claim 1 , pharmaceutically acceptable salts or stereoisomers thereof, characterized in further comprising one or more second therapeutically active agents selected from vasodilators, prostaglandin E1, prostacyclin, α-adrenergic receptor retardants, mixed α,β-blockers, α-blockers, 5α-reductase inhibitors, α2-adrenergic receptor retardants, ACE inhibitors, NEP inhibitors, central dopamine agents, vasoactive intestinal peptide, calcium channel blockers, thiazines, or mixtures thereof.
12. A method of treating erectile dysfunction and lower urinary tract symptoms, said method comprising the step of administering the compound of claim 1 , pharmaceutically acceptable salts or stereoisomers thereof.
13. A method of treating diseases selected from: hypertension, heart failure, pulmonary hypertension, erectile dysfunction, overactive bladder syndrome, and prostatic hyperplasia, said method comprising the step of administering the compound of claim 1 , pharmaceutically acceptable salts or stereoisomers thereof.
14. The method of claim 12 , wherein the disease is overactive bladder syndrome and benign prostatic hyperplasia.
15. The method of claim 13 , wherein the disease is overactive bladder syndrome and benign prostatic hyperplasia.
16. A method of manufacturing a medicament, said method comprising the step of mixing the compound of claim 1 , pharmaceutically acceptable salts or stereoisomers thereof with a pharmaceutically acceptable carrier.
17. A method of synthesizing the compound of Formula (I), pharmaceutically acceptable salts or stereoisomers as set forth in claim 1 , said method comprising the steps of:
I. reacting a first raw material with a second raw material in the presence of a first organic solvent and a first organic alkali to form a first intermediate according to the following reaction:
II. reacting the first intermediate with m-chloroperoxybenzoic acid (mCPBA) in the presence of a second organic solvent to form a second intermediate according to the following reaction:
III. reacting the second intermediate with a third raw material in the presence of a second organic alkali to form a third intermediate according to the following reaction:
IV. hydrolyzing the third intermediate in the presence of a third organic solvent and an first inorganic alkali to form a fourth intermediate according to the following reaction:
V. reacting the fourth intermediate with a fourth raw material in the presence of a fourth organic solvent, a third organic alkali, and HATU to form a fifth intermediate according to the following reaction:
VI. reacting the fifth intermediate with phosphoryl chloride in the presence of a fifth organic solvent to form a sixth intermediate according to the following reaction:
VII. basifying the sixth intermediate in the presence of a sixth organic solvent and a second inorganic alkali to form the compound of claim 1 according to the following reaction: