Note: Descriptions are shown in the official language in which they were submitted.
213~2QQ
Boehringer Mannheim Gmb~ ~ :
3685/00/WO -
New tricyclic thiazolo and thi~zino derivatives nnd
pharmaceutical agents containing them
The present invention concerns tricyclic thiazolo and
thiazino derivatives, processes for their production and
pharmaceutical agents that contain these compounds. ~ ~ ~
The invention concerns tricyclic thiazolo[3,2-c]- -
pyrimidine and thiazino[3,2-c]pyrimidine derivatives of
formula I
(I) ~
6,N ~ N~ ~ ~ :
X ^, . ~
,
in which
A represents a carbocyclic ring with 5 or 6 carbon
atoms or a heterocyclic ring with a maximum of 4
heteroatoms in which the heteroatoms can be the
same or different and denote oxygen, nitrogen or
sulphur and, if desired, the heterocycles can carry
an oxygen atom on one or several nitrogen atoms and
A is substituted, if desired, by one or several
, . , . ~. ~ ~ : .. - .
~, - :. : :
- :
. ~ . ,
... ~ 2134200
: ~
- 2 -
~ , .. '
residues R1 which can be the same or different,
X can be an oxygen or sulphur atom or the group =NH,
=N-cl-c6-alkyl or =S(0)2
R can be a straight-chained or branched, saturated or
unsaturated aliphatic residue with 1-9 C atoms
which can be substituted by phenyl or
it denotes a phenyl ring, .~
~ .~' ,'..
or it denotes a mono-, bi- or tricyclic carbocyclic :::
ring with 7-15 C atoms or a heterocyclic mono-, bi-
or tricyclic ring system with 5 or 6 ring atoms in
each case and can contain 1-4 or 1-5 heteroatoms
per ring system in which the heteroatoms are
nitrogen, sulphur or oxygen and the aforementioned
phenyl rings, the mono-, bi- or tricyclic
carbocyclic rings or the heterocyclic mono-, bi- or
tricyclic ring system is substituted, if desired,
once or several times by Cl-C6 alkyl, Cl-C6 alkoxy,
C1-C6 alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6
alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 -
alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy,
C2-C6 alkinylmercapto, amino, Cl-C6 alkylamino, di-
C1-C6 alkylamino, Cl-C6 alkylcarbonylamino, Cl-C6 ~-
alkylaminocarbonyl, Cl-C6 alkoxycarbonyl, hydroxy,
benzyloxy, phenylmercapto, phenyloxy, nitro, cyano,
halogen, trifluoromethyl, azido, formylamino,
carboxy or phenyl,
R1 denotes a hydrogen atom, a straight-chained or
- branched, saturated or unsaturated aliphatic -~ :- :
residue with 1-6 C atoms or Cl-C6 alkoxy, C1-C6 :: -~
: - ~ ~ .-: ~ .
' . ' '
-.. .. .
. ;, ,
~ ~'' '~'. ;' ' ' ' `'` `
`- ~13~2QO~ ~
- 3 -
, ~ :
alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6
alkylsulfonyl, amino, C1-C6 alkylamino, di-Cl-C6
alkylamino, sulfonamido, C1-C6 alkoxycarbonyl,
carboxy, halogen, hydroxy, nitro, cyano, azido, ~-
phenyl or benzyloxy,
R2, R3, R4 and R5 can, independently of each other, be
the same or different and each denote hydrogen, Cl-
C6 alkyl, C1-G6 hydroxyalkyl, cyano, carboxy or C1-
C6 alkoxycarbonyl or R2 and R4 can denote a further
bond between the C atoms to which they are bound,
R6 denotes hydrogen or C1-C6 alkyl,
n denotes 0, 1 or 2 and
~ ;
m denotes O or 1
as well as tautomers, enantiomers, diastereomers and
physiologically tolerated salts thereof.
,~
Compounds of similar structure (quinazoline derivatives)
are known as inhibitors of reverse transcriptase from
the earlier European Patent Application EP O 530 994. In ,
the examples 5C - 5F and 101 described therein oxazolo-
[3,2-c~pyrimidines which correspond to formula I are
described in particular in which A represents a
substituted phenyl ring and R represents a cyclopentyl,
cyclopropyl or phenyl ring or a propyl group. In --
comparison with these compounds the thiazolo[3,2-
c]pyrimidines (m=O) and thiazino[3,2-c]pyrimidines (m=1)
according to the invention exhibit an increased
pharmacological efficacy.
. :. . , : . . .
1'~.;"~ ~.
.:~ .. . . - . ,
,.,.:. :
.: . ; : . :
` ~13~00
- 4 -
The object of the present invention was to provide new `~
tricyclic thiazolo[3,2-c]pyrimidines and thiazino[3,2-c] ` ;
pyrimidines which can be used in particular as
pharmaceutically active substances for the production of
pharmaceutical agents.
The compounds of the present invention have valuable
pharmacological properties. In particular they have an
antiviral action and are suitable for the therapy and i~
prophylaxis of infections that are caused by DNA viruses
such as e.g. the herpes simplex virus, the cytomegaly
virus, papilloma viruses, the varicella-zoster virus or ~;
Epstein-Barr virus or RNA viruses such as togaviruses or
in particular retroviruses such as the oncoviruses HTLV-
I and II as well as the lentiviruses visna and the human
immunodeficiency viruses HIV-1 and 2.
The compounds of formula I appear to be particularly
suitable for the treatment of clinical manifestations of
retroviral HIV infections in humans such as persistent,
generalized lymphadenopathy (PGL), the advanced stage of
the AIDS-related complex (ARC) and the complete clinical
picture of AIDS.
The compounds according to the invention of the general
formula I have a pronounced antiviral action and are ~ `
particularly suitable for the treatment of viral and
retroviral infections. Viral infections of mammals, in
particular of humans, are widespread. Despite extensive
efforts it has previously not been possible to provide `~
chemotherapeutic agents which interfere causally or
symptcmatically with the viral or retroviral-dependent
pathological process with a discernible substantial
success. Nowadays it is not possible to heal certain
,~ ,." - : : ` '
~. . ,
. ` .
,
--- 213~200
- 5 -
viral diseases such as for example the acquired immune
deficiency syndrome (AIDS), the AIDS-related complex
(ARC) and early stages thereof, herpes, cytomegaly virus
(CMV), influenza virus and other viral infections or to
favourably influence their symptoms by chemotherapeutic ~ -
means. At present for example 3'-azido-3'-deoxy-
thymidine (AZT) known as Zidovudine or Retrovir~ is
almost all that is available for the treatment of AIDS.
However, AZT is characterized by a very narrow
therapeutic range and by very severe toxicities that
already occur in the therapeutic range (Hirsch, M.S.
(1988) J. Infec. Dis. 157, 427-431). The compounds of
the general formula I do not have these disadvantages.
They act antivirally without being cytotoxic in
pharmacologically-relevant doses.
It has now been possible to demonstrate that compounds '-`
of the general formula I inhibit ~he multiplication of
DNA and RNA viruses at the level of viral-specific DNA
and RNA transcription. The substances can influence the
multiplication of retroviruses by inhibiting the enzyme
reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA
83, 1911, 1986 and Nature 325, 773 1987).
Since there is a very great need for chemotherapeutic
agents which interfere as specifically as possible with
diseases caused by retroviruses or the symptoms thereof
without influencing the normal course of natural body
functions, the said compounds can be used to advantage
prophylactically or therapeutically in the treatment of
diseases in which a retroviral infection is of patho-
physiological, symptomatical or clinical relevance.
The compounds of formula I can be present as racemates
: : .. ~ . . ::
:, . . .
: : . . ,
.
213~%o
-- 6 --
or as optically active derivatives.
The separation of the racemates into enantiomers can be
carried out analytically, semi-preparatively and
preparatively by chromatography on suitable optically-
active phases using conventional eluting agents.
Suitable optically-active phases are for example
optically active polyacrylamides or polymethacrylamides,
some also on silica gel (e.g. ChiraSpher~ from Merck,
Chiralpak~ OT/OP from Baker), cellulose esters/
cellulose carbamates (e.g. Chiracel~ OB/OY from
Baker/Daicel), phases based on cyclodextrin or crown
ethers (e.g. Crownpak~ from Daicel) or microcrystalline -~
cellulose triacetate (Merck).
In the definition of A, A denotes a carbocyclic ring, in
particular a phenyl or cyclohexyl or cyclopentyl ring. ~ ~-
The anellated aromatic heterocyclic ring A has 5-6
carbon atoms in which up to 4 of these ring atoms can be
substituted by the heteroatoms oxygen, sulphur and/or
nitrogen. The following heterocycles are mentioned as
examples: the furan, thiophene, pyrrole, oxazole,
isoxazole, thiazole, pyrazole, imidazole, oxadiazole,
triazole, pyridine, pyridazine, pyrimidine or pyrazine
ring. If a nitrogen atom is present in the heterocyclic
ring A, the corresponding heterocycles can also be
present in the form of their N-oxides. The ring A can be
substituted by one or several, preferably one, two or
three residues Rl where the substituents R1 can be the
same or different.
An aliphatic residue R or Rl denotes a straight-chained
or branched alkyl, alkenyl or alkinyl residue with 1-9,
,.':; '' . :: . , : , ' .
;-' , :
,:' .. .: ::
. .:`::
~13~200
preferably 2-7 carbon atoms such as e.g. a propyl,
isopropyl, butyl, isobutyl, pentyl, hexyl or heptyl
residue. C2-C7 alkenyl and alkinyl residues come into
consideration as unsaturated residues, preferably C2-C
such as e.g. an allyl, dimethylallyl, butenyl,
isobutenyl, pentenyl or propinyl residue.
An aliphatic residue R which can be substituted by
phenyl is in particular a phenyl-C1-C6-alkyl group such
as e.g. a benzyl, phenethyl, phenylpropyl, or ;~
phenylbutyl residue.
If the residues R or Rl contain a phenyl ring, this can
then be substituted once, twice or three times. The
substitutents can, independently of one another, be in
the o, m or p position.
A carbocyclic ring R with 7-15 C atoms can be mono-, bi-
or tricyclic and have 5 or 6 C atoms per ring. This ring
can be saturated, unsaturated, partially saturated or
aromatic. The following ring systems are mentioned as
examples: a naphthyl, anthracenyl, phenanthrenyl,
fluorenyl, indenyl, indanyl, acenaphthylenyl, norbornyl,
adamantyl ring or a C3-C7 cycloalkyl or C5-C8
cycloalkenyl group. In addition the carbocyclic ring can
be mono- or disubstituted whereby in the case of phenyl
rings the substituents can, independently of one
another, be in the o or m position.
The heterocyclic mono-, bi- or tricyclic ring systems of
the residue R contain 5 or 6 carbon atoms per ring in
which 1-4 or 1-5 C atoms can be substituted by the
heteroatoms oxygen, sulphur and/or nitrogen. The ring
systems can be aromatic and partially or completely ;
,., :- ~ . : : :
2~342~
8 -
hydrogenated. The following ring systems are mentioned -
as examples: the pyridine, pyrimidine, pyridazine,
pyrazine, triazine, pyrrole, pyrazole, imidazole,
triazole, thiazole, oxazole, isoxazole, oxadiazole,
furazan, furan, thiophene, indole, quinoline,
isoquinoline, coumarone, thionaphthene, benzoxazole,
benzthiazole, indazole, benzimidazole, benztriazole, ~ ~-
chromene, phthalazine, quinazoline, quinoxaline,
methylenedioxybenzene, carbazole, acridine, phenoxazine,
phenothiazine, phenazine or purine system in which the
unsaturated or aromatic carbo and heterocycles can be
partially or completely hydrogenated. If these
heterocyclic rings contain a nitrogen atom, the ~;
corresponding heterocycles can also be present in the
form of their N-oxides. In addition the heterocyclic
ring system can be mono- or disubstituted in which case
the substitutents can, independently of one another,
preferably be in the o or m position.
R preferably denotes unsubstituted phenyl or phenyl
which is substituted once or twice by C1-C6 alkyl, C1-C
alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 ~ `
alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6
alkenyloxy, C1-C6 alkylamino, Cl-C6 dialkylamino, C1-C6 ` ```
alkylcarbonylamino, Cl-C6 alkylaminocarbonyl, C1-C6
alkoxycarbonyl, amino, hydroxy, nitro, azido,
trifluoromethyl, cyano or halogen in which the
aforementioned aliphatic residues preferably contain up -
to three carbon atoms.
Carbocyclic rings R are preferably biphenyl, naphthyl,
anthracenyl, indenyl, fluorenyl, acenaphthylenyl,
phenanthxenyl, norbornyl, adamantyl, C3-C6 cycloalkyl,
C5-C8 cycloalkenyl in which the carbocyclic rings can be ~-
substituted once or twice by Cl-C6 alkyl, Cl-C6 alkoxy, ~
~13 ~200
C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6
alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6
alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6
alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6
alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoro-
methyl, cyano or halogen in which the aforementioned
aliphatic residues preferably contain up to three carbon
atoms.
Heterocyclic ring systems are preferably pyrrole,
imidazole, furan, thiophene, pyridine, pyrimidine,
thiazole, triazine, indole, quinoline, isoquinoline,
coumarone, thionaphthene, benzimidazole, quinazoline,
methylenedioxybenzene, ethylenedioxybenzene, carbazole,
acridine and phenothiazine in which the heterocyclic
rings can be substituted once or twice by C1-C3 alkyl,
C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylsulfinyl,
C1-C3 alkylsulfonyl, C2-C4 alkenyl, C2-C3 alkinyl, C3-C4
alkenyloxy, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3
alkylcarbonylamino, C1-C3 alkylaminocarbonyl, C1-C3
alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoro-
methyl, cyano or halogen.
Hydrogen, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkinyl, C1-
C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylamino, C1-C
alkoxycarbonyl, amino, halogen, hydroxy, nitro, cyano
and azido are preferred for the residue R
Preferred substituents for R2, R3, R4 and R5 are -
hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, carboxy, C1-C
alkoxycarbonyl and cyano or when R2 and R4 form an ~ ~
additional bond. ~ -
X is preferably oxygen. Halogen is generally to be
': .` ` `
: , : ~ ::
~ ~.
21342~0
, .
- 10 ~
understood as fluorine, chlorine, bromine and iodine,
preferably fluorine, chlorine and bromine.
Preferred anellated heterocycles A are aromatic rings
containing nitrogen with 5 or 6 ring atoms.
Preferred residues for R are C3-C5 alkyl, C2-C5 alkenyl, ;~
C2-C4 alkinyl, benzyl, phenethyl, phenyl, phenyl which
is mono or disubstituted by C1-C3 alkylr Cl-C3 alkoxy, ;~
C1-C3 alkylmercaptor allylr allyloxyr C1-C3 alkylamino
di-Cl-C3-alkylaminor aminor hydroxyr azidor trifluoro-
methylr cyano or halogenr or phenylr naphthylr
anthracenyl, indenylr acenaphthylenylr phenanthrenyl
adamantylr cyclohexylr cyclohexenylr furylr thienylr ~ -
pyridyl, pyrimidinylr thiazolylr indolylr quinolinyl
benzimidazolylr methylenedioxyphenylr carbazolyl and -
phenothiazinyl trisubstituted by methyl or halogenr and
derivatives of the aforementioned carbocylic or
heterocyclic rings which are mono- or disubstituted by ~ ~
methyl or halogen. ~ -
.
Hydrogen, methylr ethylr isopropylr allylr methoxy
ethoxyl methylmercaptor ethylmercaptor methylaminor ~ ~-
methoxycarbonylr ethoxycarbonylr aminor azidor cyano
hydroxy and halogen are particularly preferred for Rl
wherein chlorine and bromine preferably come into
consideration as the halogen.
Hydrogenr methylr ethylr isopropyl and cyano are
particularly preferred for R2r R3r R4 and R5 or when R2 -
and R4 denote an additional bond. Those compounds of
formula I come particularly into consideration in which
R2 and R4 simultaneously denote hydrogen.
:: .
2134200
-- 1 1 --
Aromatic rings such as e.g. the phenyl, pyrrole,
oxazole, thiophene, furan, isoxazole, thiazole,
imidazole, pyridine, pyridazine, pyrimidine and pyrazine
ring are particularly preferred for A. If A represents a
carbocyclic or heterocyclic six-membered ring, those
compounds are especially preferred which in relation to
the nitrogen atom that is directly bound to the six~
membered ring of the condensed pyrimidine ring are -
substituted in the para position of the six-membered -~
ring (position 9 of the tricyclic ring system).
Especially preferred are compounds of the general
formula I in which R, R1, X, n and m have the meanings
stated above and R2, R3, R4 and R5 are hydrogen, methyl
or ethyl, in which three or four of the residues R2 to
R5 are preferably hydrogen or R2 and R4 together
represent a bond.
Hydrogen and C1-C3 alkyl are particularly preferred for
R6. o is particularly preferred for n and m.
Compounds of formula I in which R1 is a hydrogen or
halogen atom, in particular a chlorine atom, A is a
phenyl or pyridine ring which is preferably substituted
by R1 at the 9 position of the tricyclic ring system, -~
have a particularly well-pronounced pharmacological
action. In this connection those compounds of formula I
are particularly preferred in which R2-R5 denote a
hydrogen atom, m and n denote the number O and X denotes
an oxygen or sulphur atom.
The pharmaceutical agents contain at least one compound
of formula I for the treatment of viral infections and
can be administered enterally or parenterally in a
~"``' ` ~
' : '
.:
2 1 3 4 2 0 0
- 12 -
' : ~,
liquid or solid form. The usual forms of administration
such as for example tablets, capsules, coated tablets,
syrups, solutions or suspensions come into consideration ;~
as pharmaceutical forms of administration. Water is ;~
preferably used as an injection medium which contains
the usual additives for injection solutions such as
stabilizing agents, solubilizers and buffers. Such
additives are for example tartrate and citrate buffer,
ethanol, complexing agents such as ethylenediamine-
tetraacetic acid and non-toxic salts thereof and high -
molecular polymers such as li~uid polyethylene oxide to
regulate viscosity. Liquid carrier substances for
injection solutions must be sterile and are preferably
dispensed into ampoulesO Solid carrier substances are -
for example starch, lactose, mannitol, methylcsllulose,
talcum, highly dispersed silicic acids, higher molecular ;~
fatty acids such as stearic acid, gelatins, agar-agar,
calcium phosphate, magnesium stearate, animal and ~- -
vegetable fats, solid high molecular polymers such as
polyethylene glycols etc... Suitable formulations for -`~
oral administration can if desired, contain flavourings
and sweeteners. `~
' ~: '''`',-`
The dosage can depend on various factors such as mode of
application, species, age or individual condition. The
compounds according to the invention are usually
administered in amounts of 0.1 - 100 mg, preferably 0.2
- 80 mg per day and per kg body weight. It is preferable `~-
to divide the daily dose into 2-5 administrations, 1-2 ~ ~ `
tablets with a content of active substance of 0.5 -
500 mg being administered at each administration. The -~
tablets can also be retarded thus reducing the number of
administrations to 1-3 per day. The content of active
substance of the retarded tablets can be 2 - 1000 mg.
The active substance can also be administered by -`
-, i., ., ,. . . :
:: : ::, : - . :
:, : :, ::
'' ~ ;
, ~ ~
213~200
.
- 13 -
continuous infusion in which case amounts of 5 - 1000 mg -~
per day are usually adequate.
The compounds of the present invention and
pharmaceutical preparations thereof can also be used in
combination with other pharmaceutical agents for the ~ -~
treatment and prophylaxis of the infections mentioned
above. Examples of these further agents containing other
pharmaceutical agents which can be used for the
treatment and prophylaxis of HIV infections and ~ -
illnesses which accompany this disease are 3'-azido-3~
deoxyth,vmidine, 2,3'-dideoxynucleosides such as e.g. ;~ ~ -
2',3'-dideoxycytidine, 2',3'-dideoxyadenosine and 2',3'- -
dideoxyinosine or acyclic nucleosides (e.g. Acyclovir).
The compounds of the present invention and the other
pharmaceutical agent can in each case be administered
individually, simultaneously, if desired in a single or ,
two separate formulations or at different times so that
a synergistic effect is achieved.
The compounds of the general formula I according to the
invention are produced according to methods known in the
literature (Chem. Pharm. Bull. 29, 2135, 1981 or `~-~
Heterocycles 29, 1317, 1989), by reacting compounds of - `-
the general formula II
Rl ~ R ~ -
~=0
(II) --~
R~ ~ R
O
. ...
: . ~
. - , , ~ . , . .' .
. . ~
2134200
- 14 -
in which A, R, Rl and R6 have the meaning stated above
and R7 denotes a readily cleavable group such as CCl3,
CF3, oR3 or NR8R9 where R8 and R9 can be the same or
different and can for example denote Cl-C6 alkyl or
substituted or unsubstituted phenyl, phenylalkyl,
hetaryl or hetarylalkyl, with a substituted or
unsubstituted cysteamine or 3-mercapto-1-propanamine of
the general formula III
HS R2
R3 III
H2N ( ~ ~ R `~
m RS
in which R2, R3, R4, R5 and m have the meaning stated
above, in a suitable inert solvent at room temperature
to reflux temperature, possibly in the presence of
catalytic amounts of an acid such as p-toluenesulfonic
acid or a base e.g. potassium hydroxide and if desired,
compounds of formula I are subsequently converted into
other compounds of formula I and subsequently purified
by chromatography or by recrystallization. Racemates can
be separated into the antipodes by chromatography on
suitable optically active phases e.g. cellulose
triacetate.
The subsequent conversions of compounds of formula I
into other compounds of formula I concerns for example
the production of tricyclic thiazolo[3,2-c]pyrimidine
and thiazino[3,2-c]pyrimidine derivatives in which X=S.
., . ~, . .. ~ - .
, ~ .
:
~:. ~; ..... - . . . ..
~121~Q
- 15 -
,:
Compounds in which X=S are produced by reacting
compounds of formula I in which X denotes an oxygen atom
with compounds carrying sulphur groups such as e.g. ~
Lawesson's reagent. ~ -
. . :~,~''.
Compounds of the general formula I in which X=NH are
produced by converting compounds of formula I in which X
denotes an oxygen atom by firstly producing the -~
chlorimine using a chlorination reagent such as e.g.
POCl3 and treating this with ammonia.
Compounds of the general formula I in which R2 and R4
denote an additional bond are produced in a Pummerer
reaction by reacting compounds of the general formula I
in which n = 1 with an anhydride in an inert solvent -
while heating if necessary, or compounds of the general
formula I in which R2, R3, R4 or R5 denote a hydroxy~
methyl residue esterified with a carboxylic acid such as
e.g. acetic acid or a sulfonic acid such as e.g.
. . ..
toluenesulfonic acid, are heated to 50-200C under
pressure if necessary in an inert solvent in the
presence of a base such as imidazole or sodium
.: . -- . -:
hydroxide. -~
: ' ,: -, . .:'.
The compounds of the general formula II used as the ~ -
starting material are obtained from aminobenzophenone
derivatives according to methods known in the literature
by acylation. The substituted or unsubstituted 2-amino-
benzophenone derivatives can be preferably produced
according to the method described by David A. Walsh ;
(Synthesis, 677, 1980).
In addition to the compounds mentioned in the examples -
and compounds derived by combination of all meanings of
,: , ... ... . . . : . , -
.: ~ ' - ~ . , ', ' ' . ' :' .
.
~13~200
- 16 -
the substituents stated in the claims, the following
compounds of formula I come into consideration within
the scope of the present invention which can be present
as racemic mixtures or in an optically-active form or as :: ~:
pure R and S enantiomers~
1. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-
quinazolin-5-one
2. lOb-Phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]- ~ .
quinazolin-5-thione ~ .
3. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-
quinazolin-5-imine `
4. 6-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
5. 9-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H- -"~
thiazolo[3,2-c]quinazolin-5-one :~
6. 9-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
7. 9-Methoxy-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
. .
8. 10-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
9. 10-Nitro-lOb-phenyl-2,3,6,10b-tetrahydro-5H- .~ .
thiazolo[3,2-c]quinazolin-5-one
: :: ~: : ,
- . -
.
.:: . :,
,
~ :.
~13-~200
- 1
10. 7-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H~
thiazolo[3,2-c]quinazolin-5-one .:
11. 8-Methyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
'''~;''; ;'''".'".'''''`'
12. lOb-(3-Methylphenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
13. lOb-(3-Chlorophenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one ~ --
, . ,,, .: - ~
14. lOb-(4-Methoxyphenyl)-2,3,6,10b-tetrahydro-5H-
thiazoio[3,2-c]quinazolin-5-one .~
15. lOb-(2,3-Dimethylphenyl)-2,3,6,10b-tetrahydro-5H- ~ .
thiazolo[3,2-c]quinazolin-5-one
16. lOb-(3,5-Dimethylphenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one -~
.::
17. lOb-(l-Naphthyl)-2,3,6,10b-tetrahydro-5H-thiazolo- -~
[3,2-c]quinazolin-5-one ; ~--
18. lOb-(4-Indanyl)-2,3,6,10b-tetrahydro-5H-thiazolo- ;~
[3,2-c]quinazolin-5-one
19. lOb-(2-Amino-5-methylphenyl)-2,3,6,10b-tetrahydro-
5H-thiazolo[3,2-c]quinazolin-5-one - .
20. lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one `
' ' ~. " ' ' ' . , ''
- 213~QQ
- 18 -
21. lOb-(4-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
22. lOb-Thienyl-2,3,6,10b-tetrahydro-5H-thiazolo
[3,2-c]quinazolin-5-one ,~
"";"'
23. lOb-Furanyl-2,3,6,10b-tetrahydro-5H-thiazolo -.
[3,2-c]quinazolin-5-one
'~
24. llb-Phenyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]~
thiazino[3,2-c~quinazolin-6-one
,;". .
25. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-
pyrido[2,3-e]pyrimidin-5-one ~--
26. lOb-(3-Methylphenyl)-2,3,6,1Ob-tetrahydro-5H-
thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one
27. lOb-(3-Chlorophenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one
28. lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one
29. lOb-(4-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H- ~-
thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one
30. 3-Ethoxycarbonyl-lOb-phenyl-2,3,6,1Ob-tetrahydro-
5H-thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one
31. 3-Hydroxymethyl-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one
~: .
.~, , .
21342~0 ~
- 19 - '
32. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-
pyrido-[3,4-e]pyrimidin-5-one
33. lOb-(3-Ethylphenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]pyrido[3,4-e]pyrimidin-5-one
" '.,,~' ~'':.','':
34. lOb-(3-Nitrophenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]pyrido[3,4-e]pyrimidin-5-one
35. lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]pyrido[3,4-e]pyrimidin-5-one
36. lOb-Methyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]-
pyrido[3,4-e]pyrimidin-5-one
' ~ ,~:''
37. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]-
thieno[2,3-e]pyrimidin-5-one
38. 9b-(3-Methylphenyl)-2,3,6,9b-tetrahydro-5H-
thiazolo[3,2-c]thieno[2,3-e]pyrimidin-5-one
39. 9b-(3,5-Dichlorophenyl)-2,3,6,9b-tetrahydro-5H-
thiazolo[3,2-c]thieno[2,3-e]pyrimidin-5-one ~ :~
40. 9b-Phenyl-2,3,6,9b-tetrahydro-5H-thiazolo[3,2-c]- :~
furano[2,3-e]pyrimidin-5-one
41. 9b-(4-Methyl-2-pyridyl)-2,3,6,9b-tetrahydro-5H-
thiazolo[3,2-c]furano[2,3-e]pyrimidin-5-one -.
42. lOb-Phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]-
quinazolin-5-one-1-oxide -
::
`` 213~200
- 20 -
43. lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo[3,2-c]- ;~;
quinazolin-5-one-1,1-dioxide
44. lOb-Phenyl-6,10-dihydro-5H-thiazolo[3,2-c]~
quinazolin-5-one
45. lOb-(3-Methylphenyl)-6,10-dihydro-5H-thiazolo-
[3,2-c]-quinazolin-5-one -~
46. 3-Methyl-lOb-phenyl-6,10-dihydro-5H-thiazolo-
[3,2-c]-quinazolin-5-one
47. lOb-(3-Methylphenyl)-6,10-dihydro-5H-thiazolo-
[3,2-c]pyrido[2,3-e]pyrimidin-5-one
48. 3-Methyl-lOb-(3-methylphenyl)-6,10-dihydro-5H-
thiazolo[3,2-c]pyrido[2,3-e]pyrimidin-5-one ~
' :
Example
~............................................... ~:
lOb-Phenyl-2,3,6,1~-tetrahydro-5H-thiazolo-
[3,2-c]quinazo~ -5-one
., ... -
a) 5.8 ml (60.8 mmol) ethyl chloroformate in 25 ml
toluene is added dropwise while stirring at 10C to -
10 g (50.7 mmol) 2-aminobenzophenone in 125 ml
toluene and 4.9 ml pyridine. After one hour the
mixture is shaken three times with water, the ` ~-
organic phase is separated, dried and evaporated.
The oil obtained is triturated with isohexane and
the crystals are suction filtered.
, : ~ :
' .
2 1 3 ~ 2 0 0
- 21 -
12.3 g 2-ethoxycarbonylaminobenzophenone of melting
point 73-75C is obtained. --
b) 5 g (18.6 mmol) 2-ethoxycarbonylaminobenzophenone, ;
2.9 g (37.1 mmol) cysteamine and 0.5 g p-toluene~
sulfonic acid are heated in 100 ml dimethyl-
formamide (DMF) to 140C for 52 hours under
nitrogen. Subsequently the DMF is removed by
distillation, the residue is dissolved in water and
extracted twice by shaking with dichloromethane.
The organic phase is dried, evaporated and the ~ -
residue is chromatographed over silica gel (mobile
solvent: isohexane:ethyl acetate, 7:3). Evaporating
the desired fractions and recrystallizing the
residue from ethanol yields 3.5 g of the title
compound of m.p. 212-215C.
~xample 2
llb-Phenyl-3,4,7,11b-tetrahydro-2H,6H-[1,3]thiazino-
[3,2-c]quinazolin-6-one
5 g (18.6 mmol) 2-ethoxycarbonylaminobenzophenone (from
example la), 3.4 g (37.1 mmol) 3-mercapto-1-propanamine
and 0.5 g p-toluenesulfonic acid are heated in 100 ml
dimethylformamide (DMF) to 140C for 52 hours under
nitrogen. Subsequently the DMF is removed by
distillation, the residue is dissolved in water and
extracted twice by shaking with dichloromethane. The
organic phase is dried, evaporated and the residue is i -~
chromatographed over silica gel (mobile solvent:
isohexane:ethyl acetate, 7:3). Evaporating the desired -
fractions and recrystallizing the residue from ethanol
yields 3.2 g of the title compound of m.p. 240-243C.
,:. ; . i .
,. ,. ~ . ,
2 1 3 4 2 0 0
- 22 -
Example 3
3-Hydroxymethyl-lOb-phenyl-2,3,6,10-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one
a) 10 g (50.7 mmol) 2-aminobenzophenone is reacted
with 8.6 g (55 mmol) phenyl chloroformate
analogously to example 1 a. After processing and
triturating with isohexane, 15.6 g 2-phenoxy-
carbonylaminobenzophenone of m.p.115-117C is
obtained. -
.~ '
b) 22.19 g (70 mmol) 2-Phenoxycarbonylaminobenzo-
phenone, 22 g (210 mmol) cysteinol and 2.2 g p-
toluenesulfonic acid were refluxed in 500 ml
toluene for 24 hours under nitrogen. Subsequently
the toluene was removed by distillation and the oil
was purified by column chromatography (mobile
solvent: ethyl acetate/toluene = 80:20). The pooled
fractions of the desired substance were
concentrated by evaporation and the residue was
crystallized from toluene. 3.5 g of the title
compound of m.p. 188-190C is obtained.
Exam~le 4 -; -~
9-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H-thiazolo-
[3,2-c]quinazolin-5-one
In analogy to example 3 b 3.0 g (8.5 mmol) 2-phenoxy-
carbonylamino-5-chlorobenzophenone, 1.3 g (17 mmol)
cysteamine and 0.3 g p-toluenesulfonic acid in 150 ml
toluene were boiled for 4 hours in a water separator.
.. - . .
. - , . .
-,~ -
, :
;.. - . . .
::: . .
.. ~: . . .
2134200
- 23 - ~ ~
''~ ' '' ~ ''
The toluene phase was shaken with 2 N hydrochloric acid
and sodium carbonate solution, concentrated by
evaporation and the residue was crystallized from
ethanol. 2.1 g of the title compound of m.p. 187-194C
is obtained.
Ex~mple S
The following compounds are obtained analogously to
example 4:
';
5 a) 10-Chloro-lOb-phenyl-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one of m.p. 264-265C
from ethanol
5 b) lOb-(3-Methylphenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one of m.p. 236-240C -
from ethanol
~ ': .' .'
5 c) lOb-(3-Chlorophenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one of m.p. 226-227C
from ethanol
5 d) lOb-(3,5-Dimethylphenyl)-2,3,6,1Ob-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one of m.p. 243-256C
from ethanol
. .
5 e) lOb-(3,5-Dichlorophenyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one of m.p. 260-261C
from ethanol
~; :
1 3 ~ 2 0 0 ~ ~ ,
- 24 -
5 f) lOb-(6-Methyl-2-pyridyl)-2,3,6,10b-tetrahydro-5H-
thiazolo[3,2-c]quinazolin-5-one of m.p. 260-261C
from ethanol
Ex mple 6 ~ ;
6-Methyl-lob-phenyl-2,3,6,10b-tetrahydro-5H-thiasolo-
[3,2-c]quinazolin-5-one
0.5 g (1.8 mmol) of the compound obtained in example 1 b
was dissolved in 10 ml DMF and admixed with 65 mg
(2.7 mmol) NaH and 0.14 ml (2.2 mmol) methyl iodide. `
After 2 hours at 25C the DMF was removed by
distillation, the residue was taken up in dichloro-
methane, washed with water and the organic phase was
dried and concentrated by evaporation. After
crystallization from ethanol, 0.4 g of the title
compound of m.p. 172-174C is obtained.
: :. ~ ::: ,:
~aople 7
lOb-Phenyl-2,3,6,1Ob-tetrahydro-5H-thiazolo[3,2-c]-
quinazolin-5-thione
3.0 g (11 mmol) of the compound obtained in example 1 b
and 8.8 g (22 mmol) ~awesson reagent were heated to
reflux for 16 hours in 150 ml toluene. Subsequently ~;
water was added, undissolved material was separated and
the organic phase was dried and concentrated by
evaporation. The residue was purified over silica gel
(mobile solvent: ethyl acetate/isohexane, 40:60). 1.5 g
of the title compound of m.p. 208-215C is obtained ~`
aPter crystallization from ethanol.
~.. ,~., . ... . ~ .
:, :
.
: ~ :
~ 1 34 2 ~ 0
- 25 ~
,''
Exampl2 8
lOb-Phenyl-2,3,6,10b-tetrahydro-5H-thiazolo-
~3,2-c]quinazolin-5-imine
-:
a) 0.25 g (0.84 mmol) of the compound obtained in
example 7 was admixed in 5 ml DMF with 31 mg NaH and -~
0.06 ml methyl iodide. After 1 hour the DMF was removed ~
by distillation, methylene chloride and water were ~ ~;
added, it was acidified to pH 5 and the organic phase
was separated. After drying and evaporating, 250 mg lOb- ;
phenyl-5-methylmercapto-2,3-dihydrothiazolo-
[3,2-c]quinazoline is obtained as an oil, Rf=0.9
(toluene/dioxanetwater).
b) 250 mg of the previous compound was shaken for 9
hours in an autoclave at 80C with 15 ml ethanol and -~
10 ml liquid ammonia. After evaporation the residue was
chromatographed over silica gel (mobile solvent: 80 %
ethyl acetate - 20 % isohexane). After concentrating the
desired fractions by evaporation and crystallizing from -
ethyl acetate, 75 mg of the title compound of m.p. 200-
204C is obtained.
Bx~lmDle 9
~ -:
Inhibition of reverse transcriptase (RT)
'~
The screening test system consisted of purified RT from
HIV-l which was expressed in E. coli by genetic
engineering methods and the components of the initiation
complex such as the in-vitro transcripts of the HIV-
LTR's with the adjacent primer binding site as the
~'
' ' : ,,
! ': :
~ 1 3~
- 26 -
template and an 18mer oligonucleotide which is -
complementary to the primer binding site as the primer.
The [3H~-thymidine-5'-triphosphate incorporation was ~ :.
measured by counting in a B-counter. ~:~
Results: .
ExampleInhibition of the HIV-RT ;:-:
IC50 tl~N
1 b 0.47
: .
2 0.51
_ '
7 0.03 ~ :
4 O.C3
6 6.20
: '
5 b 0.03 :~
~ ~:
5 f 0.20
: . . . .
:
.~ -,
,~;,
