WO2000038668A2 - Use of a nitrosourea derivative for prevention or treatment of acute allograft rejection - Google Patents
Use of a nitrosourea derivative for prevention or treatment of acute allograft rejection Download PDFInfo
- Publication number
- WO2000038668A2 WO2000038668A2 PCT/US1999/030985 US9930985W WO0038668A2 WO 2000038668 A2 WO2000038668 A2 WO 2000038668A2 US 9930985 W US9930985 W US 9930985W WO 0038668 A2 WO0038668 A2 WO 0038668A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- straight
- carbon atoms
- branched alkyl
- alkyl group
- Prior art date
Links
- 0 CC(CC(*)CC1)(C*1N)N Chemical compound CC(CC(*)CC1)(C*1N)N 0.000 description 6
- MOGNTIBIOAPHSR-SREVYHEPSA-N C[O](C)C(CCCC1O)C1/C=C\C(N(CCCl)N=O)=O Chemical compound C[O](C)C(CCCC1O)C1/C=C\C(N(CCCl)N=O)=O MOGNTIBIOAPHSR-SREVYHEPSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
- A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- the invention relates to the field of organ transplantation.
- the present invention relates to methods for helping to prevent rejection of organ transplants by the recipient.
- the present invention also relates to pharmaceutical compositions for helping to prevent rejection of organ transplants by treatment of the donor.
- Immune response of an organ transplant recipient includes activation of the recipient's T-cells.
- Immune systems of animals are designed such that they help to protect the body by attacking anything in the body that the body does not recognize. In this way, immune systems help to combat foreign bodies, such as viruses and bacteria that find their way into a body.
- an organ from a donor represents foreign matter to the immune system of the recipient .
- organ transplant will still act as a foreign substance for the purposes of inducing an immune response in a recipient's body.
- the immune response to an organ transplant typically referred to as an allograft, includes the activation of T-cells.
- conventual immunosuppression therapy includes at least one immunosuppressing drug administered to the recipient.
- These drugs include Cyclosporine, Azathioprine, steroids, Tacrolimus, and/or Mycophenolate Mofetil. Any one or more of these drugs may be administered individually or in combination, simultaneously or successively to suppress immune response in the recipient's body. These drugs act non specifically and broadly impair the recipient's immune system to reduce the immune response against the graft .
- transplant patients are more susceptible to contracting infections. This may be particularly damaging to transplant patients in the time just after receiving the transplanted organ since the patients will also be weak as a result of undergoing major surgery. Additionally, at this time, it is desired for transplant patients to heal. In other words, it is desired that the transplant recipient's body expend energy in healing and incorporating the transplanted organ into the body rather than fighting to reject the organ or fighting infections resulting from a compromised immune system. Moreover, one should keep in mind that infection is a major cause of death at anytime after transplant because the recipient must always take immunosuppressive drugs.
- the present invention provides a method for addressing the above-described as well as other problems by providing a treatment that reduces graft rejection.
- the present invention may also result in eliminating or reducing immunosuppressing compounds that must be administered to a patient, thus significantly reducing the patient's susceptibility to infection.
- an aspect of the present invention provides a method for treating an organ donor prior to harvesting organ to reduce graft rejection in a recipient and a method for reducing acute allograft graft rejection. According to these methods, an amount effective to reduce graft rejection of at least one compound selected from the group consisting of compounds having formulas I, II, III, IV, V, VI, and VII is administered to an organ donor:
- X is F or Cl ;
- R x is a straight or branched alkyl group having from 1 to 7 carbon atoms ;
- R 2 is a straight or branched alkyl group having from 1 to 7 carbon atoms
- R 3 is H or a straight or branched alkyl group having from 1 to 7 carbon atoms ;
- Z is H, OH, or a straight or branched alkyl group including from
- the OH groups may be substituted anywhere except where Y is present and are not on the same carbon atom; in Formula III, the OH group may be substituted anywhere except where Y is present; in Formula IV, the OH group may be substituted anywhere except where Y is present; in Formula V, Z may be substituted anywhere except at C-l, C-6, and C-4 if Z is OH; in Formula VI, Z may be substituted anywhere except at C-l, C-3, and C-5 if Z is OH; and in Formula VII, Z may be at C-l, C-2, and C-3 except not on C-l if Z is OH.
- compositions that includes an amount effective to reduce graft rejection of at least one compound selected from the group consisting of compounds having the above formulas I, II, III, IV, V, VI, and VII.
- the present invention provides methods for preventing or treating acute allograft rejection by treating an organ donor prior to harvesting of the organs from the donor.
- the present invention permits eliminating or reducing dosages of immunosuppressing compounds to the recipient. Eliminating or reducing dosages of immunosuppressing drugs eliminates or reduces the concomitant adverse effects associated with the drugs. In fact, it has been found that at least one compound of the present invention was more effective than Methotrexate or other known compounds when utilized as a donor pretreatment for preventing allograft rejection.
- the present invention provides methods for treating an organ donor prior to harvesting organs to reduce graft rejection in recipient.
- the method includes administering to an organ donor prior to harvesting of the organ an amount effective to reduce graft rejection of at least one of the following compounds:
- X is F or Cl ;
- R x is a straight or branched alkyl group having from 1 to 7 carbon atoms ;
- R 2 is a straight or branched alkyl group having from 1 to 7 carbon atoms
- R 3 is H or a straight or branched alkyl group having from 1 to 7 carbon atoms ;
- Z is H, OH, or a straight or branched alkyl group including from
- the OH groups may be substituted anywhere except where Y is present and are not on the same carbon atom; in Formula III, the OH group may be substituted anywhere except where Y is present; in Formula IV, the OH group may be substituted anywhere except where Y is present; in Formula V, Z may be substituted anywhere except at C-l, C-6, and C-4 if Z is OH; in Formula VI, Z may be substituted anywhere except at C-l, C-3, and C-5 if Z is OH; and in Formula VII, Z may be at C-l, C-2, and C-3 except not on C-l if Z is OH.
- Administration of at least one of the above compounds may begin about 6 hours to about 24 hours prior to removal of the organ from the donor.
- An example of a suitable dosage is approximately the LD 50 value as determined in rats and then extrapolated to humans for the drug being administered.
- the dosage can be readily determined by those skilled in the art once aware of this disclosure without undue experimentation.
- the present invention may be utilized in treating a donor for any organ transplant, including heart, kidney, pancreas, and/or liver.
- Compounds of the present invention typically belong to the class of compounds known as nitrosoureas .
- the donor rats were Fischer strain and the recipients were Long-Evans strains. These strains are mismatched at the major histocompatibility antigenic site (Ag locus).
- intra abdominal heterotopic cardiografting was performed using a modification of techniques described by Ono and Lindsey, Improved Technique of Heart Transplantation In Rats, Journal of Thoracic and Cardiovascular Surgery, 57: 225 (1969) and Lee et al . , Heterotopic Heart and Lung Transplantation in the Rat, American Journal of Pathology, 59: 279 (1970) , the entire contents of the disclosures of both of which are hereby incorporated by reference .
- a total dose of 20 milligrams per kilogram of the above compound was administered to donor rats 24 hours prior to transplantation.
- survival was prolonged from 10 to 25-60 days.
- Survival for 60 days indicated permanent survival, in other words, while typically surviving 10 days, the rats lived for 25-60 days, with the rats living to 60 days having a permanent survival.
- the rats surviving for 60 days were sacrificed after two years and microscopic evaluation revealed normal hearts .
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU23901/00A AU2390100A (en) | 1998-12-29 | 1999-12-28 | Method for prevention or treatment of acute allograft rejection and a pharmaceutical composition therefor |
CA002357977A CA2357977A1 (en) | 1998-12-29 | 1999-12-28 | Method for prevention or treatment of acute allograft rejection and a pharmaceutical composition therefor |
EP99967652A EP1140060A2 (en) | 1998-12-29 | 1999-12-28 | Use of a nitrosourea derivative for prevention or treatment of acute allograft rejection |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22160298A | 1998-12-29 | 1998-12-29 | |
US09/221,602 | 1998-12-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000038668A2 true WO2000038668A2 (en) | 2000-07-06 |
WO2000038668A3 WO2000038668A3 (en) | 2000-12-07 |
Family
ID=22828491
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/030985 WO2000038668A2 (en) | 1998-12-29 | 1999-12-28 | Use of a nitrosourea derivative for prevention or treatment of acute allograft rejection |
Country Status (5)
Country | Link |
---|---|
US (1) | US6503948B2 (en) |
EP (1) | EP1140060A2 (en) |
AU (1) | AU2390100A (en) |
CA (1) | CA2357977A1 (en) |
WO (1) | WO2000038668A2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1507099A (en) * | 1974-08-08 | 1978-04-12 | Suami T | Nitrosourea derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2845574A1 (en) * | 1978-10-19 | 1980-04-24 | Deutsches Krebsforsch | CCNU SUBSTITUTED ANALOGS BY HETEROCYCLIC RINGS OR ALKYL RESIDUES AND METHOD FOR THE PRODUCTION THEREOF |
JPS6178724A (en) * | 1984-09-25 | 1986-04-22 | Tetsuo Suami | Antitumor agent |
-
1999
- 1999-12-28 CA CA002357977A patent/CA2357977A1/en not_active Abandoned
- 1999-12-28 AU AU23901/00A patent/AU2390100A/en not_active Abandoned
- 1999-12-28 WO PCT/US1999/030985 patent/WO2000038668A2/en not_active Application Discontinuation
- 1999-12-28 EP EP99967652A patent/EP1140060A2/en not_active Withdrawn
-
2002
- 2002-04-17 US US10/123,185 patent/US6503948B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1507099A (en) * | 1974-08-08 | 1978-04-12 | Suami T | Nitrosourea derivatives |
Non-Patent Citations (8)
Title |
---|
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ASANUMA, FUMIKI ET AL: "Effect of DONU, a new water-soluble derivative of nitrosourea, on human tumors serially transplanted into nude mice" retrieved from STN Database accession no. 101:183584 XP002145477 & J. JPN. SOC. CANCER THER. (1982), 17(8), 2035-43 , * |
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MURAKAMI, MASUO ET AL: "Nitrosourea derivatives" retrieved from STN Database accession no. 80:82228 XP002145475 & JP 48 013537 B (YAMANOUCHI PHARMACEUTICAL CO., LTD.) 27 April 1973 (1973-04-27) * |
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SUAMI, TETSUO ET AL: "Nitrosourea derivatives as neoplasm inhibitors" retrieved from STN Database accession no. 105:72683 XP002145476 & JP 61 078724 A (KIRIN BREWERY CO., LTD., JAPAN;ASAHI GLASS CO., LTD.) 22 April 1986 (1986-04-22) * |
JOHNSTON, THOMAS P. ET AL: "Studies on synthesis and anticancer activity of selected N-(2-fluoroethyl)-N-nitrosoureas" J. MED. CHEM. (1984), 27(11), 1422-6 , XP000929925 * |
JOHNSTON, THOMAS PATRICK ET AL: "Synthesis of potential anticancer agents. XXXVI. N-nitrosoureas. 2. Haloalkyl derivatives" J. MED. CHEM. (1966), 9(6), 892-910 , XP000929924 * |
KENDE M: "DETERMINATION OF THE SUPPRESSION OF THE CELLULAR IMMUNE RESPONSE OF MICE WITH DONOR -SPECIFIC GAMMA GLOBULIN DURING CHIMERIC STATE." KENDE, M., J. GAINER AND M. CHIRIGOS (ED.). PROGRESS IN CLINICAL AND BIOLOGICAL RESEARCH, VOL. 161. CHEMICAL REGULATION OF IMMUNITY IN VETERINARY MEDICINE;PROCEEDINGS OF A SYMPOSIUM, BETHESDA, MD., USA, SEPT. 19-20, 1983. XV+599P. ALAN R. LISS, INC.:, XP000937435 * |
MONTGOMERY, JOHN A.: "Chemistry and structure-activity studies of the nitrosoureas" CANCER TREAT. REP. (1976), 60(6), 651-64 , XP000934378 * |
SOOTS A ET AL: "PPROLONGATION OF RAT CARDIAC ALLO GRAFT SURVIVAL BY DONOR PRE TREATMENT SCREENING OF ANTI NEOPLASTIC DRUGS." TRANSPLANTATION (BALTIMORE), (1978) 25 (5), 259-264. , XP000934381 * |
Also Published As
Publication number | Publication date |
---|---|
WO2000038668A3 (en) | 2000-12-07 |
US20020151601A1 (en) | 2002-10-17 |
US6503948B2 (en) | 2003-01-07 |
CA2357977A1 (en) | 2000-07-06 |
EP1140060A2 (en) | 2001-10-10 |
AU2390100A (en) | 2000-07-31 |
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