U.S. patent application number 09/812094 was filed with the patent office on 2001-10-18 for viral treatment.
This patent application is currently assigned to The Procter & Gamble Company. Invention is credited to Camden, James Berger.
Application Number | 20010031773 09/812094 |
Document ID | / |
Family ID | 23079226 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031773 |
Kind Code |
A1 |
Camden, James Berger |
October 18, 2001 |
Viral treatment
Abstract
A pharmaceutical composition that inhibits or slows the growth
of viruses in animals, particularly in mammals, is disclosed. This
same composition is can be used to treat viral infections,
particularly hepatitis C, herpes simplex, Kaposi's sarcoma and HIV.
The composition preferably comprises from about 10 mg to about 6000
mg of a (5-aryl-1,2,4-thiadiazol- )-3-yl thiourea derivative or
(5-aryl-1,2,4-thiadiazol)-3-yl urea derivative of the formula: 1
wherein X is oxygen or sulfur, R is hydrogen or alkyl having from
1-3 carbons, n is 0-4, R.sub.1 is independently selected from the
group consisting of hydrogen, alkyl having from 1 to 7 carbon
atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the
formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 1 to 6, or a
pharmaceutically acceptable acid addition salt or prodrug thereof.
The preferred compound is (5-phenyl-1,2,4-thiadazol-3-yl)
thiourea.
Inventors: |
Camden, James Berger; (West
Chester, OH) |
Correspondence
Address: |
Rose Ann Dabek
The Procter & Gamble Company
Ivorydale Technical Center
5299 Spring Grove Avenue
Cincinnati
OH
45217
US
|
Assignee: |
The Procter & Gamble
Company
|
Family ID: |
23079226 |
Appl. No.: |
09/812094 |
Filed: |
March 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09812094 |
Mar 19, 2001 |
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09535172 |
Mar 27, 2000 |
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6258831 |
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09535172 |
Mar 27, 2000 |
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09281896 |
Mar 31, 1999 |
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Current U.S.
Class: |
514/361 ;
424/85.4; 514/263.31; 514/263.32 |
Current CPC
Class: |
A61K 38/21 20130101;
A61K 38/21 20130101; A61K 31/70 20130101; A61K 31/433 20130101;
A61K 31/70 20130101; A61P 31/20 20180101; A61P 35/00 20180101; A61K
45/06 20130101; A61P 31/18 20180101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61P 31/14 20180101; A61K 2300/00 20130101; A61K
31/52 20130101; A61P 31/10 20180101; A61K 31/52 20130101 |
Class at
Publication: |
514/361 ;
514/264; 424/85.4 |
International
Class: |
A61K 031/443; A61K
031/522; A61K 038/21 |
Claims
What is claimed is:
1. A method of treating viral infections comprising administering
to a patient in need thereof a therapeutically effective amount of
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivative having the formula:
6wherein X is oxygen or sulfur, R is hydrogen or alkyl having from
1-3 carbons, n is 0-4, R.sub.1 is independently selected from the
group consisting of hydrogen, alkyl having from 1 to 7 carbon
atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the
formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 1 to 6, or
the pharmaceutically acceptable acid addition salt or prodrugs
thereof.
2. A method of treating viral infections according to claim 1
wherein the virus is selected from the group consisting of HIV,
herpes simplex, hepatitis and Kaposi's sarcoma.
3. A method according to claim 2 wherein said viral infection is
hepatitis C or hepatitis B.
4. A method according to claim 3 wherein said viral infection is
HIV.
5. A method of treating HIV, herpes simplex or hepatitis according
to claim 2 comprising administering a therapeutically effective
amount of a pharmaceutical composition comprising
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea or the pharmaceutical
addition salt thereof or the prodrugs thereof.
6. A method according to claim 5 wherein said method comprises
administering to a patient in need thereof from about 1 mg/kg body
weight to about 10000 mg/kg body weight of said
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative.
7. A method according to claim 1 wherein said treatment comprises
administering a combination therapy with said
(5-aryl-1,2,4-thiadiazol)-3- -yl thiourea derivative or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivative.
8. A method according to claim 7 wherein said combination therapy
administration of a member selected from the group consisting of
AZT, TC-3, protease inhibitors, cyclovir, famciclovir,
valacyclovir, Ribavirin, interferon, combinations of Ribavirin, and
Interferon, beta globulin and a recombinant alpha interferon
9. A method according to claim 1 wherein said
(5-aryl-1,2,4-thiadiazol)-3-- yl thiourea is administered in a
solid form and wherein said solid form includes a carrier selected
from the group consisting of lactose, sucrose, gelatin and
agar.
10. A method according to claim 9 wherein from about 10 mg/kg body
weight to about 6000 mg/kg body weight of said
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea is administered.
11. A method according to claim 10 wherein said
(5-aryl-1,2,4-thiadiazol)-- 3-yl thiourea is administered in a
liquid form and wherein said liquid dosage form is selected from
the group consisting of aqueous solutions, alcohol solutions,
emulsions, suspensions, and suspensions reconstituted from
non-effervescent and effervescent preparations and suspensions in
pharmaceutically acceptable fats or oils.
12. A method of treating viral infections comprising administering
a therapeutically effective amount of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea having the formula:
7wherein X is sulfur, R is hydrogen, n is 0-4, R.sub.1 is
independently selected from the group consisting of hydrogen or
alkyl having from 1 to 7 carbon atoms or the prodrugs or
pharmaceutically acceptable addition salt thereof.
13. A method according to claim 12 wherein R.sub.1 is hydrogen and
n is 4 and R is hydrogen.
14. A method of treating viral infections according to claim 13
wherein the virus is selected from the group consisting of herpes
simplex, hepatitis and Kaposi's sarcoma.
15. A method of treating hepatitis C comprising administering a
therapeutically effective amount of a pharmaceutical composition
comprising (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea or the
pharmaceutical addition salt thereof.
16. A method according to claim 15 wherein said pharmaceutical
composition comprises from about 1 mg/kg to about 6000 mg/kg of
said (5-aryl-1,2,4-thiadiazol)-3-yl thiourea.
17. A method according to claim 16 wherein said method further
administration of a combination therapy wherein said combination
therapy comprises administration of a member selected from the
group consisting of cyclovir, famciclovir or valacyclovir,
Ribavirin, interferon or combinations of Ribavirin and Interferon
or beta globulin or mixtures thereof.
18. A method of treating herpes simplex comprising administering a
therapeutically effective amount of a pharmaceutical composition
comprising (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea or a
pharmaceutical addition salt thereof.
19. A method of treating fungal infections comprising administering
a therapeutically effective amount of composition having the
formula: 8wherein X is oxygen or sulfur, R is hydrogen or alkyl
having from 1-3 carbons, n is 0-4, R.sub.1 is independently
selected from the group consisting of hydrogen, alkyl having from 1
to 7 carbon atoms, chloro, bromo or fluoro, oxychloro, alkoxy
having the formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 1
to 6, or the pharmaceutically acceptable acid addition salt or
prodrugs thereof.
20. A method of treating fungal infections according to claim 20
wherein said pharmaceutical composition comprises
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea or the pharmaceutical
addition salt thereof.
21. A method of treating bovine diarrhea virus comprising
administering a therapeutically effective amount of composition
having the formula: 9wherein X is oxygen or sulfur, R is hydrogen
or alkyl having from 1-3 carbons, n is 0-4, R.sub.1 is
independently selected from the group consisting of hydrogen, alkyl
having from 1 to 7 carbon atoms, chloro, bromo or fluoro,
oxychloro, alkoxy having the formula --O(CH.sub.2).sub.yCH.sub.3
wherein y is from 1 to 6, or the pharmaceutically acceptable acid
addition salt or prodrugs thereof.
22. A pharmaceutical composition for treating viral infections
comprising a therapeutically effective amount of
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivative having the formula:
10wherein X is oxygen or sulfur, R is hydrogen or alkyl having from
1-3 carbons, n is 0-4, R.sub.1 is independently selected from the
group consisting of hydrogen, alkyl having from 1 to 7 carbon
atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the
formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 1 to 6, or
the pharmaceutically acceptable acid addition salt or prodrugs
thereof.
23. A pharmaceutical composition according to claim 23 comprising a
pharmaceutically acceptable carrier and from about 1 mg to about
6000 mg of (5-aryl-1,2,4-thiadiazol)-3-yl thiourea or its
pharmaceutical addition salt
24. A pharmaceutical composition according to claim 24 wherein said
pharmaceutical acceptable acid addition salt are selected from the
group consisting of chlorides, bromides, sulfates, nitrates,
phosphates, sulfonates, formates, tartrates. maleates, malates,
citrates, benzoates, salicylates, ascorbates and mixtures
thereof.
25. A pharmaceutical composition according to claim 25 comprising
from about 150 mg to about 5000 mg of said
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea.
26. A pharmaceutical composition according to claim 24 wherein said
composition further comprises a pharmaceutical carrier.
27. A pharmaceutical composition according to claim 27 which is in
a solid form comprising a carrier selected from the group
consisting of lactose, sucrose, gelatin and agar.
28. A pharmaceutical composition according to claim 28 in a liquid
form wherein said liquid dosage form is selected from the group
consisting of aqueous solutions, emulsions, suspension solutions,
and suspensions reconstituted from non-effervescent and
effervescent preparations.
29. A pharmaceutical composition according to claim 29 wherein said
liquid dosage form further comprises a member selected from the
group consisting of suspending agents, diluents, sweeteners,
flavorants, colorants, preservatives, emulsifying agents and
coloring agents, and mixtures thereof.
30. A method of treating HIV according to claim 1 comprising
administering a therapeutically effective amount of a
pharmaceutical composition comprising
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea or a pharmaceutical
addition salt thereof.
31. A method of treating herpes simplex according to claim 1
comprising administering a therapeutically effective amount of a
pharmaceutical composition comprising
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea or a pharmaceutical
addition salt thereof.
32. A method of treating hepatitis C according to claim 1
comprising administering a therapeutically effective amount of a
pharmaceutical composition comprising
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea or a pharmaceutical
addition salts thereof.
Description
[0001] This application is a continuation in part of application of
J. B. Camden, Ser. No. 09/281,896 filed Mar. 31, 1999.
TECHNICAL FIELD
[0002] This invention is a pharmaceutical composition that is
effective against the treatment of viruses. The composition can be
used to treat viral infections, notably hepatitis, including
hepatitis C virus (HCV) hepatitis B virus (HBV), human
immunodeficiency syndrome (HIV), and Kaposi sarcoma (HHV8). The
composition comprises one or more
(5-aryl-1,2,4-thiadiazol)-3-yl-urea or
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives. Method of
treating viral infections are also disclosed.
BACKGROUND OF THE INVENTION
[0003] HIV and other viral infections such as hepatitis are a few
of the leading causes of death. HIV is the virus known to cause
acquired immunodeficiency syndrome (AIDS) in humans. HIV is a
disease in which a virus is replicated in the body or in host
cells. The virus attacks the body's immune system.
[0004] Several drugs have been approved for treatment of this
devastating disease, including azidovudine (AZT), didanosine
(dideoxyinosine, ddI), d4T, zalcitabine (dideoxycytosine, ddC),
nevirapine, lamivudine (epivir, 3TC), saquinavir (Invirase),
ritonavir (Norvir), indinavir (Crixivan), and delavirdine
(Rescriptor). See M. I. Johnston & D. F. Hoth, Science,
260(5112), 1286-1293 (1993) and D. D. Richman, Science, 272(5270),
1886-1888 (1996). An AIDS vaccine (Salk's vaccine) has been tested
and several proteins which are chemokines from CD8 have been
discovered to act as HIV suppressors. In addition to the above
synthetic nucleoside analogs, proteins, and antibodies, several
plants and substances denved from plants have been found to have in
vitro anti-HIV activity. However, HIV virus is not easily destroyed
nor is there a good mechanism for keeping the host cells from
replicating the virus.
[0005] Thus, medical professionals continue to search for drugs
that can prevent HIV infections, treat HIV carriers to prevent
their disease from progressing to full-blown deadly AIDS, and to
treat the AIDS patient.
[0006] Herpes simplex virus (HSV) types 1 and 2 are persistent
viruses that commonly infect humans; they cause a variety of
troubling human diseases. HSV type 1 causes oral "fever blisters"
(recurrent herpes labialls), and HSV type 2 causes genital herpes,
which has become a major venereal disease in many parts of the
world. No fully satisfactory treatment for genital herpes currently
exists. In addition, although it is uncommon, HSV can also cause
encephalitis, a life-threatening infection of the brain. (The Merck
Manual, Holvey, Ed., 1972; Whitley, Herpes Simplex Viruses, In:
Virology, 2nd Ed., Raven Press (1990)). A most serious HSV-caused
disorder is dendritic keratitis, an eye infection that produces a
branched lesion of the cornea, which can in turn lead to permanent
scarring and loss of vision. Ocular infections with HSV are a major
cause of blindness. HSV is also a virus which is difficult, if not
impossible to cure.
[0007] Hepatitis is a disease of the human liver. It is manifested
with inflammation of the liver and is usually caused by viral
infections and sometimes from toxic agents. Hepatitis may progress
to liver cirrhosis, liver cancer, and eventually death. Several
viruses such as hepatitis A, B, C, D, E and G are known to cause
various types of viral hepatitis. Among them, HBV and HCV are the
most serious. HBV is a DNA virus with avirion size of 42 nm. HCV is
a RNA virus with a virion size of 30-60 nm. See D. S. Chen, J.
Formos. Med. Assoc., 95(1), 6-12 (1996).
[0008] Hepatitis C infects 4 to 5 times the number of people
infected with HIV. Hepatitis C is difficult to treat and it is
estimated that there are 500 million people infected with it
worldwide (about 15 time those infected with HIV). No effective
immunization is currently available, and hepatitis C can only be
controlled by other preventive measures such as improvement in
hygiene and sanitary conditions and interrupting the route of
transmission. At present, the only acceptable treatment for chronic
hepatitis C is interferon which requires at least six (6) months of
treatment and or ribavarin which can inhibit viral replication in
infected cells and also improve liver function in some people.
Treatment with interferon however has limited long term efficacy
with a response rate about 25%.
[0009] Hepatitis B virus infection can lead to a wide spectrum of
liver injury. Moreover, chronic hepatitis B infection has been
linked to the subsequent development of hepatocellular carcinoma, a
major cause of death. Current prevention of HBV infection is a
hepatitis B vaccination which is safe and effective. However,
vaccination is not effective in treating those already infected
(i.e., carriers and patients). Many drugs have been used in
treating chronic hepatitis B and none have been proven to be
effective, except interferon.
[0010] Treatment of HCV and HBV with interferon has limited success
and has frequently been associated with adverse side effects such
as fatigue, fever, chills, headache, myalgias, arthralgias, mild
alopecia, psychiatric effects and associated disorders, autoimmune
phenomena and associated disorders and thyroid dysfunction.
[0011] Because the interferon therapy has limited efficacy and
frequent adverse effects, a more effective regimen is needed.
[0012] In the present invention it has been discovered that the
compounds described above are useful for the treatment of hepatitis
C virus, hepatitis B virus, herpes simplex and the treatment of HIV
infection and other viral infections.
SUMMARY OF THE INVENTION
[0013] A pharmaceutical composition for administering to treating
animals, and in particular, warm blooded animals and humans,
infected with a virus. The composition comprises a therapeutically
effective amount of an anti-viral compound and optionally a
pharmaceutical carrier. The anti-viral compound is selected from
the group consisting of (5-aryl-1,2,4-thiadiazol)-3-yl thiourea
derivative or (5-aryl-1,2,4-thiadiazol)-3-yl urea derivative having
the formula: 2
[0014] wherein X is oxygen or sulfur, R is hydrogen or alkyl having
from 1-3 carbons, n is 0-4, R.sub.1 is independently selected from
the group consisting of hydrogen, alkyl having from 1 to 7 carbon
atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the
formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 1 to 6 or a
pharmaceutical addition salt or prodrug thereof.
[0015] Preferred anti-viral compositions comprise a therapeutically
effective amount of an anti-viral compound having the formula:
3
[0016] The compositions can be used to treat hepatitis C, hepatitis
B, herpes simplex and other viral infections.
[0017] More specifically, this invention provides an anti-viral
composition comprising a pharmaceutical carrier and a
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative or
(5-aryl-1,2,4-thiadiazol)-3-yl urea derivative as defined herein
along with a method for treating viral infections for example,
hepatitis C, hepatitis B, other hepatitis infections, HIV,
influenza, and rhinoviruses, Kaposi's sarcoma, herpes simplex, and
the like. The (5-aryl-1,2,4-thiadiazol)-3-yl thiourea or
corresponding urea derivatives are also fungicidal and can be used
to treat certain fungal infections. This same composition has
utility against some fungi, in particular those which are common in
HIV patients. Moreover the compounds are effective in the treatment
of Bovine Diarrhea Virus and can be used in veterinary treatment
for such disease.
[0018] The present invention also provides methods for the
treatment of HIV infection comprising administering to a host
infected with HIV a pharmaceutically or therapeutically effective
or acceptable amount of a compound as described above.
[0019] The present invention also comprises the use of a
combination therapy in the treatment of viral infections.
[0020] The compositions can be used in conjunction with other
treatments. The route of administration is the same as for other
medical treatments. The drug can be given daily or from 1 to 4
times a week.
DETAILED DESCRIPTION OF THE INVENTION
[0021] A. Definitions
[0022] As used herein, a "pharmaceutically acceptable" component is
one that is suitable for use with humans and/or animals without
undue adverse side effects (such as toxicity, irritation, and
allergic response) commensurate with a reasonable benefit/risk
ratio.
[0023] As used herein, the term "safe and effective amount" refers
to the quantity of a component which is sufficient to yield a
desired therapeutic response without undue adverse side effects
(such as toxicity, irritation, or allergic response) commensurate
with a reasonable benefit/risk ratio when used in the manner of
this invention.
[0024] As used herein, the term "therapeutically effective amount"
is meant an amount of a compound of the present invention effective
to yield the desired therapeutic response. For example to inhibit
HIV infection or treat the symptoms of infection in a host or an
amount effective to treat hepatitis. The specific therapeutically
effective amount will, obviously, vary with such factors as the
particular condition being treated, the physical condition of the
patient, the type of mammal or animal being treated, the duration
of the treatment, the nature of concurrent therapy (if any), and
the specific formulations employed and the structure of the
compounds or its derivatives.
[0025] As used herein, a "pharmaceutical addition salt" is a salt
of the arylthiazolyl thiourea or urea which are modified by making
an acid or base salt of the compounds. Examples of pharmaceutical
addition salts include, but are not limited to, mineral or organic
acid salt of basic residues such as amines, alkali or organic salt
of acidic residues such as carboxylic acids. Preferably the salts
are made using an organic or inorganic acid. These preferred acid
addition salts are chlorides, bromides, sulfates, nitrates,
phosphates, sulfonates, formates, tartrates, maleates, malates,
citrates, benzoates, salicylates, ascorbates, and the like.
[0026] As used herein, a "pharmaceutical carrier" is a
pharmaceutically acceptable solvent, suspending agent or vehicle
for delivering the anti-viral agent to the animal or human. The
carrier can be liquid or solid and is selected with the planned
manner of administration in mind.
[0027] As used herein, the terms "anti-viral compounds" are the
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadiazol)-3-yl urea derivative and the
pharmaceutical addition salts or prodrugs thereof. The preferred
anti-viral compound is 5-phenyl-3-thioureido-1,2,4-thiadiazole.
[0028] As used herein, the term "(5-aryl-1,2,4-thiadiazol)-3-yl
thiourea derivatives or "(5-aryl-1,2,4-thiadiazol)-3-yl urea
derivatives" or "aryl thiadiazolyl thiourea or urea derivatives"
includes compounds having the formula: 4
[0029] wherein X is oxygen or sulfur, R is hydrogen or alkyl having
from 1-3 carbons, n is 0-4, R.sub.1 is independently selected from
the group consisting of hydrogen, alkyl having from 1 to 7 carbon
atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the
formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 1 to 6 or its
pharmaceutical addition salt or its prodrug.
[0030] As used herein, "Alkyl" can be any branched, straight chain
or cyclic alkane or alkene generally having less than 8
carbons.
[0031] As used herein "Aryl" is any substituted phenyl compound and
including phenyl itself wherein R is hydrogen and n is 5.
[0032] As used herein, the term "Prodrugs" are considered to be any
covalently bonded carriers which release the active parent drug
according to the formula of derivatives described above in vivo
when such prodrug is administered to a mammalian subject or patient
in need of treatment. Prodrugs of the arylthiadiazolyl thiourea or
urea derivatives are prepared by modifying functional groups
present in the compounds in such a way that the modifications are
cleaved, either in routine manipulation or in vivo, to the parent
compounds. Prodrugs include compounds wherein free hydroxyl,
sulfhydryl, or amine groups are bonded to any group that, when
administered to a mammalian subject, cleaves to form a free
hydroxyl, amino, or sulfhydryl group, respectively. Examples of
prodrugs include, but are not limited to, acetate, formate, or
benzoate derivatives of alcohol and amine functional groups in the
arylthiazolyl thiourea derivatives or arylthiazoloyl urea
derivative; phosphate esters, dimethylglycine esters,
aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters
of alcohol and phenol functional groups or the, aminoalkylbenzyl
amides, aminoalkyl amides and carboxyalkyl amides of the amino
functional groups in the arylthiazolyl thiourea derivatives or
arylthiazoloyl urea derivative; and the like.
[0033] As used herein "viruses" includes viruses which infect
animals or mammals, including humans. Viruses includes HIV,
influenza, polio viruses, herpes simplex, hepatitis B, hepatitis C
and other viral strains of hepatitis, Kaposi's sarcoma,
rhinoviruses, and the like.
[0034] As used herein "combination therapy" means that the patient
in need of the drug is treated or given another drug for the
disease in conjunction with the arylthiazolyl thiourea or
arylthiazolyl urea derivatives. This combination therapy can be
sequential therapy where the patient is treated first with one or
more drugs and then the other, or two or more drugs are given
simultaneously.
[0035] B. The Anti-Viral Compounds
[0036] The anti-viral material is (5-aryl-1,2,4-thiadiazol)-3-yl
thiourea derivative or (5-aryl-1,2,4-thiadiazol)-3-yl urea
derivative or their pharmaceutical addition salt or prodrugs having
the formula: 5
[0037] wherein X is oxygen or sulfur, R is hydrogen or alkyl having
from 1-3 carbons, n is 0-4, R.sub.1 is independently selected from
the group consisting of hydrogen, alkyl having from 1 to 7 carbon
atoms, chloro, bromo or fluoro, oxychloro, alkoxy having the
formula --O(CH.sub.2).sub.yCH.sub.3 wherein y is from 0 to 6,
preferably from 2 to 4. Preferably the
(5-aryl-1,2,4-thiadiazol)-3-yl-urea or
(5-aryl-1,2,4-thiadiazol)-3-yl-thiourea derivative is substituted
with an alkyl of less than 4 carbons, a halogen, preferably a
chloro in the 7 or 8 position and the remaining substituents of the
benzene ring are hydrogen. The most preferred anti-viral is
(5-phenyl-1,2,4-thiadiazol)-3-- yl thiourea.
[0038] Pharmaceutical addition salt of the arylthiazolyl thiourea
or arylthiazolyl urea derivatives include the conventional
non-toxic salt or the quaternary ammonium salt of the arylthiazolyl
thiourea or arylthiazolyl urea derivatives formed, for example,
from non-toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from inorganic
acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,
phosphoric, nitric and the like; and the salts prepared from
organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like.
[0039] C. Synthesis
[0040] The arylthiazolyl thiourea or arylthiazolyl urea derivatives
can be prepared in a number of ways well known to one skilled in
the art of organic synthesis. The arylthiazolyl thiourea or
arylthiazolyl urea derivatives can be synthesized using the methods
described below, together with synthetic methods known in the art
of synthetic organic chemistry, or variations thereon as
appreciated by those skilled in the art. Preferred methods include
but are not limited to those methods described below. Each of the
references cited below are hereby incorporated herein by
reference.
[0041] The compounds can be synthesized by a desulphurization of
aromatic thioureas or urea compounds using hydrogen peroxide in
alkali or by reacting the corresponding
3-amino-5-aryl-1,2,4-thiadiazole with ethoxy carbonyl
isothiocyanate to produce the ethoxycarbonyl-3-(5'-aryl-1',2',4--
thiadiazol-3'-yl)thiourea or 3-(5'-aryl-1',2',4-thiadiazol-3'-yl)
urea which is then reacted with sodium hydroxide in ethanol and
then acidified.
[0042] (5-Phenyl-1,2,4-thiadizol)-3-yl thiourea is prepared by the
method described in Kurzer, et al, J. Chem. Soc. Perkin Trans.
1(2), 311-314 (1985) and Kurzer, et al. J. Heterocycl. Chem., 26
(2), 355-60 (1989).
[0043] (5-Phenyl-1,2,4-thiadizol)-3-yl thiourea can also be
prepared by the hydrolysis of
3-[N-benzoylthioureido]-5-phenyl-1,2,4-thiadiazole using 3 molar
potassium hydroxide at about 60.degree. C. The mixture is cooled,
and then acidified with concentrated hydrochloric acid.
Concentrated ammonium hydroxide is then used to basify the
resultant product. The material from this hydrolysis procedure is
pure (about 99%) and the yield is high.
[0044] The pharmaceutical addition salt of the present invention
can be synthesized from the arylthiazolyl thiourea or arylthiazolyl
urea derivatives which contain a basic or acidic moiety by
conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of these compounds
with a stoichiometric amount of the appropriate base or acid in
water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ethanol,
isopropanol, or acetonitrile are preferred. Lists of suitable salts
are found in Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of
which is hereby incorporated by reference. The disclosures of all
of the references cited herein are hereby incorporated herein by
reference in their entirety.
[0045] D. Dosage
[0046] The compounds can be administered in one dose, continuously
or intermittently throughout the course of treatment. Methods of
determining the most effective means and dosage of administration
are well known to those of skill in the art. The compounds can be
administered in one dose, continuously or intermittently throughout
the course of treatment. The compounds may also be given daily or
from 1 to 4 times a week. The compounds of the present invention
can be given in one or more doses on a daily basis or from one to
three times a week. Twice weekly dosing over a period of at least
several weeks is preferred. Often the anti-viral compounds will be
administered for extended periods of time and may be administered
for the lifetime of the patient. Methods of determining the most
effective means and dosage of administration are well known to
those of skill in the art. Single or multiple administrations can
be carried out with one dose level and pattern being selected by
the administrator.
[0047] The compounds are generally safe. The oral LD.sub.50 is
greater than 6000 mg/kg in mice and there are no special handling
requirements. By way of general guidance, a dosage of as little as
about 1 milligrams (mg) per kilogram (kg) of body weight and
preferably as little as 10 mg/kg and up to about 10,000 mg per kg
of body weight is suitable. Preferably from 10 mg/kg to about 5000
mg/kg of body weight is used. Most preferably the doses are between
250 mg/kg to about 5000 mg/kg. Generally, the dosage in man is
lower than for small warm blooded mammals such as mice. By way of
guidance the human dose is about {fraction (1/12)} that of mice.
Thus, if 25 mg/kg is effective in mice, a dose of 2 mg/kg would be
used for a 60 kg person, and a typical dosage would be 120 mg.
[0048] The dosage administered will, of course, vary depending upon
known factors, such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the age,
health and/or weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired.
[0049] E. Method of Administering and Dosage Delivery Forms
[0050] The compounds of the present invention can be administered
by any suitable means including, but not limited to, for example,
oral, rectal, nasal, topical (including transdermal, aerosol,
buccal and sublingual), vaginal, parenteral (including
subcutaneous, intramuscular, intravenous and intradermal),
intravesical or injection into or around the virus.
[0051] The dosage amounts are based on the effective inhibitory
concentrations observed in anti-viral studies. The preferred route
will vary with the (1) condition and age of the recipient, (2)
virus and being treated (3) nature of the infection and (4) desired
blood levels. It is believed that parenteral treatment by
intravenous, subcutaneous, or intramuscular application of the
compounds of the present invention formulated with an appropriate
carrier, other antiviral agents or compounds or diluents to
facilitate application will be the preferred method of
administering the compounds to warm blooded animals.
[0052] The (5-aryl-1,2,4-thiadizol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives are preferably
micronized or powdered so that it is more easily dispersed and
solubilized by the body. Processes for grinding or pulverizing
drugs are well known in the art. For example, a hammer mill or
similar milling device can be used. The preferred particle size is
less than about 100.mu. and preferably less than 50.mu.. These
compounds are not very soluble, and therefore are preferably given
in tablet form or as a suspension. Suitable methods of
administering the compounds of the present invention and dosage
forms can be found herein below.
[0053] The (5-aryl-1,2,4-thiadizol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives of this invention
can be administered as treatment for viral infections by any means
that produces contact of the active agent with the agent's site of
action in the body. They can be administered by any conventional
means available for use in conjunction with pharmaceuticals, either
as individual therapeutic agents or in a combination of
therapeutic. Preferably the compounds of the present invention are
administered as a pharmaceutical formulation comprising at least
one compound of the present invention, as defined above, together
with one or more pharmaceutically acceptable carriers. It can be
co-administered in the form of a tablet or capsule, as an
agglomerated powder or in a liquid form or as a liposome.
[0054] The compounds of the present invention may also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamallar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[0055] The (5-aryl-1,2,4-thiadizol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives of the present
invention can also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxylpropylmethacrylamide-phenol,
polyhydroxyethylaspartamidepheno- l, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds of the present invention can be coupled
to a class of biodegradable polymers useful in achieving controlled
release of a drug, for example, polylactic acid, polyglycolic acid,
copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked
or amphipathic block copolymers of hydrogels.
[0056] 1. Combination Therapy
[0057] The compounds of the present invention may additionally be
combined with other antiviral compounds to provide an operative
combination. It is intended to include any chemically compatible
combination of a compound of this inventive group with other
compounds of the inventive group or other compounds outside of the
inventive group, as long as the combination does not eliminate the
antiviral activity of the compound of this inventive group. For
example, one or more (5-aryl-1,2,4-thiadiazol)-- 3-yl thiourea
derivatives or (5-aryl-1,2,4-thiadizol)-3-yl urea derivatives can
be combined with other antiviral agents or potentiators.
Potentiators are materials which affect the body's response to the
anti-viral agent. In the case of HIV a combination therapy with
AZT, TC-3 or protease inhibitors is effective. In the case of
hepatitis, cyclovir, famciclovir or valacyclovir, Ribavirin,
interferon or combinations of Ribavirin and Interferon or beta
globulin is administered as a combination therapy. For herpes, a
recombinant alpha interferon can be used as a combination
therapy.
[0058] In some embodiments of the invention, a
(5-aryl-1,2,4-thiadiazol)-3- -yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives is used in
combination with one or more other therapeutic agents, such as
anti-inflammatory, anti-viral, anti-fungal, amoebicidal,
trichomonocidal, analgesic, anti-neoplastic, anti-hypertensives,
anti-microbial and/or steroid drugs, to treat antiviral infections.
In some preferred embodiments, viral infections are treated with a
combination of one or more (5-aryl-1,2,4-thiadiazol)-3-yl thiourea
derivatives or (5-aryl-1,2,4-thiadizol)-3-yl urea derivatives with
one or more of beta-lactam antibiotics, tetracyclines,
chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides,
nitrofurazone, nalidixic acid, cortisone, hydrocortisone,
betamethasone, dexamethasone, fluocortolone, prednisolone,
triamcinolone, indomethacin, sulindac, acyclovir, amantadine,
rimantadine, recombinant soluble CD4 (rsCD4), anti-receptor
antibodies (for rhinoviruses), nevirapine, cidofovir (Vistide.TM.),
trisodium phosphonoformate (Foscarnet.TM.), famcyclovir,
pencyclovir, valacyclovir, nucleic acid/replication inhibitors,
interferon, zidovudine (AZT, Retrovir.TM.), didanosine
(dideoxyinosine, ddI, Videx.TM.), stavudine (d4T, Zerit.TM.),
zalcitabine (dideoxycytosine, ddC, Hivid.TM.), nevirapine
(Viramune.TM.), lamivudine (Epivir.TM., 3TC), protease inhibitors,
saquinavir (Invirase.TM., Fortovase.TM.), ritonavir (Norvir.TM.),
nelfinavir (Viracept.TM.), efavirenz (Sustiva.TM.), abacavir
(Ziagen.TM.), amprenavir (Agenerase.TM.) indinavir (Crixivan.TM.),
ganciclovir, AzDU, delavirdine (Rescriptor.TM.), rifampin,
clathiromycin, erythropoietin, colony stimulating factors (G-CSF
and GM-CSF), non-nucleoside reverse transcriptase inhibitors,
nucleoside inhibitors, adriamycin, fluorouracil, methotrexate,
asparaginase and combinations thereof.
[0059] A "potentiator" can be any material which improves or
increase the efficacy of the pharmaceutical composition or acts as
an immunomodulator. One such potentiator is triprolidine and its
cis-isomer which is used in combination with more
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives and optionally
another therapeutic agent and or anti-viral agent. Triprolidine is
described in U.S. Pat. No. 5,114,951 (1992). Another potentiator is
procodazole, 1H-benzimidazole-2-propanoic acid;
[.beta.-(2-benzimidazole) propionic acid;
2-(2-carboxyethyl)benzimidazole; propazol]. Procodazole is a
non-specific immunoprotective agent against viral and bacterial
infections used with the compositions claimed herein. It is
effective with one or more (5-aryl-1,2,4-thiadiazol)-3-yl thiourea
derivatives or (5-aryl-1,2,4-thiadizol)-3-yl urea derivatives in
treating viral infections and can be combined with one or more
other therapeutic agents.
[0060] The combination therapy can be sequential, that is the
treatment with one agent first and then the second agent, or it can
be treatment with both agents at the same time. The sequential
therapy can be within a reasonable time after the completion of the
first therapy before beginning the second therapy. The treatment
with both agents at the same time can be in the same daily dose or
in separate doses. For example treatment with one agent on day 1
and the other on day 2. The exact regimen will depend on the
disease being treated, the severity of the infection and the
response to the treatment.
[0061] 2. Unit Dosage
[0062] The compounds of the present invention may administered in a
unit dosage form and may be prepared by any methods well known in
the art. Such methods include combining the compounds of the
present invention with a carrier or diluent which constitutes one
or more accessory ingredients. Typically, the formulations are
prepared by uniformly mixing the active ingredient with liquid
carriers or finely divided solid carriers or both, and then if
necessary shaping the product. A pharmaceutical carrier is selected
on the basis of the chosen route of administration and standard
pharmaceutical practice. Each carrier must be "acceptable" In the
sense of being compatible with the other ingredients of the
formulation and not injurious to the subject. This carrier can be a
solid or liquid and the type is generally chosen based on the type
of administration being used. Examples of suitable solid carriers
include lactose, sucrose, gelatin, agar and bulk powders. Examples
of suitable liquid carriers include water, pharmaceutically
acceptable fats and oils, alcohols or other organic solvents,
including esters, emulsions, syrups or elixirs. suspensions,
solutions and/or suspensions, and solution and or suspensions
reconstituted from non-effervescent granules and effervescent
preparations reconstituted from effervescent granules. Such liquid
carriers may contain, for example, suitable solvents,
preservatives, emulsifying agents, suspending agents, diluents,
sweeteners, thickeners, and melting agents. Preferred carriers are
edible oils, for example, corn or canola oils. Polyethylene
glycols, e.g. PEG, are also good carriers.
[0063] Dosage forms (compositions suitable for administration)
comprise from about 1 milligram to about 1000 milligrams of active
ingredient per dosage unit. Preferably the dosage forms will
contain from about 10 mg to about 500 mg. In these pharmaceutical
compositions the active ingredient will ordinarily be present in an
amount of about 0.5 to about 95% by weight based on the total
weight of the dosage unit.
[0064] 3. Pharmaceutical Kits
[0065] The present invention also includes pharmaceutical kits
useful, for example, for the treatment of hepatitis infection,
which comprise one or more containers containing a pharmaceutical
composition comprising a therapeutically effective amount of a
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives. Such kits can
further include, if desired, one or more of various conventional
pharmaceutical kit components, such as, for example, containers
with one or more pharmaceutically acceptable carriers, additional
containers, etc., as will be readily apparent to those skilled in
the art. Printed instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, can also be included in the kit. In the present
disclosure it should be understood that the specified materials and
conditions are important in practicing the invention but that
unspecified materials and conditions are not excluded so long as
they do not prevent the benefits of the invention from being
realized.
[0066] Specific examples of pharmaceutical acceptable carriers and
excipients that may be used to formulate oral dosage forms of the
present invention are described in U.S. Pat. No. 3,903,297 to
Robert, issued Sep. 2, 1975.
[0067] Techniques and compositions for making dosage forms useful
in the present invention are described herein below.
[0068] Oral formulations suitable for use in the practice of the
present invention include capsules, gels, cachets, tablets,
effervescent or non-effervescent powders or tablets, powders or
granules; as a solution or suspension in aqueous or non-aqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil
emulsion. The compounds of the present invention may also be
presented as a bolus, electuary or paste.
[0069] The formulations for oral administration may comprise a
non-toxic, pharmaceutically acceptable, inert carrier such as
lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol,
cyclodextrin and cyclodextrin derivatives and the like.
[0070] Capsule or tablets can be easily formulated and can be made
easy to swallow or chew. Tablets may contain suitable binders,
lubricants, diluents, disintegrating agents, coloring agents,
flavoring agents, flow-inducing agents, and melting agents. A
tablet may be made by compression or molding, optionally with one
or more additional ingredients. Compressed tables may be prepared
by compressing the active ingredient in a free flowing form (e.g.,
powder, granules) optionally mixed with a binder (e.g., gelatin,
hydroxypropylmethlcellose), lubricant, inert diluent, preservative,
disintegrant (e.g., sodium starch glycolate, cross-linked
carboxymethyl cellulose) surface-active or dispersing agent.
Suitable binders include starch, gelatin, natural sugars such as
glucose or beta-lactose, corn sweeteners, natural and synthetic
gums such as acacia, tragacanth, or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, and the like.
Lubricants used in these dosage forms include sodium oleate, sodium
stearate, magnesium stearate, sodium benzoate, sodium acetate,
sodium chloride, and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, xanthan gum,
and the like. Molded tablets may be made by molding in a suitable
machine a mixture of the powdered active ingredient moistened with
an inert liquid diluent.
[0071] The tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of the
active ingredient. Tablets may also optionally be provided with an
enteric coating to provide release in parts of the gut other than
the stomach.
[0072] Formulations suitable for topical administration in the
mouth wherein the active ingredient is dissolved or suspended in a
suitable carrier include lozenges which may comprise the active
ingredient in a flavored carrier, usually sucrose and acacia or
tragacanth; gelatin, glycerin, or sucrose and acacia; and
mouthwashes comprising the active ingredient in a suitable liquid
carrier.
[0073] Topical applications for administration according to the
method of the present invention include ointments, cream,
suspensions, lotions, powder, solutions, pastes, gels, spray,
aerosol or oil. Alternately, a formulation may comprise a
transdermal patch or dressing such as a bandage impregnated with an
active ingredient and optionally one or more carriers or diluents.
To be administered in the form of a transdermal delivery system,
the dosage administration will, of course, be continuous rather
than intermittent throughout the dosage regimen.
[0074] The topical formulations may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogues.
[0075] The oil phase of the emulsions of the composition used to
treat subjects in the present invention may be constituted from
known ingredients in a known manner. This phase may comprise one or
more emulsifiers. For example, the oily phase comprises at least
one emulsifier with a fat or an oil or with both a fat and an oil
or a hydrophilic emulsifier is included together with a lipophilic
emulsifier which acts as a stabilizer. Together, the emulsifier(s)
with or without stabilizer(s) make up an emulsifying was, and the
wax together with the oil and/or fat make up the emulsifying
ointment base which forms the oily dispersed phase of the cream
formulations.
[0076] Emulsifiers and emulsion stabilizers suitable for use in the
formulation include Tween 60, Span 80, cetosteryl alcohol, myristyl
alcohol, glyceryl monostearate and sodium lauryl sulphate,
paraffin, straight or branched chain. mono-or dibasic alkyl esters,
mineral oil. The choice of suitable oils or fats for the
formulation is based on achieving the desired cosmetic properties,
the properties required and compatibility with the active
ingredient.
[0077] The compounds may also be administered vaginally for
example, as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient.
Such carriers are known in the art.
[0078] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising, for example, cocoa
butter or a salicylate.
[0079] Formulations suitable for nasal administration may be
administered in a liquid form, for example, nasal spray, nasal
drops, or by aerosol administration by nebulizer, including aqueous
or oily solutions of the active ingredient. Formulations for nasal
administration, wherein the carrier is a solid, include a coarse
powder having a particle size, for example, of less than about 100
microns, preferably less than about 50 microns, which is
administered in the manner in which snuff is taken, i.e., by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose.
[0080] Formulations suitable for parenteral administration include
aqueous and non-aqueous isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending systems which are designed to target the
compound to blood components or one or more organs. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials. Extemporaneous
injections solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
[0081] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral administration
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or combined, are suitable stabilizing
agents. Also used are citric acid and its salts and sodium EDTA. In
addition, parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol. Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
[0082] Intravenously, the most preferred doses can range from about
1 to about 10 mg/kg/minute during a constant rate infusion.
(5-Aryl-1,2,4-thiadizol)-3-yl derivatives or
(5-aryl-1,2,4-thiadizol)-3-y- l urea derivatives can be
administered in a single daily dose, or the total daily dosage can
be administered in divided doses of two, three, or four times
daily. The (5-aryl-1,2,4-thiadizol)-3-yl-derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives can be given in one
or more doses on a daily basis or from one to three times a
week.
[0083] The present invention additionally include administering
compounds of the herein described formula for the use in the form
of veterinary formulations, which may be prepared, for example, by
methods that are conventional in the art.
[0084] Useful pharmaceutical dosage forms for administration of the
compounds of this invention are illustrated as follows:
[0085] Capsules
[0086] A large number of unit capsules are prepared by filling
standard two-piece hard gelatin capsules each with 100 milligrams
of powdered active ingredient, 150 milligrams of lactose, 50
milligrams of cellulose, and 6 milligrams magnesium stearate.
[0087] Soft Gelatin Capsules
[0088] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil is prepared and injected
by means of a positive displacement pump into gelatin to form soft
gelatin capsules containing 100 milligrams of the active
ingredient. The capsules are washed and dried.
[0089] Tablets
[0090] A large number of tablets are prepared by conventional
procedures so that the dosage unit was 100 milligrams of active
ingredient, 0.2 milligrams of colloidal silicon dioxide, 5
milligrams of magnesium stearate, 275 milligrams of
microcrystalline cellulose, 11 milligrams of starch and 98.8
milligrams of lactose. Appropriate coatings can be applied to
increase palatability or delay absorption.
[0091] Injectable
[0092] A parenteral composition suitable for administration by
injection is prepared by stirring 1.5% by weight of active
ingredient in 10% by volume propylene glycol and water. The
solution is made isotonic with sodium chloride and sterilized.
[0093] Liposomes can also be used for injectable compositions.
[0094] Suspension
[0095] An aqueous suspension is prepared for oral administration so
that each 5 ml contain 100 mg of finely divided active ingredient,
200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate,
1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin.
[0096] G. Method of Treatment
[0097] The method of treatment can be any suitable method which is
effective in the treatment of the particular virus or viral
infection that is being treated. Treatment includes administering a
therapeutically effective amount of the compounds of the present
invention in a form described herein above, to a subject in need of
treatment. As previously described, the composition can be
administered oral, rectal, topical, vaginally, nasally,
parenterally, intravenously and the like. The method of applying an
effective amount varies depending on the viral infection being
treated and the desired blood level. It is believed that parenteral
treatment by intravenous, subcutaneous, or intramuscular
application of (5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives
or (5-aryl-1,2,4-thiadizol)-3-yl urea derivatives, formulated with
an appropriate carrier, additional viral inhibiting compound or
compounds or diluent to facilitate application will be the
preferred method of administering the compounds to mammals or warm
blooded animals.
[0098] H. Test Methods
[0099] The Protease Inhibition Assay
[0100] Protease inhibition is evaluated using a fluorometric
method. Enzyme (Bachem) is diluted to 116 .mu.gm/ml in 50 mM NaOAC,
5 mM DTT, 2 mM EDTA, 10% glycerol (pH 5.0) and stored as 10 .mu.l
samples at -20.degree. C. HIV protease substrates I (Molecular
Probes) are diluted to a working concentration of 0.32
nmoles/.mu.l. Enzyme (20 .mu.l) and drug (20 .mu.l) are added to
each well of a microtiter plate as appropriate. Positive and
negative controls are evaluated in parallel. Fluorescence is
quantitated on Labsystems Fluroskan II using 355 nm/460 nm at
37.degree. C. at time zero and at 30 minute intervals for 2 hours.
In instances where auto-fluorescence precludes use of the
fluorometric, HIV-1 protease assay or confirmation of a result is
required, an HPLC based protease assay can be employed.
[0101] Integrase Inhibition Assay
[0102] A biochemical integrase assay described by Craigie et at
(HIV, vol. 2: A practical Approach) Biochemistry, Molecular Biology
and Drug Discovery, Ed. J. Karn 1995) to screen agents for their
ability to inhibit HIV-1 integrase can be used. In this system, a
kinased oligonucleotide serves as the target of 3' processing and
the subsequent strand transfer reaction. The 3' processing reaction
involves the removal of 2 nucleotides from the 3' ends of the
substrate. This is followed by the strand transfer reaction in
which the 3' ends are joined to the exposed 5' ends. The 20 .mu.l
reaction mixture contains 25 mM MOPS (pH 7.2), 100 g/ml BSA, 10 mM
.beta.-mercaptoethanol, 10% glycerol, 7.5 mM MnCl.sub.2, 25 nM (7
ng) substrate (Oligo's Etc., Wilsonville, Oreg.) and 200 nM (128
ng) integrase (NIAID AIDS Research and Reference Reagent Program,
Bethesda, Md.). The reaction proceeds at 37.degree. C. for 1-2
hours and is terminated by the addition of 20 .mu.l of sequencing
stop solution (USB Amersham, Arlington Heights, Ill.). The reaction
products are visualized by autoradiography following
electrophoresis in 15% polyacrylamide 6M Urea gel. The substrate
migrates as a 30 mer, the product of 3' processing migrates as an
N-2 band and the strand transfer products migrate more slowly at
various sizes larger than the substrate.
[0103] Toxicity Values
[0104] Toxicity quantification involves the XTT-based evaluation.
Assays were designed to characterize the long term effects of the
compounds on virus production and to characterize the longer term
effects of the compounds on virus production from chronically HIV
infected cells.
[0105] CEM-SS cells chronically infected with HIV isolate, for
example SKI (CEM-SKI) are cultured in RPM11640 tissue culture
medium supplemented with 10% fetal bovine serum and antibiotics.
Selection is performed by culturing the cells in the presence of
the compound to be tested in T25 flasks. CEM-SKI or other infected
cells with no added drug are used as the control cells.
[0106] Cells are allowed to grow to a density of approximately
1.times.106 cells/ml and are then passaged at a 1:10 dilution.
After a period of time, usually one week intervals of drug
treatment, cells are evaluated to determine if the inhibitory
activity of the compound has been affected by treatment of the
cells with either compound. The drug concentration in the flask is
then increased two-fold and the cells maintained as above.
[0107] The cell populations contain integrated copies of the HIV
genome and constitutively produce HIV at relatively high levels or
are latently infected and only produce virus after stimulation with
phorbol esters, tumor necrosis factor or IL6(U1 and ACH2).
Reductions in virus products were observed when quantifying
supernatant reverse transcriptase activity.
[0108] Reverse Transcriptase Inhibition Assay
[0109] A recombinant, purified HIV-1 reverse transcriptase (RT)
enzyme provided by Dr. Steven Hughes (ABL,NCI-FCRDC) is used.
Characterization of the RT inhibitory properties of selected test
compounds is performed utilizing a RT assay described by Boyer et
al (1993) with minor modifications. Briefly recombinant RT enzymes
are assayed in microtiter plates in a 100 ml reaction mixture
containing 25 mM Tris-HCl, pH 8.0, 75 mM KCL, 8 mM MgCl.sub.2, 2 mM
DTT, 10 mMdGTP, 0.01 U rC:dG template (Pharmacia), 10 mCi
[P.sup.32]-a-dGTP (800 Ci/mmol), and the test compound at indicated
concentrations.
[0110] The RT enzyme concentration employed in these assays ranged
from 0.4-0.9 mgm/ml for the different recombinant proteins; all the
RT enzymes reactions are allowed to proceed for 30 min at
37.degree. C. before termination of the enzyme reaction by addition
of 10% TCA; 100-mg of heat-denatured, sonicated salmon sperm DNA is
also added to aid DNA precipitation and recovery.
[0111] Upon termination of the enzyme reaction, the TCA
precipitated DNA is harvested onto glass fiber filters (GF/C),
washed twice with ice-cold 10% TCA and subjected to liquid
scintillation counting. To increase sample throughput and minimize
sample handling of this assay, a 96 well glass fiber filter plate
and vacuum manifold (Millpore) is used to harvest and wash the
DNA.
[0112] The labeled DNA samples are subsequently counted directly in
the multi-well plate by addition of 20 ml scintillation fluid
(OptiPhase Super Mix, Wallac) to each well and using a MicroBeta 96
well scintillation counter (Wallac).
EXAMPLE 1
Mechanism
[0113] The mechanism of action of the
(5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives or
(5-aryl-1,2,4-thiadizol)-3-yl urea derivatives is not known.
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea did not show activity as
a protease inhibitor method or as an integrase inhibitor. The
compound was screened using a fluorometric (protease inhibition
assay) and autoradiography (integrase inhibition assay).
[0114] These results are summarized in the following tables:
1 Concentration (nM) 0 1 10 100 1000 Protease Inhibition by 654021F
- a known protease inhibitor % no drug control 100.0 99.0 99.7 91.3
29.3 Protease Inhibition by (5-phenyl-1,2,4-thiadiazol)-3-yl
thiourea % no drug control 100.0 100.2 103.1 99.9 88.0
[0115] The EC.sub.50 value is >100 .mu.g/ml for
(5-phenyl-1,2,4-thiadia- zol)-3-yl thiourea and 0.699 .mu.M/ml for
654021.
[0116] The results of the test using the compounds of the present
invention are summarized as follows:
2 Concentration (.mu.g/ml) 0 0.1 1 10 100 HIV-1 Integrase
Inhibition by (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea % no drug
control 100.0 98.8 107.8 116.8 106.1 HIV-1 Integrase Inhibition by
TPX - a known integrase inhibitor % no drug control 100.0 86.1 26.8
31.2
[0117] The EC.sub.50 value is 0.648 .mu.M for TPX and >100
.mu.g/ml for (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea.
[0118] These tests demonstrate that the mechanism for the effective
activity against HIV is not as a protease inhibitor or as an
integrase inhibitor.
[0119] The following examples are illustrative and are not meant to
be limiting to the invention.
EXAMPLE 2
BVDV Testing
[0120] (5-Phenyl-1,2,4-thiadiazol)-3-yl thiourea was tested in
vitro against BVDV at a dose range of 316 .mu.g/ml to 0.011
.mu.g/ml and compared to Ribavirin at 0.032 .mu.M/ml to 10
.mu.M/ml. The solvent was DMSO (dimethylsulfoxide) and a control
test of DMSO was screened at a dose range of 1% to 0.00316%. The
Antiviral Index (AI) which is the TC.sub.50/IC.sub.50 is greater
than 4000. A second screening test using
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea had an AI of 1000.4. The
AI for Ribavirin at 50% is 2.25. DMSO had no effect, as
expected.
[0121] BVDV is a bovine diarrhea virus and is a well known
surrogate virus for hepatitis C which cannot be cultured in
vitro.
[0122] This test demonstrates the efficacy of
(5-phenyl-1,2,4-thiadiazol)-- 3-yl thiourea in treating hepatitis C
type viruses.
EXAMPLE 3
Herpes Simplex Testing
[0123] (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea was tested against
HSV-2MS, a herpes simplex virus -2 in vero cells and compared with
Acyclovir. The IC.sub.50 for Acyclovir is 0.81 and 0.85 in a
replicate study. The TC.sub.50, is >1 and the TI or therapeutic
index is >1.2. For (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea the
IC.sub.50 is 159.6 ,the TC.sub.50 is >200, the TI or therapeutic
index is >1.3.
[0124] This test demonstrates that phenyl thiadiazolyl thiourea
derivatives are effective in treating herpes simplex.
EXAMPLE 4
Kaposi's Sarcoma
[0125] (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea was tested against
Kaposi's Sarcoma, a herpes virus, in vitro using the HHV8 cell
line, TPA-induced BCBL-1 cells. The DNA copy number and the
toxicity value were measured and compared with Cidofovir.
3 Data for Cidofovir Conc. .mu.M 25 8 2.5 0.8 0.25 0.08 0 DNA Copy
Number (per 3 .mu.l) sample 1 0 8.9 1329.8 7521 6668.9 8485.1
8855.9 sample 2 0.0 0.0 1198.3 5985.4 6336.3 7948.1 9744.2 sample 3
0.0 0.0 1275.7 1819.5 6995.5 9000.8 8075.7 average 0.0 3.0 1276.9
5108.6 6666.9 8478.0 8891.9 % virus 0.0 0.0 14.3 57.5 75.0 95.3
100.0 control Toxicity Values sample 1 0.443 0.639 0.794 0.824
0.867 0.864 0.954 sample 2 0.398 0.700 0.684 0.770 0.819 0.797
0.924 sample 3 0.447 0.677 0.704 0.814 0.934 0.780 1.030 average
0.430 0.672 0.728 0.803 0.874 0.814 0.970 % cell 4403 69.3 75.0
82.8 90.1 83.9 100.0 control
[0126]
4 Data for (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea Conc. .mu.M
200 64 20 6.4 2 0.64 0 DNA Copy Number (per 3 .mu.l) sample 1 489.6
149.8 747.8 1003.5 1100.2 1200.5 1657.8 sample 2 163.7 1114.5 841.6
1084.5 1000.7 1258.4 1567.4 sample 3 578.7 994.6 991.2 1009.7
1189.7 1198.4 1398.4 average 410.7 753.0 860.2 1032.6 1096.9
12198.1 1541.2 % virus 26.6 48.9 55.8 67.0 71.2 79.1 100.0 control
Toxicity Values sample 1 0.215 0.539 1.060 0.901 0.941 0.983 0.914
sample 2 0.202 0.628 1.032 0.874 1.064 1.098 0.861 sample 3 0.201
0.407 0.939 0.986 1.027 0.935 0.864 average 0.206 0.525 1.011 0.921
1.011 1.006 0.880 % cell 23.4 59.7 114.8 104.6 114.9 114.3 100.0
control
[0127] IC.sub.50 .mu.M=56.8
[0128] TC.sub.50 .mu.M=100.3
[0129] TI=1.8
[0130] This screening test demonstrates the effectiveness of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against Kaposi's sarcoma,
a herpes virus.
EXAMPLE 5
Hepatitis
[0131] In an in vitro virus production test of hepatitis B, HEPG2
2.2.15 the following results were obtained with
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea.
5 Conc. .mu.g/ml 200 64 20 6.4 2 0.64 0 DNA Copy Number (per 3
.mu.l) sample 1 61.5 98.6 49.1 180.2 149.3 131.5 271.2 sample 2
20.5 76.0 54.6 46.7 20.3 155.2 244.0 sample 3 97.9 87.8 22.0 59.4
83.4 150.8 278.4 mean 60.0 87.5 41.9 95.4 84.3 145.8 284.5 % virus
control 22.7 33.1 15.8 36.1 31.9 55.1 100 Toxicity Values sample 1
0.800 0.973 0.909 1.015 0.916 1.079 1.133 sample 2 0.818 0.962
0.966 0.940 0.881 0.985 1.122 sample 3 0.928 1.037 0.921 1.218
0.959 0.999 1.065 mean 0.849 0.991 0.932 1.058 0.919 1.021 1.107 %
cell control 76.7 89.5 84.2 95.6 83.0 92.3 100.0
[0132] The IC.sub.50 is 0.94 .mu.g/ml: the TC.sub.50 is >200
.mu.g/ml and the therapeutic index or TI is 212.8.
[0133] In a replicate experiment, the IC.sub.50 is 0.76 .mu.g/ml;
the TC.sub.50 is >200 .mu.g/ml, and the TI is 263.2.
[0134] For comparison 3TC was tested and the following data were
obtained:
6 Conc. .mu.g/ml 1 0.32 0.1 0.032 0.01 0.0032 0 DNA Copy Number
(per 3 .mu.l) sample 1 6.0 36.7 73.0 192.6 286.1 265.4 308.6 sample
2 3.9 45.1 74.8 243.2 192.3 328.0 304.5 sample 3 2.1 56.5 60.5
255.3 276.7 247.9 246.8 mean 4.0 46.1 69.4 230.4 251.7 280.4 286.7
% virus control 1.4 13.1 24.2 80.4 87.8 97.8 100.0 Toxicity Values
sample 1 1.423 1.082 1.151 1.074 1.001 1.009 1.146 sample 2 1.256
1.207 1.220 1.153 1.081 1.173 1.249 sample 3 1.322 1.227 1.200
1.316 1.099 1.230 1.363 mean 1.334 1.172 1.190 1.181 1.060 1.137
1.253 % cell control 106.5 93.6 95.0 94.3 84.6 90.8 100.0
[0135] The IC.sub.50 is 0.089 .mu.g/ml; the TC.sub.50 is >1
.mu.g/ml and the TI is 14.6.
[0136] In a replicate experiment, the IC.sub.50 is 0.021 .mu.g/ml;
the TC.sub.50 is >1 .mu.g/ml and the TI is >47.6.
[0137] (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea can be used to
treat hepatitis B.
EXAMPLE 6
CEMRF
[0138] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against an HIV-1 cell
line, CEMRF was conducted at three different levels. The results
with CEMRF cells was reported at weekly intervals. The data is
summarized below.
7 CEMRF cell line Day 4 11 18 25 32 39 46 53 No Drug 4338 2847 3216
3843 2924 3084 2815 2113 7 .mu.g/ml 5423 2249 2951 3606 2655 2570
2952 2241 15 .mu.g/ml 6226 2530 3842 2647 2128 2104 1843 1958 30
.mu.g/ml 4659 1767 2369 1847 2008 659 924 1438
[0139] The CEMRF is a viral strain of the CEMSS cell line. This
test demonstrates the effectiveness of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea in treating HIV-1.
EXAMPLE 7
CEMIIIB
[0140] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against an HIV-1 cell
line, CEMIIIB was conducted at three different levels. The results
with CEMIIIB cells was reported at weekly intervals. The data is
summarized below.
8 CEMIIIB Day 4 11 18 25 32 39 46 53 No Drug 5665 7735 7184 5010
5452 7382 11423 11781 7 .mu.g/ml 4849 6658 7078 5221 5329 7349
11262 11286 15 .mu.g/ml 5078 5733 6057 4980 4273 6329 10361 9844 30
.mu.g/ml 5251 6200 6952 4110 3337 4233 9238 3527
[0141] The CEMIIIB is a viral strain of the CEMSS cell line.
EXAMPLE 8
CEMROD
[0142] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against an HIV-2 cell
line, CEMROD was conducted at three different levels. The results
with CEMROD cells was reported at weekly intervals. The data is
summarized below.
9 CEMROD Day 4 11 18 25 32 39 46 53 No Drug 7041 9468 11612 8853
8795 6947 8270 7233 7 .mu.g/ml 6593 8676 10912 9356 8803 6655 8280
7549 15 .mu.g/ml 6815 8202 10389 7816 6672 7087 6457 6544 30
.mu.g/ml 6626 6582 7494 4421 4056 2118 4117 4779
[0143] The CEMROD cell line is a viral strain of the CEMSS cell
line.
EXAMPLE 9
U937IIIB
[0144] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against an HIV-1 cell
line, U937IIIB was conducted at three different levels. The results
with U937IIIB cells were reported at weekly intervals. The data is
summarized below.
10 Day 4 11 18 25 32 39 46 53 No Drug 13419 11165 8246 6241 3286
5858 3861 4946 7 .mu.g/ml 9368 8889 7566 5781 3414 5346 4085 4832
15 .mu.g/ml 9710 8025 5435 6064 2479 4377 3867 3510 30 .mu.g/ml
9549 7639 3551 4611 1855 2410 1550 1819
[0145] The U937IIIB cell line is viral strain of the U937 cell
line.
EXAMPLE 10
U937RF
[0146] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against U937RF, a
protease resistant strain, was conducted at three different levels.
The results with U937RF cells were reported at weekly intervals.
The data is summarized below.
11 Day 4 11 18 25 32 39 46 53 No Drug 1522 1787 4849 6943 4331 5982
3061 5665 7 .mu.g/ml 1627 1526 4086 5303 4827 6008 3586 5726 15
.mu.g/ml 1575 1482 3772 2654 1594 3538 2426 3976 30 .mu.g/ml 1751
1237 2892 735 1035 1265 1358 2333
EXAMPLE 11
Protease Resistant HIV Strains
[0147] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against U937JE225R, a
protease resistant strain, was conducted at three different levels.
The results with U937JE225R cells was reported at weekly intervals.
The data is summarized below.
12 Day 4 11 18 25 32 39 46 53 No Drug 17369 13829 12419 10076 6887
11668 10289 10655 7 .mu.g/ml 12165 9465 10341 9079 6797 9792 9915
1094 15 .mu.g/ml 11151 9935 9738 7104 6426 10618 10471 9756 30
.mu.g/ml 12033 9859 11874 5281 4154 5379 5239 4423
[0148] Similar results are obtained with U937KN1272, a protease
resistant strain, reported below.
13 Day 4 11 18 25 32 39 46 53 No Drug 105239 80338 72031 62080
29644 46674 28686 35449 7 .mu.g/ml 119839 78089 74773 78997 31156
41326 31024 31209 15 .mu.g/ml 103341 80161 73939 74262 26305 28635
18073 22110 30 .mu.g/ml 114070 89087 72398 38006 6908 14779 5663
10534
EXAMPLE 12
HIV-2
[0149] An in vitro screening test of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against an HIV-2 virus,
CEMROD was performed.
[0150] The results of one test are shown below
Reverse Transcriptase Activity
[0151]
14 Conc. .mu.g/ml 0 0.32 1 3.2 1.0 32 100 sample 1 4752 4664 4005
4166 3001 1832 72 sample 2 4989 6972 4407 3318 3077 1550 48 sample
3 4709 4717 5392 3334 3547 1876 52 average 4817 5451 4601 3606 3208
1753 57 % virus 100 113.2 95.5 74.9 66.6 36.4 1.2 control
[0152]
15 Toxicity Values Conc. .mu.g/ml 0 0.32 1 3.2 1.0 32 100 sample
1.1039 1.181 1.055 0.987 0.871 0.518 0.113 1 sample 1.193 1.206
1.093 0.984 0.881 0.491 0.117 2 sample 1.202 1.203 1.066 0.965
0.921 0.517 0.115 3 average 1.178 1.197 1.071 0.979 0.891 0.509
0.115 % cell 100 101.6 90.9 83.1 75.6 43.2 9.8 control
EXAMPLE 13
HIV-1
[0153] A long term in vitro study of
(5-phenyl-1,2,4-thiadiazol)-3-yl thiourea against an HIV-1 cell
line, CEMSKI was conducted at three different levels. The results
with CEMSKI cells was reported at weekly intervals. The data is
summarized below.
16 CEMSKI cell line Day 4 11 18 25 32 39 46 53 No Drug 7041 9468
11612 8853 8795 6947 8270 7233 7 .mu.g/ml 6593 8676 10912 9356 8803
6655 8280 7549 15 .mu.g/ml 6815 8202 10389 7816 6672 7087 6457 6544
30 .mu.g/ml 6626 6582 7494 4421 4056 2118 4117 4779
[0154] This test was repeated and similar results were
obtained:
17 CEMSKI cell line Day 4 11 18 25 32 39 46 53 No Drug 7036 7735
8174 4516 3213 9070 14059 12904 7 .mu.g/ml 6224 6658 7207 5725 3161
9602 13984 11578 15 .mu.g/ml 5685 5733 6236 3752 2451 5526 12397
9662 30 .mu.g/ml 4789 5200 4821 2418 1651 3386 9353 6466
[0155] The CEMSKI cell like is a viral strain of the CEMSS cell
line.
EXAMPLE 14
Anti-fungal Activity
[0156] (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea was tested against
a number of fungi in vitro. It was active against Cryptococcus
neoformans and Curvularai lunata. The cidal activity for the C.
neoformans is high enough that it is clear static against this
yeast. This test was conducted using a method based upon NCCLS
reference method M-27A published in 1997. Solvent, medium and
growth controls were set-up with the tests. Once these were read to
validate the test performance, the QC fungi were read to insure
they had expected results. These steps validated the test system.
DMSO was used as a drug-chemical solvent. These test were read
following incubation at 35.degree. C. when the QC organisms
(Candida spp.) showed good growth. MIC values were concentration in
which growth was inhibited or reduced at least 90% in comparison to
the control growth. The 90% cut-off is necessary for azoles, which
are static and not cidal. The FMC or cidal level, was determined by
sub-culturing a sample form each tube showing no growth.
[0157] Curvularia lunata causes mycotic keratitis, sinus and deep
organ infections. It is opportunistic in immunocompromised
patients.
[0158] Cryptococcus neoformans is an opportunistic pathogen
involving the central nervous system in AIDS. It is a yeast having
protective polysaccharide capsule that is a basidiomycete.
[0159] The abbreviations used for the compounds are:
[0160] AmB is amphotericin B
[0161] Thia is thiabendazole
[0162] Methyl is methyl 1,2-benzmimidazole carbamate or benomyl
[0163] Itra is Itraconazole
[0164] Phth is (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea
18 MIC data (.mu.g/ml) Curvularia lunata Phth AmB Thia Methyl Itra
0.03 0.06 0.03 0.03 0.03
[0165]
19 MIC data (.mu.g/ml) Cryptococcus neoformans Phth AmB Thia Methyl
Itra 32 0.125 32 8 0.03
[0166]
20 MFC data (.mu.g/ml) Cryptococcus neoformans Phth AmB Thia Methyl
Itra 32 0.5 32 32 32
[0167]
21 MFC data (.mu.g/ml) Curvularia lunata Phth AmB Thia Methyl Itra
0.03 0.125 32 32 0.06
[0168] (5-phenyl-1,2,4-thiadiazol)-3-yl thiourea is effective
against these two fungi which are commonly found in AIDs patients.
These phenyl thiadiazolyl derivatives can be used to treat HIV and
to prevent the development of secondary fungal infections.
* * * * *