6493-05-6

Basic information

• Product Name: Pentoxifylline
• Synonyms: TRENTAL;1-(5-Oxohexyl)-3,7-dimethylxanthine;1-(5-oxohexyl)-theobromin;1-(5-Oxohexyl)theobromine;1-(5-oxohexyl)-Theobromine;1H-Purine-2,6-dione, 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-;3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1h-purine-6-dione;3,7-Dimethyl-1-(5-oxohexyl)-1H,3H-purin-2,6-dione
• CAS NO: 6493-05-6
• Molecular Formula: C₁₃H₁₈N₄O₃
• Molecular Weight: 278.31
• EINECS: 229-374-5
• Product Categories: All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Cyclic Nucleotide related;pentoxifylline
• Mol File: 6493-05-6.mol
• Article Data: 12

Chemical Properties

• Melting Point: 98-100°C
• Boiling Point: 421.13°C (rough estimate)
• Flash Point: 275.1 °C
• Appearance: white/solid
• Density: 1.1713 (rough estimate)
• Refractive Index: 1.6000 (estimate)
• Storage Temp.: Store at RT
• Solubility: H2O: ≥43 mg/mL
• PKA: 0.50±0.70(Predicted)
• Merck: 14,7136
• CAS DataBase Reference: Pentoxifylline(CAS DataBase Reference)
• NIST Chemistry Reference: Pentoxifylline(6493-05-6)
• EPA Substance Registry System: Pentoxifylline(6493-05-6)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Safety Statements: 36
• WGK Germany: 3
• RTECS: XH2475000
• Hazardous Substances Data: 6493-05-6(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Solid

Originator

Trental,Albert Roussel ,W. Germany ,1972

Uses

Different sources of media describe the Uses of 6493-05-6 differently. You can refer to the following data:
1. Pentoxifylline is a methylxanthine phospho-diesterase inhibitor with favorable antiinflammatory effects and immunoregulatory properties.A metabolite of Pentifylline. Methylxanthine derivative that improves blood flow by decreasing blood viscosity. Phosphodiesterase inhibitor. Inhibits the synthesis of tumor necrosis factor a (TNF-a).
2. Pentoxifylline can increase red blood cell deformability, reduce blood viscosity, and decrease platelet aggregation and thrombus formation. Pentoxifylline is an oral agent that improves perfusion of occluded vessels and is used to treat systemic vascular diseases. The retinal flow velocity in patients with RVO treated with pentoxifylline improved compared with placebo, but the study had a small number of patients (n = 8) and short follow-up (4 weeks), and no visual outcome data were reported.
3. Pentoxifylline has been used:used in the combinatorial treatment with itraconazole for paracoccidioidomycosis (PCM)to treat harvested sperms to check the effect of ′pentoxifylline exposed sperms′ in the contribution of embryonic growthto intrathecally inject female and male mice to investigate whether astrocytes and microglia could be causally involved in the maintenance of pain-like behaviour

Indications

Pentoxifylline at a dose of 400 mg three times a day after meals was reported to alleviate the symptoms in a small open trial.

Manufacturing Process

A solution of 35.4 g of 1-bromohexanone-5 in 200 ml of ethanol was gradually mixed at the reflux temperature with vigorous stirring with 39.7 g of theobromine-sodium in 100 ml of water. After 3 hours reflux the unreacted theobromine was filtered off with suction, the filtrate was evaporated to dryness, the residue was dissolved in water and the solution was extracted with chloroform. The chloroform was distilled off and 1-(5'-oxohexyl)-3,7 Pentoxifylline dimethylxanthine was obtained as residue; after recrystallization from isopropanol, it melted at 102°C to 103°C (about 25% yield, calculated on the reacted theobromine).

Brand name

Pentoxil (Upsher Smith); Trental (Sanofi Aventis).

Therapeutic Function

Vasodilator

Biological Activity

Phosphodiesterase inhibitor that blocks production of TNF- α and other cytokines. Displays antinociceptive activity.

Biochem/physiol Actions

Pentoxifylline?(PTX) is considered as a nonspecific phosphodiesterase inhibitor. It possesses rheologic properties. Pentoxifylline?is used to treat peripheral vascular disease. It has the ability to block the phosphorylation of I kappa B-alpha (I?Bα) in serines 32 and 36.

Veterinary Drugs and Treatments

In horses, pentoxifylline has been used as adjunctive therapy for cutaneous, vasculitis, endotoxemia and for the treatment of navicular disease. Pentoxifylline has been used in dogs to treat immune-mediated dermatologic conditions, enhance healing, and reduce inflammation caused by ulcerative dermatosis in Shelties and Collies and for other conditions where improved microcirculation may be of benefit. It is being investigated for adjunctive therapy for dilated cardiomyopathy in Doberman pinschers. Pentoxifylline has been tried in conjunction with prednisolone to decrease vasculitis associated with FIP in cats. Pentoxifylline’s major indications for humans include symptomatic treatment of peripheral vascular disease (e.g., intermittent claudication, sickle cell disease, Raynaud’s, etc.) and cerebrovascular diseases where blood flow may be impaired in the microvasculature.

InChI:InChI=1/C13H18N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8H,4-7H2,1-3H3

Synthetic route

theobromine / (83-67-0) + (5-oxohexyl) mesylate → pentoxyphylline (6493-05-6)

Conditions	Yield
With potassium carbonate In ethanol; water at 50℃; for 16h;	91.1%

theobromine / (83-67-0) + 6-Bromo-2-hexanone (10226-29-6) → pentoxyphylline (6493-05-6)

Conditions	Yield
With sodium hydroxide In isopropyl alcohol at 120℃; for 24h; Yield given;

theobromine / (83-67-0) + 6-chloro-2-hexanone (10226-30-9) → pentoxyphylline (6493-05-6)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 18h;

theobromine / (83-67-0) → pentoxyphylline (6493-05-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium methylate / methanol / Inert atmosphere; Reflux 2: sodium iodide / acetone / Reflux 3: (2-(dimethylamino)-N-(quinolin-8-yl)acetamido)nickel(II) chloride; manganese / N,N-dimethyl-formamide / 16 h / 20 °C / Sealed tube View Scheme

1-(4-chlorobutyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (78449-22-6) → pentoxyphylline (6493-05-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium iodide / acetone / Reflux 2: (2-(dimethylamino)-N-(quinolin-8-yl)acetamido)nickel(II) chloride; manganese / N,N-dimethyl-formamide / 16 h / 20 °C / Sealed tube View Scheme

C15H17N3NiO2 + 1-(4-iodobutyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione → pentoxyphylline (6493-05-6)

Conditions	Yield
With manganese; (2-(dimethylamino)-N-(quinolin-8-yl)acetamido)nickel(II) chloride In N,N-dimethyl-formamide at 20℃; for 16h; Sealed tube;	16.6 mg

pentoxyphylline (6493-05-6) → 3,7-dimethyl-1-(4,4,6,6,6-pentadeutero-5-oxohexyl)-1H-purine-2,6(3H,7H)-dione (1185879-03-1)

Conditions	Yield
With water-d2; potassium carbonate In toluene at 55 - 87℃;	99.96%
Stage #1: pentoxyphylline With water-d2; potassium carbonate for 24h; Reflux; Stage #2: With water-d2 for 24h; Reflux;	93%
With water-d2; potassium carbonate for 48h; Reflux;	93%
With water-d2; potassium carbonate In toluene at 87℃;	90%
With water-d2; potassium carbonate In toluene at 85 - 87℃; for 4h;

pentoxyphylline (6493-05-6) → C13H17(2)HN4O3

Conditions	Yield
With potassium tert-butylate; deuterium In tetrahydrofuran at 55℃; under 750.075 Torr; for 24h; regioselective reaction;	99%
With deuteromethanol; silver carbonate In tetrahydrofuran at 50℃; for 24h;	98%
With [(N,N’-bis(1R,2R,3R,5S)-(−)-isopinocampheyl-1,2-ethanediimine-radical)NiI(μ2-H)]2; deuterium In tetrahydrofuran at -196 - 45℃; under 760.051 Torr; for 24h; Sealed tube;	93%

pentoxyphylline (6493-05-6) → 1-(5-hydroxyhexyl)theobromine (6493-06-7, 100324-80-9, 100324-81-0)

Conditions	Yield
With methanol; sodium tetrahydroborate In acetonitrile at 0 - 20℃; for 3.33333h;	95%
With sodium tetrahydroborate In methanol at 20℃;	92%
With sodium tetrahydroborate In methanol for 1h;	80%

pentoxyphylline (6493-05-6) → lisofylline (100324-81-0) + (+)-(S)-3,7-dimethyl-1-(5-hydroxyhexyl)-3,7-dihydropurine-2,6-dione (100324-80-9)

Conditions	Yield
With Saccharomyces cerevisiae KKPU In phosphate buffer at 30℃; for 120h; Product distribution; Further Variations:; Solvents; Temperatures; Reagents; time;	A 95% B n/a
With potassium tert-butylate; hydrogen; C106H135ClIrNO2P2 In propan-1-ol at 20℃; under 6080.41 - 9120.61 Torr; Glovebox; Overall yield = 99 percent; Optical yield = 86 percent ee;
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol; dichloromethane / 0.67 h / 0 - 5 °C 2: immobilized Candida antarctica type B lipase Chirazyme L-2, C-3 / chloroform / 1 h / 60 °C / Sealed tube View Scheme

pentoxyphylline (6493-05-6) → 8-bromo-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With N-Bromosuccinimide In dichloromethane; water for 120h;	95%
With N-Bromosuccinimide In dichloromethane; water for 120h;	95%

pentoxyphylline (6493-05-6) → pentoxifylline-d5 (1185995-18-9)

Conditions	Yield
With tris(pentafluorophenyl)borate; water-d2 In tetrahydrofuran at 100℃; for 12h; Solvent; Inert atmosphere; regioselective reaction;	95%
With water-d2; potassium carbonate at 80℃; for 12h; Reagent/catalyst;

pentoxyphylline (6493-05-6) → 1-(5-aminohexyl)-3,7-dimethylxanthine

Conditions	Yield
With nickel(II) tetrafluoroborate hexahydrate; ammonia; hydrogen; bis(2-diphenylphosphinoethyl)phenylphosphine In 2,2,2-trifluoroethanol at 120℃; for 24h; chemoselective reaction;	93%
With ammonia; hydrogen In tetrahydrofuran at 120℃; for 24h;	77%

potassium cyanide + ammonium carbonate (506-87-6) + pentoxyphylline (6493-05-6) → C15H20N6O4

Conditions	Yield
In ethanol; water at 20℃; for 24h; Bucherer-Bergs Reaction; chemoselective reaction;	92%

dibutylamine (111-92-2) + pentoxyphylline (6493-05-6) → 1-(5-(dibutylamino)hexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol at 130℃; under 3750.38 - 37503.8 Torr; Autoclave;	88%

pentoxyphylline (6493-05-6) + 2-bromo-2,2-difluoro-1-morpholine-1-yl-ethanone (149229-27-6) → 8-(1,1-difluoro-2-morpholino-2-oxoethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,4,5,7-tetrahydro-1H-purine-2,6-dione

Conditions	Yield
With tris[2-phenylpyridinato-C2,N]iridium(III); potassium acetate In dichloromethane at 20℃; for 36h; Inert atmosphere; Schlenk technique; Irradiation;	82%

bis(((trifluoromethyl)sulfinyl)oxy)zinc (39971-65-8) + pentoxyphylline (6493-05-6) → 3,7-dimethyl-1-(5-oxohexyl)-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione (1346252-46-7)

Conditions	Yield
With tert.-butylhydroperoxide In dichloromethane; water at 25℃;	79%
With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 8h; Reagent/catalyst; Electrochemical reaction;	53%

pentoxyphylline (6493-05-6) → C26H34N8O5

Conditions	Yield
With sodium ethanolate In isopropyl alcohol at 0 - 60℃; for 2h; Temperature; Reagent/catalyst; Solvent;	77.2%

Langlois reagent (2926-29-6) + pentoxyphylline (6493-05-6) → 3,7-dimethyl-1-(5-oxohexyl)-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione (1346252-46-7)

Conditions	Yield
With mesoporous graphitic carbon nitride In dimethyl sulfoxide at 25℃; Irradiation;	76%
With lithium perchlorate; 9-(2-mesityl)-10-methylacridinium perchlorate In acetonitrile at 23℃; for 16h; Inert atmosphere; Irradiation; Electrochemical reaction;	72%

benzonitrile (100-47-0) + pentoxyphylline (6493-05-6) → 1-(5-(benzylamino)hexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione hydrochloride

Conditions	Yield
Stage #1: benzonitrile; pentoxyphylline With hydrogen In 2-methyltetrahydrofuran at 110℃; under 11251.1 Torr; for 20h; High pressure; Autoclave; Stage #2: With hydrogenchloride In diethyl ether	76%

pentoxyphylline (6493-05-6) + methyl iodide (74-88-4) → 1-(5-oxohexyl)-3,7,9-trimethylxanthine iodide

Conditions	Yield
In N,N-dimethyl-formamide at 75℃; for 48h; Sealed tube;	75.2%

pentoxyphylline (6493-05-6) → 1-(5-hydroxyhexyl-5-d)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1185995-43-0)

Conditions	Yield
With samarium diiodide; water-d2 In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; regioselective reaction;	75%
With samarium diiodide; water-d2 In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; chemoselective reaction;	75%

bis(((difluoromethyl)sulfinyl)oxy)zinc + pentoxyphylline (6493-05-6) → 8-(difluoromethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (1355729-57-5)

Conditions	Yield
With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water at 23℃; for 22h; regioselective reaction;	72%
With tert.-butylhydroperoxide In dichloromethane; water at 25℃;	72%
With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water for 22h;	72%
With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 60℃; for 8h; Reagent/catalyst;	49%
With tert.-butylhydroperoxide; trifluoroacetic acid In nonane; dimethyl sulfoxide at 20℃;	6.8%

pentanonitrile (110-59-8) + pentoxyphylline (6493-05-6) → 3,7-dimethyl-1-(5-(pentylamino)hexyl)-3,7-dihydro-1H-purine-2,6-dione hydrochloride

Conditions	Yield
Stage #1: pentanonitrile; pentoxyphylline With hydrogen In 2-methyltetrahydrofuran at 110℃; under 11251.1 Torr; for 20h; High pressure; Autoclave; Stage #2: With hydrogenchloride In diethyl ether	72%

bis(3-methoxyphenyl)acetylene (59647-77-7) + pentoxyphylline (6493-05-6) → (E)-1-(5-oxohexyl)-3,7-dimethyl-8-[1,2-di(3-methoxyphenyl)ethenyl]-3,7-dihydro-1H-purine-2,6-dione + (Z)-1-(5-oxohexyl)-3,7-dimethyl-8-[1,2-di(3-methoxyphenyl)ethenyl]-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With 2,2-dimethylbutyric acid; Pd{dba(OMe)}2; tricyclohexylphosphine In 1,4-dioxane at 120℃; for 24h; Inert atmosphere; Overall yield = 78 %;	A 70% B n/a

ammonium hydroxide (1336-21-6) + ammonium chloride + pentoxyphylline (6493-05-6) → 1-(5-aminohexyl)-3,7-dimethylxanthine

Conditions	Yield
With ammonium acetate; sodium cyanoborohydride In methanol; dichloromethane; water	68%

ammonium hydroxide (1336-21-6) + ammonium chloride + pentoxyphylline (6493-05-6) → 1-(5-aminohexyl)-3,7-dimethylxanthine + 1-(9'-acetoxy-10'-bromodecyl)-3,7-dimethylxanthine

Conditions	Yield
With ammonium acetate; sodium cyanoborohydride In methanol; dichloromethane; water	A 68% B n/a

ethanol (64-17-5) + pentoxyphylline (6493-05-6) → 8-(1-hydroxyethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (1016900-98-3)

Conditions	Yield
With di-tert-butyl peroxide for 24h; Irradiation;	66%

trimethylsilyl trifluoromethanesulfonate (27607-77-8) + pentoxyphylline (6493-05-6) → 3,7-dimethyl-1-(6,6,6-trifluoro-5-methyl-5-(trimethylsilyloxy)hexyl)-1H-purine-2,6(3H,7H)dione

Conditions	Yield
With cesium fluoride In tetrahydrofuran at 0 - 20℃; for 2h;	66%

2-Aminonicotinaldehyde (7521-41-7) + pentoxyphylline (6493-05-6) → 3,7-dimethyl-1-[4-(1,8-naphthyridin-2-yl)butyl]-3,7-dihydro-1H-purine-2,6-dione + 3,7-dimethyl-1-[3-(2-methyl-[1,8]naphthyridin-3-yl)-propyl]-3,7-dihydro-purine-2,6-dione

Conditions	Yield
With 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane; sulfuric acid In methanol; ethanol at 60℃; for 2.75h; Friedlaender reaction;	A 65% B n/a
With sodium hydroxide; sulfuric acid In methanol at 65 - 70℃; Friedlaender reaction; Title compound not separated from byproducts;

triphenylmethyl alcohol (76-84-6) + pentoxyphylline (6493-05-6) → 1-(5-hydroxy-5-phenylhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With potassium phosphate; chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium tert-butylate; C69H57N2O2(1+)*BF4(1-)*H(1+) In toluene at 125℃; for 24h; Sealed tube;	64%

2,2’-bis(benzo[d]isothiazol-3(2H)-one-1,1’-dioxide)-iodobenzene + pentoxyphylline (6493-05-6) → 8-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With iodine In chloroform at 20℃; for 16h; Irradiation; regioselective reaction;	63%

3-azidopropylamine (88192-19-2) + pentoxyphylline (6493-05-6) → 1-(5-((3-azidopropyl)amino)hexyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
Stage #1: 3-azidopropylamine; pentoxyphylline With acetic acid In methanol at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride at 20℃; for 2h;	60%

pentoxyphylline (6493-05-6) + isopropyl alcohol (67-63-0) → (RS,RS)-1-{[2-hydroxy-2-methylcyclobutyl]methyl}-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione + 8-(1-hydroxy-1-methylethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (1016900-95-0) + N-allyltheobromine (2530-99-6) + 1-(5-hydroxyhexyl)theobromine (6493-06-7, 100324-80-9, 100324-81-0)

Conditions	Yield
With acetone for 24h; Irradiation;	A 5% B 55% C 17% D 4%

pentoxyphylline (6493-05-6) + difluoromethanesulfinate salt → 8-(difluoromethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione (1355729-57-5)

Conditions	Yield
With mesoporous graphitic carbon nitride In dimethyl sulfoxide at 25℃; Irradiation;	54%

Upstream product

• 83-67-0 theobromine / 
• 10226-29-6 6-Bromo-2-hexanone 
• 26342-06-3 6-amino-hexan-2-one 
• 78449-22-6 1-(4-chlorobutyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione 
• 10226-30-9 6-chloro-2-hexanone 

Downstream Products

• 6493-06-7 1-(5-hydroxyhexyl)theobromine 
• 7726-11-6 formyl bromide 
• 1016900-96-1 8-(1-hydroxymethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione 
• 2530-99-6 N-allyltheobromine 
• 1016900-95-0 8-(1-hydroxy-1-methylethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione 
• 100324-81-0 lisofylline 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 100324-80-9 (+)-(S)-3,7-dimethyl-1-(5-hydroxyhexyl)-3,7-dihydropurine-2,6-dione 

Relevant articles and documents

Synthesis method of pentoxifylline

The invention belongs to the field of medicine synthesis, and discloses a synthesis method of pentoxifylline, which is characterized in that 4-(nitrogen methyl acyl chloride)-1-methylimidazole-5-acyl chloride and amino-5-hexanone are subjected to condensation ring closing, and the target product pentoxifylline is synthesized by only one-step reaction. The pentoxifylline synthesis method provided by the invention is simple in synthesis process, and byproducts obtained in the reaction process can be recycled to synthesize pentoxifylline again. The method is suitable for synthesizing pentoxifylline, and the synthesized pentoxifylline is used for preparing pentoxifylline for injection.

Pentoxifylline compound

The invention discloses a pentoxifylline compound. The compound is measured by using powder X-ray diffractometry and characteristic diffraction peaks are displayed by representing the 2 theta+/- 0.2 degrees at the places of 7.6 degrees, 7.8 degrees, 12.7 degrees, 13.6 degrees and 15.2 degrees. The pentoxifylline compound prepared by the method has the advantages of good stability, high purity andless impurities, and is simple in process, high in yield, strong in repeatability, high in medication safety and effectiveness, the incidence rate of the adverse reactions is greatly reduced, and thepentoxifylline compound is suitable for industrial production.

Glycation Cross-link Breakers to Increase Resistance to Enzymatic Degradation

The present invention relates to a method to treat a grafts, implant, scaffold, and constructs, including allografts, xenografts, autografts, and prosthetics comprising collagen, with an inhibitor of collagen cross-links and/or advanced glycation endproducts (AGE), in order to alleviate the mechanical weakness induced by the cross-links The invention also provides for kits for use in the operating theater during autograft, allograft or xenograft procedures, or for preparing allograft, xenografts or prosthetics that have not been already treated prior to packaging. The kit comprises a first agent or agents that inhibit collagen cross-links and/or advanced glycation endproducts, instructions for use, optionally a wash or rinse agent, and a device for containing the graft and first agent.