IP Library › Granted Patent US 8,575,331
Granted Patent B2
US 8,575,331 · App. 12/876,997 · Granted Nov 5, 2013

Synthesis and use of 2′-substituted-N6-modified nucleosides

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Quick Facts
Patent No.
US 8,575,331
App. No.
12/876,997
Granted
Nov 5, 2013
Kind
B2
Abstract

An improved method of preparing a sugar modified nucleoside analog includes a protocol in which a hydroxy group of a sugar is selectively deprotected and oxidized prior to nucleophilic modification of the corresponding carbonyl group. The modified sugar is then coupled to a heterocyclic base that is modified with a dual nucleophilic reagent in a further step that provides N6-modified adenosine analogs with high stereoselectivity.

Claims (17)

1. A compound having a structure according to Formula I

wherein R is selected from the group consisting of N(CH 2 CH 3 )NH 2 , N(CH 3 )OH, NHOCH 2 CH 3 , N(CH 3 )NHCH 3 , NHNHCH 3 , and NHNHOCH 3 .

2. The compound of claim 1 , wherein R is NHNHOCH 3 .

3. A compound having a structure according to Formula I

wherein R is selected from the group consisting of NHOCH 2 CH 3 , N(CH 3 )NHCH 3 , and NHNHCH 3 .

4. The compound of claim 3 , wherein R is NHOCH 2 CH 3 .

5. The compound of claim 3 , wherein R is N(CH 3 )NHCH 3 .

6. The compound of claim 3 , wherein R is NHNHCH 3 .

7. A method of synthesizing a compound of Formula I,

wherein R is selected from the group consisting of N(CH 2 CH 3 )NH 2 , N(CH 3 )OH, NHOCH 2 CH 3 , N(CH 3 )NHCH 3 , NHNHCH 3 , and NHNHOCH 3 , comprising reacting 6-Chloro-9H-(2′-β-C-methyl-β-D-ribofuranosyl)purine or 6-Chloro-9H-(2′-β-C-methyl-2′, 3′, 5′-tri-O-benzoyl-β-D-ribofuranosy)purine with a nucleophilic reagent selected from the group consisting of NH(CH 2 CH 3 )NH 2 , NH(CH 3 )OH, NH 2 OCH 2 CH 3 , NH(CH 3 )NHCH 3 , NH 2 NHCH 3 , and NH 2 NHOCH 3 .

8. The method of claim 7 , wherein the reacting step comprises reacting 6-Chloro-9H-(2′-β-C-methyl-β-D-ribofuranosyl)purine with the nucleophilic reagent.

9. The method of claim 7 , wherein the reacting step comprises reacting 6-Chloro-9H-(2′-β-C-methyl-2′, 3′, 5′-tri-O-benzoyl-β-D-ribofuranosyl)purine with the nucleophilic reagent.

10. The method of claim 7 , wherein reacting 6-Chloro-9H-(2′-β-C-methyl- β-D-ribofuranosyl)purine or 6-Chloro-9H-(2′-β-C-methyl-2′, 3′, 5′-tri-O-benzoyl-β-D-ribofuranosyl)purine with the nucleophilic reagent occurs in a non-basic environment.

11. The method of claim 10 , wherein the non-basic environment comprises at least one solvent selected from the group consisting of ethanol and methylene chloride.

12. The method of claim 7 , wherein reacting 6-Chloro-9H-(2′-β-C-methyl-β-D-ribofuranosyl)purine or 6-Chloro-9H-(2′-β-C-methyl-2′, 3′,5′-tri-O-benzoyl-β-D-ribofuranosyl)purine with the nucleophilic reagent occurs under a protective atmosphere.

13. The method of claim 7 , wherein reacting 6-Chloro-9H-(2′-β-C-methyl-β-D-ribofuranosyl)purine or 6-Chloro-9H-(2′-β-C-methyl-2′, 3′, 5′-tri-O-benzoylβ-D-ribofuranosyl)purine with the nucleophilic reagent occurs at a temperature of at least 40° C.

14. The method of claim 13 , wherein the temperature is at least 70° C.

Assignments (11)
RELEASE OF SECURITY INTEREST Recorded Nov 20, 2025
From: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
To: ATON PHARMA, INC.; BAUSCH & LOMB INCORPORATED; BAUSCH & LOMB PHARMA HOLDINGS CORP.; COMMONWEALTH LABORATORIES, LLC; DOW PHARMACEUTICAL SCIENCES, INC.; ECR PHARMACEUTICALS CO., INC.; LABORATOIRE CHAUVIN S.A.S.; MEDICIS PHARMACEUTICAL CORPORATION; ONPHARMA INC.; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.; SALIX PHARMACEUTICALS, LTD.; SALIX PHARMACEUTICALS, INC.; SANTARUS, INC.; SOLTA MEDICAL, INC.; SYNERGETICS USA, INC.; TECHNOLAS PERFECT VISION GMBH; VALEANT CANADA LP; VALEANT PHARMACEUTICALS INTERNATIONAL; VALEANT PHARMACEUTICALS INTERNATIONAL, INC.; VALEANT PHARMACEUTICALS NORTH AMERICA LLC; WIRRA IP PTY LIMITED; VALEANT PHARMA POLAND SP. Z O.O.; VALEANT PHARMACEUTICALS LUXEMBOURG S.A R.L.; VALEANT PHARMACEUTICALS IRELAND LIMITED
Reel/Frame 073637/0001 →
RELEASE OF SECURITY INTEREST Recorded Nov 20, 2025
From: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
To: BAUSCH HEALTH AMERICAS, INC.; BAUSCH & LOMB INCORPORATED; BAUSCH HEALTH US, LLC; SOLTA MEDICAL, INC.; MEDICIS PHARMACEUTICAL CORPORATION; SALIX PHARMACEUTICALS, INC.; SALIX PHARMACEUTICALS, LTD.; SANTARUS, INC.; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.
Reel/Frame 073637/0126 →
RELEASE OF SECURITY INTEREST Recorded Nov 20, 2025
From: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
To: BAUSCH HEALTH IRELAND LIMITED; BAUSCH HEALTH COMPANIES INC.; BAUSCH HEALTH, CANADA INC.; TECHNOLAS PERFECT VISION GMBH; VALEANT PHARMACEUTICALS LUXEMBOURG S.A R.L.; VALEANT PHARMA POLAND SPOLKA Z ORGANICZONA ODPOWIEDZIALNOSCIA; VALEANT SP. Z.O.O.
Reel/Frame 073637/0222 →
RELEASE OF SECURITY INTEREST Recorded Apr 8, 2025
From: BARCLAYS BANK PLC, AS COLLATERAL AGENT
To: SOLTA MEDICAL, INC.; PRECISION DERMATOLOGY, INC.; BAUSCH HEALTH IRELAND LIMITED (F/K/A/ VALEANT PHARMACEUTICALS IRELAND LIMITED); SALIX PHARMACEUTICALS, INC.; SALIX PHARMACEUTICALS, LTD; SANTARUS, INC.; MEDICIS PHARMACEUTICAL CORPORATION; HUMAX PHARMACEUTICAL S.A.; SOLTA MEDICAL IRELAND LIMITED; BAUSCH & LOMB MEXICO, S.A. DE C.V.; BAUSCH+LOMB OPS B.V.; BAUSCH HEALTH AMERICAS, INC.; BAUSCH HEALTH COMPANIES INC.; BAUSCH HEALTH HOLDCO LIMITED; BAUSCH HEALTH MAGYARORSZAG KFT (A/K/A BAUSCH HEALTH HUNGARY LLC); BAUSCH HEALTH POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA (F/K/A VALEANT PHARMA POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA); BAUSCH HEALTH US, LLC; BAUSCH HEALTH, CANADA INC. / SANTE BAUSCH, CANADA INC.; ICN POLFA RZESZOW SPOLKA AKCYJNA (A/K/A ICN POLFA RZESZOW S.A.); ORAPHARMA, INC.; PRZEDSIEBIORSTWO FARMACEUTYCZNE JELFA SPOLKA AKCYJNA (A/K/A PRZEDSIEBIORSTWO FARMACEUTYCZNE JELFA S.A.); SOLTA MEDICAL DUTCH HOLDINGS B.V.; V-BAC HOLDING CORP.; VRX HOLDCO LLC; 1261229 B.C. LTD.; 1530065 B.C. LTD.
Reel/Frame 070778/0199 →
SECURITY AGREEMENT (SECOND LIEN) Recorded Oct 5, 2022
From: BAUSCH HEALTH US, LLC; BAUSCH HEALTH AMERICAS, INC.; MEDICIS PHARMACEUTICAL CORPORATION; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.; SALIX PHARMACEUTICALS, INC.; SALIX PHARMACEUTICALS, LTD.; SANTARUS, INC.; SOLTA MEDICAL, INC.
To: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
Reel/Frame 061606/0468 →
SECURITY AGREEMENT (FIRST LIEN) Recorded Oct 4, 2022
From: BAUSCH HEALTH US, LLC; BAUSCH HEALTH AMERICAS, INC.; MEDICIS PHARMACEUTICAL CORPORATION; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.; SALIX PHARMACEUTICALS, INC.; SALIX PHARMACEUTICALS, LTD.; SANTARUS, INC.; SOLTA MEDICAL, INC.
To: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
Reel/Frame 061595/0066 →
SECURITY INTEREST Recorded Oct 5, 2021
From: BAUSCH & LOMB IRELAND LIMITED; BAUSCH HEALTH COMPANIES INC.; DR. GERHARD MANN CHEM.-PHARM. FABRIK GMBH; TECHNOLAS PERFECT VISION GMBH
To: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
Reel/Frame 057821/0800 →
INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Jul 3, 2019
From: BAUSCH HEALTH IRELAND LIMITED; BAUSCH HEALTH COMPANIES INC.; BAUSCH HEALTH, CANADA INC.; TECHNOLAS PERFECT VISION GMBH; VALEANT PHARMACEUTICALS LUXEMBOURG S.À R.L.; VALEANT PHARMA POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA; VALEANT SP. Z O. O.
To: THE BANK OF NEW YORK MELLON, AS COLLATERAL AGENT
Reel/Frame 049672/0652 →
SECURITY INTEREST Recorded Mar 11, 2019
From: BAUSCH HEALTH AMERICAS, INC.; BAUSCH & LOMB INCORPORATED; BAUSCH HEALTH US, LLC; SOLTA MEDICAL, INC.; MEDICIS PHARMACEUTICAL CORPORATION; SALIX PHARMACEUTICALS, INC.; SALIX PHARMACEUTICALS, LTD.; SANTARUS, INC.; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.
To: THE BANK OF NEW YORK MELLON, AS NOTES COLLATERAL AGENT
Reel/Frame 048556/0758 →
SECURITY INTEREST Recorded Feb 26, 2018
From: ATON PHARMA, INC.; BAUSCH & LOMB INCORPORATED; BAUSCH & LOMB PHARMA HOLDINGS CORP.; COMMONWEALTH LABORATORIES, LLC; DOW PHARMACEUTICAL SCIENCES, INC.; ECR PHARMACEUTICALS CO., INC.; LABORATOIRE CHAUVIN S.A.S.; MEDICIS PHARMACEUTICAL CORPORATION; ONPHARMA INC.; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.; SALIX PHARMACEUTICALS, LTD.; SALIX PHARMACEUTICALS, INC.; SANTARUS, INC.; SOLTA MEDICAL, INC.; SYNERGETICS USA, INC.; TECHNOLAS PERFECT VISION GMBH; VALEANT CANADA LP; VALEANT PHARMACEUTICALS INTERNATIONAL; VALEANT PHARMACEUTICALS INTERNATIONAL, INC.; VALEANT PHARMACEUTICALS NORTH AMERICA LLC; WIRRA IP PTY LIMITED; VALEANT PHARMA POLAND SP. Z O.O.; VALEANT PHARMACEUTICALS LUXEMBOURG S.A R.L.; VALEANT PHARMACEUTICALS IRELAND LIMITED
To: BARCLAYS BANK PLC, AS COLLATERAL AGENT
Reel/Frame 045444/0299 →
SECURITY INTEREST Recorded Feb 26, 2018
From: ATON PHARMA, INC.; BAUSCH & LOMB INCORPORATED; BAUSCH & LOMB PHARMA HOLDINGS CORP.; COMMONWEALTH LABORATORIES, LLC; DOW PHARMACEUTICAL SCIENCES, INC.; ECR PHARMACEUTICALS CO., INC.; LABORATOIRE CHAUVIN S.A.S.; MEDICIS PHARMACEUTICAL CORPORATION; ONPHARMA INC.; ORAPHARMA, INC.; PRECISION DERMATOLOGY, INC.; SALIX PHARMACEUTICALS, LTD.; SALIX PHARMACEUTICALS, INC.; SANTARUS, INC.; SOLTA MEDICAL, INC.; SYNERGETICS USA, INC.; TECHNOLAS PERFECT VISION GMBH; VALEANT CANADA LP; VALEANT PHARMACEUTICALS INTERNATIONAL; VALEANT PHARMACEUTICALS INTERNATIONAL, INC.; VALEANT PHARMACEUTICALS NORTH AMERICA LLC; WIRRA IP PTY LIMITED; VALEANT PHARMA POLAND SP. Z O.O.; VALEANT PHARMACEUTICALS LUXEMBOURG S.A R.L.; VALEANT PHARMACEUTICALS IRELAND LIMITED
To: THE BANK OF NEW YORK MELLON, AS COLLATERAL AGENT
Reel/Frame 045444/0634 →