Claims for Patent: 7,777,058

Summary for Patent: 7,777,058

Title:	Disulfide, sulfide, sulfoxide, and sulfone derivatives of cyclic sugars and uses thereof
Abstract:	In the present invention there are disclosed new derivatives of dianhydrohexite mononitrate corresponding to formula (I), tautomers, pharmaceutically acceptable salts, prodrugs and solvates thereof: ##STR00001## as well as pharmaceutical compositions comprising these compounds and uses thereof.
Inventor(s):	Moliner; Jose Repolles (Barcelona, ES), Perez-Rasilla; Eduardo Salas (Barcelona, ES), Coy; Francisco Pubill (Barcelona, ES)
Assignee:	Lacer S.A. (Barcelona, ES)
Application Number:	12/400,394
Patent Claims:	1. A pharmaceutical composition which comprises a thrombolytic agent in combination with a compound of Formula I having the formula ##STR00038## or pharmaceutically acceptable salt of the compound of Formula I wherein n is an integer of 0, 1, or 2, X represents --S(O).sub.m--, --(C.dbd.O)--or a single bond, wherein m is an integer of 0, 1, or 2, with the proviso that when X represents --(C.dbd.O)--, then n is 0, R represents hydrogen or is a residue R.sup.a, which residue R.sup.a is selected from the group consisting of: C.sub.1-6 alkyl; C.sub.2-6 alkenyl; C.sub.3-8 cycloalkyl; C.sub.3-8 cycloalkyl, wherein one CH.sub.2 group is replaced by O, S, NH or NCH.sub.3; C.sub.4-8 cycloalkenyl; C.sub.4-8 cycloalkenyl, wherein one CH.sub.2 group is replaced by O, S, N or NCH.sub.3; phenyl; pyridyl; thiophenyl; nitrosyl; S-cysteinyl; S-glutathionyl; and ##STR00039## wherein R* is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-8 cycloalkyl, C.sub.4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO.sub.2 and halogen; wherein R.sup.a optionally is substituted by one to three groups independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-8 cycloalkyl, C.sub.4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO.sub.2 and halogen, provided that when RXS(O).sub.n- and --ONO.sub.2 are trans to each other with respect to the ring plane as depicted in formulae (Ia) and (Ib): ##STR00040## then RXS(O).sub.n- does not represent ##STR00041## wherein Z is an C.sub.1-C.sub.4 alkyl group, aryl group, or an aralkyl group. 2. The pharmaceutical composition according to claim 1, which further comprises an anticoagulant agent. 3. The pharmaceutical composition according to claim 1, which further comprises an antithrombotic agent. 4. The pharmaceutical composition according to claim 1, which further comprises an immunoglobulin or a fragment thereof having a specificity for glycoprotein IIb/IIIa. 5. The pharmaceutical composition according to claim 1, which further comprises a hypolipemiant agent. 6. A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00042## wherein: n is an integer of 0, 1, or 2, X represents --S(O).sub.m-- or a single bond, wherein in is an integer of 0, 1, or 2, and R represents hydrogen or is a residue R.sup.a, which residue R.sup.a is selected from the group consisting of: C.sub.1-6 alkyl; C.sub.2-6 alkenyl; C.sub.3-8 cycloalkyl; C.sub.3-8 cycloalkyl, wherein one CH.sub.2 group is replaced by O, S, N or NCH.sub.3; C.sub.4-8 cycloalkenyl; C.sub.4-8 cycloalkenyl, wherein one CH.sub.2 group is replaced by O, S, N or NCH.sub.3; phenyl; pyridyl; thiophenyl; nitrosyl; S-cysteinyl; S-glutathionyl; and ##STR00043## wherein R* is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-8 cycloalkyl; C.sub.4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO.sub.2 and halogen, wherein R.sup.a optionally is substituted by one to three groups independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkeny, C.sub.3-8 cycloalkyl, C.sub.4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO.sub.2 and halogen, which process comprises conducting the following steps: a) effecting the hydrolysis of a compound of formula (IIa): ##STR00044## wherein R' is C.sub.1-C.sub.6 alkyl, preferably methyl, to obtain the following compound: ##STR00045## and (b) optionally, effecting on the compound prepared according to the step (a): I. an oxidation reaction to obtain: ##STR00046## optionally followed by a second oxidation to obtain the following compound: ##STR00047## wherein: n is 1 or 2, X is --S(O).sub.m--, wherein m is 0, 1 or 2, and R* represents hydroxyl or ONO.sub.2; II. a substitution reaction to obtain: a compound according to formula (I), wherein: n is an integer of 0, X represents a bond, and R does not represent nitrosyl, optionally followed by an oxidation to obtain a compound according to formula (I), wherein: n is an integer of 0, X represents --S(O).sub.m--, wherein m is an integer of 0 or 1, and R does not represent nitrosyl; III. a substitution reaction to obtain: a compound according to formula (I), wherein: n is an integer of 0, and X represents --S--; optionally followed by an oxidation to obtain a compound according to formula (I), wherein: n is an integer of 1 or 2, and X represents --S(O).sub.m--, wherein m is 0, 1 or 2; or IV. a nitrosation reaction to obtain: ##STR00048## 7. A process according to claim 6 for preparing a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: ##STR00049## wherein: n is an integer of 0, 1, or 2, X represents --S(O).sub.m-- or a single bond, wherein in is an integer of 0, 1, or 2, and R represents hydrogen or is a residue R.sup.a, which residue R.sup.a is selected from the group consisting of: C.sub.1-6 alkyl; C.sub.2-6 alkenyl; C.sub.3-8 cycloalkyl; C.sub.3-8 cycloalkyl, wherein one CH.sub.2 group is replaced by O, S, NH or NCH.sub.3; C.sub.4-8 cycloalkenyl; C.sub.4-8 cycloalkenyl, wherein one CH.sub.2 group is replaced by O, S, N or NCH.sub.3; phenyl; pyridyl; thiophenyl; nitrosyl; S-cysteinyl; S-glutathionyl; and ##STR00050## wherein R* is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-8 cycloalkyl, C.sub.4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO.sub.2 and halogen, wherein R.sup.a optionally is substituted by one to three groups independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-8 cycloalkyl, C.sub.4-8 cycloalkenyl, acetyloxy, hydroxyl, ONO.sub.2 and halogen, and wherein said process comprises the following steps: (a) effecting the hydrolysis of a compound of formula (IIa): ##STR00051## wherein R' is C.sub.1-6 alkyl, preferably methyl, to obtain 2-thioisosorbide 5-mononitrate (1), ##STR00052## and (b) optionally, effecting on the compound (1) prepared according to the step (a): I. an oxidation reaction to obtain: 5,5'-dinitrato-2,2'-dithio-diisosorbide (2) or 2-(isosorbidyl-2'-dithio-isosorbide 5-mononitrate (8), optionally followed by a second oxidation to obtain a compound according to formula (Ie): ##STR00053## wherein: n is 1 or 2, X is --S(O).sub.m--, wherein in is 0, 1 or 2, and R* represents hydroxyl or ONO.sub.2; II. a substitution reaction to obtain a compound according to formula (Ia), wherein: n is an integer of 0, X represents a bond, and R does not represent nitrosyl, optionally followed by an oxidation to obtain: a compound according to formula (Ia), wherein: n is an integer of 0, X represents --S(O).sub.m--, wherein in is an integer of 0 or 1, and R does not represent nitrosyl; III. a substitution reaction to obtain: a compound according to formula (Ia), wherein: n is an integer of 0, and X represents --S--; optionally followed by an oxidation to obtain a compound according to formula (Ia), wherein: n is an integer of I or 2, and X represents --S(O).sub.m--, wherein in is 0, 1 or 2; or IV. a nitrosation reaction to obtain: S-nitroso-2-thioisosorbide 5-mononitrate (6). 8. A process according to claim 6 that includes steps (a) and (b) II for the preparation of: 2-[(R)-methylsulfinyl]isosorbide 5-mononitrate, and/or 2-[(S)-methylsulfinyl]isosorbide 5-mononitrate. 9. A process according to claim 7, that includes the separation of both diastereoisomers. 10. A process for preparing a compound of formula (11) or a pharmaceutically acceptable salt thereof: ##STR00054## which process comprises the following steps: a) effecting an oxidation of a compound of formula III ##STR00055## wherein R' is C.sub.1--C.sub.6 alkyl, preferably methyl, to obtain 2,2'-dithiodiisosorbide (10), ##STR00056## (b) effecting a nitration of the compound prepared in step (a) with a nitrating agent in the presence of a carboxylic anhydride, preferably acetic anhydride. 11. The pharmaceutical composition according to claim 1, wherein either one or both of m and n is 0. 12. The pharmaceutical composition according to claim 1, wherein X represents a single bond of --S--. 13. The pharmaceutical composition according to claim 1, wherein R represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-8 cycloalkyl, C.sub.4-8 cycloalkenyl, (C.sub.1-6 alkyl) C.sub.3-8 cycloalkyl, (C.sub.1-6 alkyl) C.sub.4-8 cycloalkenyl, phenyl, (C.sub.1-6 alkyl)phenyl, 5-acetyloxyisosorbid-2-yl, 5-hydroxyisosorbid-2-yl or 5-nitratoisosorbid-2-yl. 14. The pharmaceutical composition according to claim 1, wherein R is C.sub.1-6 alkyl. 15. The pharmaceutical composition according to claim 1, wherein the compound of Formula I is a compound according to formula (Ic) or Id): ##STR00057## 16. The pharmaceutical composition according to claim 1, where the compound of Formula I is selected from: 2-thioisosorbide 5-mononitrate, 5,5'-dinitrate-2,2'-dithiodiisosorbide, 2-methylthioisosorbide 5-mononitrate, 2-[(R)-methylsulfinyl] isosorbide 5-mononitrate, 2-[(S)-methylsulfinyl]isosorbide 5-mononitrate 2-methylsulfinylisosorbide 5-mononitrate, 2-methylsulfonylisosorbide 5-mononitrate, S-nitroso-2-thiososorbide 5-mononitrate, 2-(tetrahydropyran-2-yl-thio) isosorbide 5-monoitrate, 2-(isosorbidy2'dithio) isosorbide 5-mononitrate, and 2-(5'-acetyloxyisosorbidyl-2'-dithio) isosorbide 5-mononitrate. 17. The pharmaceutical composition according to claim 1, wherein the thrombolytic agent is a plasminogen activator, urokinase, streptokinase, alteplase or anistreplase. 18. The pharmaceutical composition according to claim 2, wherein the anticoagulant agent is heparin, dicoumarol, acenocoumarol, enoxaparine or pentosan polysulfate. 19. The pharmaceutical composition according to claim 3 wherein the antithrombotic agent is acetylsalicylic acid, dipyridamole, ticlopidine, clopidrogel, triflusal, pentosan polysulfate or abciximab. 20. The pharmaceutical composition according to claim 5 wherein the hypolipemiant agent is simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, eptastatin, n, acitemate, glunicate and rosuvastatin.

Details for Patent 7,777,058

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2039-03-29
Genentech, Inc.	ACTIVASE	alteplase	For Injection	103172	11/13/1987		2039-03-29
Genentech, Inc.	CATHFLO ACTIVASE	alteplase	For Injection	103172	09/04/2001		2039-03-29
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2039-03-29