U.S. patent application number 10/510867 was filed with the patent office on 2005-06-23 for 1-or 3-thia-benznaphthoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof.
This patent application is currently assigned to PLIVA-ISTRAZIVACKI INSTITUT D.D.D.. Invention is credited to Mercep, Mladen, Mesic, Milan, Ozimec, Ivana, Pesic, Dijana, Trojko, Rudolf.
Application Number | 20050137249 10/510867 |
Document ID | / |
Family ID | 28686901 |
Filed Date | 2005-06-23 |
United States Patent
Application |
20050137249 |
Kind Code |
A1 |
Mercep, Mladen ; et
al. |
June 23, 2005 |
1-or 3-thia-benznaphthoazulenes as inhibitors of tumour necrosis
factor production and intermediates for the preparation thereof
Abstract
The present invention relates to 1- or 3-thiabenzonaphthoazulene
derivafives to their pharmacologically acceptable salts and
solvates, to processes and intermediates for the preparation
thereof as well as to their antiinflammatory effects, especially to
the inhibition of tumour necrosis factor-alpha (TNF-alpha)
production and the inhibition of interleukin-1 (IL-1) production as
well as to their analgetic action.
Inventors: |
Mercep, Mladen; (Zagreb,
HR) ; Mesic, Milan; (Zagreb, HR) ; Pesic,
Dijana; (Sibenik, HR) ; Ozimec, Ivana;
(Trnovec, HR) ; Trojko, Rudolf; (Zagreb,
HR) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Assignee: |
PLIVA-ISTRAZIVACKI INSTITUT
D.D.D.
PRILAZ BARUNA FILIPOVICA 29
ZAGREB
HR
|
Family ID: |
28686901 |
Appl. No.: |
10/510867 |
Filed: |
February 23, 2005 |
PCT Filed: |
April 9, 2003 |
PCT NO: |
PCT/HR03/00014 |
Current U.S.
Class: |
514/443 ;
549/42 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 43/00 20180101; A61P 31/18 20180101; A61P 25/00 20180101; A61P
31/04 20180101; A61P 17/00 20180101; A61P 1/04 20180101; A61P 19/02
20180101; C07D 333/80 20130101; Y02P 20/55 20151101; A61P 37/02
20180101; A61P 29/00 20180101; A61P 11/06 20180101; A61P 37/08
20180101; A61P 31/12 20180101; A61P 9/00 20180101; A61P 19/06
20180101; A61P 17/06 20180101; A61P 13/12 20180101; C07D 495/04
20130101 |
Class at
Publication: |
514/443 ;
549/042 |
International
Class: |
A61K 031/381; C07D
495/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 10, 2002 |
HR |
P020303A |
Claims
1. Compound of the formula I 18wherein X may be CH.sub.2 or a
hetero atom such as O, S, S(.dbd.O), S(.dbd.O).sub.2, or NR.sup.1,
wherein R.sup.a is hydrogen or a protecting group; Y and Z
independently from each other denote one or more identical or
different substituents linked to any available carbon atom, and may
be halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkinyl, trifluoromethyl, halo-C.sub.1-C.sub.4
alkyl, hydroxy, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
C.sub.1-C.sub.4 alkanoyl, amino, amino-C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylamino, N--(C.sub.1-C.sub.4-alkyl)amino,
N,N-di(C.sub.1-C.sub.4-alkyl)amino, thiol, C.sub.1-C.sub.4
alkylthio, sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.4 alkylsulfmyl, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, nitro; G.sub.A or G.sub.B: 19independently from
each other denote one or more identical or different substituents
linked to any available carbon atom, and may be halogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkinyl, trifluoromethyl, halo-C.sub.1-C.sub.4 alkyl, hydroxy,
C.sub.1-C.sub.4 alkoxy, trifluoromethoxy, C.sub.1-C.sub.4 alkanoyl,
amino, amino-C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylamino,
N--(C.sub.1-C.sub.4-alkyl)amino,
N,N-di(C.sub.1-C.sub.4-alkyl)amino, thiol, C.sub.1-C.sub.4
alkylthio, sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.4 alkylsulfinyl, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, nitro; R.sup.1 may be halogen, an optionally
substituted C.sub.1-C.sub.7 alkyl or C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkinyl, an optionally substituted aryl or
heteroaryl and a heterocycle, hydroxy, hydroxy-C.sub.2-C.sub.7
alkenyl, hydroxy-C.sub.2-C.sub.7 alkinyl, C.sub.1-C.sub.7 alkoxy,
thiol, thio-C.sub.2-C.sub.7 alkenyl, thio-C.sub.2-C.sub.7 alkinyl,
C.sub.1-C.sub.7 alkylthio, amino-C.sub.1-C.sub.7 alkyl,
amino-C.sub.2-C.sub.7 alkenyl, amino-C.sub.2-C.sub.7 alkinyl,
amino-C.sub.1-C.sub.7 alkoxy, C.sub.1-C.sub.7 alkanoyl, aroyl,
oxo-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkanoyloxy, carboxy, an
optionally substituted C.sub.1-C.sub.7 alkyloxycarbonyl or
aryloxycarbonyl, carbamoyl, N--(C.sub.1-C.sub.7-alkyl)carbamoyl,
N,N-di(C.sub.1-C.sub.7-alkyl)carbamoyl, cyano-C.sub.1-C.sub.7
alkyl, sulfonyl, C.sub.1-C.sub.7 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.7 alkylsulfinyl, nitro, or a substituent of the
formula II 20wherein R.sup.2 and R.sup.3 simultaneously or
independently from each other may be hydrogen, C.sub.1-C.sub.4
alkyl, aryl or together with N have the meaning of an optionally
substituted heterocycle or heteroaryl; n represents an integer from
0 to 3; m represents an integer from 1 to 3; Q.sub.1 and Q.sub.2
represent, independently from each other, oxygen, sulfur or groups:
21wherein the substituents y.sub.1 and y.sub.2 independently from
each other may be hydrogen, halogen, an optionally substituted
C.sub.1-C.sub.4 alkyl or aryl, hydroxy, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkanoyl, thiol, C.sub.1-C.sub.4 alkylthio,
sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl, C.sub.1-C.sub.4
alkylsulfinyl, nitro or together form carbonyl or imino group; as
well as pharmacologically acceptable salts and solvates
thereof.
2. Compound according to claim 1, wherein X has a meaning of S or
O.
3. Compound according to claim 2, wherein Y and Z have a meaning of
H.
4. Compound according to claim 3, wherein G.sub.A or G.sub.B have a
meaning of structures 22
5. Compound according to claim 4, wherein R.sup.1 has a meaning of
CO.sub.2Et, CH.sub.2OH.
6. Compound according to claim 4, wherein R.sup.1 has a meaning of
the formula II.
7. Compound according to claim 6, wherein the symbol m has the
meaning of 1, n has the meaning of 1 or 2, Q.sub.1 has the meaning
of O and Q.sub.2 has the meaning of CH.sub.2.
8. Compound according to claim 7, wherein R.sup.2 and/or R.sup.3
have the meaning of H, CH.sub.3 or together with N the meaning of
morpholine-4-yl, piperidine-1-yl or pyrrolidine-1-yl.
9. Selected compounds according to claim 5:
8-oxa-1-thia-benzo[e]naphtho[3- ,2-h]azulene-2-carboxylic acid
ethyl ester; 1,8-dithia-benzo[e]naphtho[3,2-
-h]azulene-2-carboxylic acid ethyl ester;
3,10-dithia-benzo[e]naphtho[1,2-- h]azulene-2-carboxylic acid ethyl
ester; 10-oxa-3-thia-benzo[e]naphtho[1,2- -h]azulene-2-carboxylic
acid ethyl ester; 11-methoxy-8-oxa-1-thia-benzo[e]-
naphtho[3,2-h]azulene-2-carboxylic acid ethyl ester;
6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[],
2-h]azulene-2-carboxylic acid ethyl ester;
10,11,12,13-tetrahydro-8-oxa-1-
-thia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid ethyl ester;
(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;
(1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;
(3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-yl)-methanol;
(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-yl)-methanol;
(11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;
(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-yl)-met-
hanol;
(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene--
2-yl)-methanol.
10. Selected compounds and salts according to claim 8:
dimethyl-[2-(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethy-
l]-amine;
dimethyl-[3-(8-oxa-1-thia-benzo[elnaphtho[3,2-h]azulene-2-ylmeth-
oxy)-propyl]-amine;
3-(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmeth-
oxy)-propylamine;
dimethyl-[3-(1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2--
ylmethoxy)-propyl]-amine;
dimethyl-[2-(3,10-dithia-benzo[e]naphtho[1,2-h]a-
zulene-2-ylmethoxy)-ethyl]-amine;
dimethyl-[3-(3,10-dithia-benzo[e]naphtho-
[1,2-h]azulene-2-ylmethoxy)-propyl]-amine;
dimethyl-[2-(10-oxa-3-thia-benz-
o[e]naphtho[1,2-h]azulene-2-ylmethoxy)-ethyl]-amine;
dimethyl-[3-(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-pro-
pyl]-amine;
dimethyl-[3-(11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azu-
lene-2-ylmethoxy)-propyl]-amine;
dimethyl-[2-(6,7,8,9-tetrahydro-10-oxa-3--
thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-ethyl]-amine;
dimethyl-[3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azule-
ne-2-ylmethoxy)-propyl]-amine;
3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e-
]naphtho[1,2-h]azulene-2-ylmethoxy)-propylamine;
methyl-[3-(6,7,8,9-tetrah-
ydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propyl]-amin-
e;
dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]-
azulene-2-ylmethoxy)-ethyl]-amine;
dimethyl-[3-(10,11,12,13-tetrahydro-8-o-
xa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propyl]-amine;
4-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-
-ylmethoxy)-ethyl]-morpholine;
1-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-b-
enzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-ethyl]-piperidine;
1-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-
-ylmethoxy)-ethyl]-pyrrolidine;
dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa--
1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propyl]-amine;
dimethyl-[1-methyl-
(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[-
3,2-h]azulene-2-ylmethoxy)-ethyl]-amine.
11. Process for the preparation of the compounds of the formula I
23wherein X may be CH.sub.2 or a hetero atom such as O, S,
S(.dbd.O), S(.dbd.O).sub.2, or NR.sup.a, wherein R.sup.a is
hydrogen or a protecting group; Y and Z independently from each
other denote one or more identical or different substituents linked
to any available carbon atom, and may be halogen, C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkinyl,
trifluoromethyl, halo-C.sub.1-C.sub.4 alkyl, hydroxy,
C.sub.1-C.sub.4 alkoxy, trifluoromethoxy, C.sub.1-C.sub.4 alkanoyl,
amino, amino-C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylamino,
N--(C.sub.1-C.sub.4-alkyl)amino,
N,N-di(C.sub.1-C.sub.4-alkyl)amino, thiol, C.sub.1-C.sub.4
alkylthio, sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.4 alkylsulfinyl, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, nitro; G.sub.A or G.sub.B: 24independently from
each other denote one or more identical or different substituents
linked to any available carbon atom, and may be halogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkinyl, trifluoromethyl, halo-C.sub.1-C.sub.4 alkyl, hydroxy,
C.sub.1-C.sub.4 alkoxy, trifluoromethoxy, C.sub.1-C.sub.4 alkanoyl,
amino, amino-C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylamino,
N--(C.sub.1-C.sub.4-alkyl)amino,
N,N-di(C.sub.1-C.sub.4-alkyl)amino, thiol, C.sub.1-C.sub.4
alkylthio, sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.4 alkylsulfinyl, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, nitro; R.sup.1 may be halogen, an optionally
substituted C.sub.1-C.sub.7 alkyl or C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkinyl, an optionally substituted aryl or
heteroaryl and a heterocycle, hydroxy, hydroxy-C.sub.2-C.sub.7
alkenyl, hydroxy-C.sub.2-C.sub.7 alkinyl, C.sub.1-C.sub.7 alkoxy,
thiol, thio-C.sub.2-C.sub.7 alkenyl, thio-C.sub.2-C.sub.7 alkinyl,
C.sub.1-C.sub.7 alkylthio, amino-C.sub.1-C.sub.7 alkyl,
amino-C.sub.2-C.sub.7 alkenyl, amino-C.sub.2-C.sub.7 alkinyl,
amino-C.sub.1-C.sub.7 alkoxy, C.sub.1-C.sub.7 alkanoyl, aroyl,
oxo-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkanoyloxy, carboxy, an
optionally substituted C.sub.1-C.sub.7 alkyloxycarbonyl or
aryloxycarbonyl, carbamoyl, N--(C.sub.1-C.sub.7-alkyl)carbamoyl,
N,N-di(C.sub.1-C.sub.7-alkyl)carbamoyl, cyano-C.sub.1-C.sub.7
alkyl, sulfonyl, C.sub.1-C.sub.7 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.7 alkylsulfinyl, nitro, or a substituent of the
formula II 25wherein R.sup.2 and R.sup.3 simultaneously or
independently from each other may be hydrogen, C.sub.1-C.sub.4
alkyl, aryl or together with N have the meaning of an optionally
substituted heterocycle or heteroaryl; n represents an integer from
0 to 3; m represents an integer from 1 to 3; Q.sub.1 and Q.sub.2
represent, independently from each other, oxygen, sulfur or groups:
26wherein the substituents y.sub.1 and y.sub.2 independently from
each other may be hydrogen, halogen, an optionally substituted
C.sub.1-C.sub.4 alkyl or aryl, hydroxy, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkanoyl, thiol, C.sub.1-C.sub.4 alkylthio,
sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl, C.sub.1-C.sub.4
alkylsulfinyl, nitro or together form carbonyl or imino group; as
well as of pharmacologically acceptable salts and solvates thereof,
characterized in that the preparation processes comprise a) for the
compounds of the formula I, wherein R.sup.1 is alkyloxycarbonyl, a
cyclisation of a compound of the formula III 27with esters of
mercaptoacetic acid; b) for the compounds of the formula I, wherein
Q.sub.1 has the meaning of --O--, a reaction of alcohols of the
formula V 28with compounds of the formula IV 29wherein R.sup.4 has
a meaning of a leaving group; c) for the compounds of the formula
I, wherein Q.sub.1 has a meaning of --O--, --NH--, --S-- or
--C.ident.C--, a reaction of the compounds of the formula Va
30wherein L has the meaning of a leaving group, with the compounds
of the formula IVa 31d) for the compounds of the formula I, wherein
Q.sub.1 has the meaning of a hetero atom --O--, --NH-- or --S--, a
reaction of the compounds of the formula Vb 32with the compounds of
the formula IV, wherein R.sup.4 has the meaning of a leaving group;
e) for the compounds of the formula I, wherein Q.sub.1 has the
meaning of --C.dbd.C--, a reaction of the compounds of the formula
Vb, wherein Q.sub.1 has the meaning of carbonyl, with phosphorous
ylides.
12. Use of the compounds of the formula I according to claim 5 as
intermediates for the preparation of novel compounds of
benzonaphthoazulene class having an antiinflammatory action.
13. Use of the compounds of the fornmula I according to claim 6 as
inhibitors of production of cytokins or inflammation mediators in
the treatment and prophylaxis of any pathological condition or
disease induced by excessive unregulated production of cytokins or
inflammation mediators in such a way that a non-toxic dose of
appropriate pharmaceutical preparations may be administered per os,
parenterally or locally.
Description
TECHNICAL FIELD
[0001] The present invention relates to benzonaphthoazulene
derivatives of tiophene class, to their pharmacologically
acceptable salts and solvates, to processes and intermediates for
the preparation thereof as well as to their antiinflammatory
effects, especially to the inhibition of tumour necrosis
factor-.alpha. (TNF-.alpha.) production and the inhibition of
interleukin-1 (IL-1) production as well as to their analgetic
action.
PRIOR ART
[0002] Some 1,3-diaza-dibenzoazulene derivatives and salts thereof
are well-known as a novel class of compounds having an
antiinflammatory action (U.S. Pat. No. 3,711,489, U.S. Pat. No.
4,198,421 and CA 967,573). In the literature, from the class of
1-thia-dibenzoazulenes there are disclosed derivatives substituted
in 2-position with methyl, methyl-ketone, nitro group or with
carboxylic group derivatives (Cagniant P G, C. R. Hebd. Sceances
Acad. Sci., 1976, 283:683-686), and 1-thia-dibenzoazulene
derivatives having alkyloxy substituents in 2-position (WO
01/878990), which also possess a strong antiinflammatory
action.
[0003] Well-known are also some benzonaphthoazulenes of the
thiophene class such as
9,14-dihydro-9,14-dioxo-8-oxa-1-thia-benzo[e]naphtho[3,2-h]-
azulenes, wherein 3-position is substituted by a cyano group and in
2-position there may be amine, urea or acetamide as a substituent
(Nyiondi-Bonguen E et al., J. Chem. Soc., Perkin Trans. 1, 1994,
15:2191-2195). However, according to our knowledge and to available
literature data, benzonaphthoazulenes of thiophene class of the
present invention are not known. It is also not known that such
compounds could possess an antiinflammatory action as inhibitors of
TNF-.alpha. secretion and inhibitors of IL-1 secretion as well as
an analgetic action. In 1975 TNF-.alpha. was defined as a serum
factor induced by endotoxin and causing tumour necrosis in vitro
and in vivo (Carswell E A et al., Proc. Natl. Acad. Sci. U.S.A.,
1975, 72:3666-3670). Besides an antitumour action, TNF-.alpha. also
possesses numerous other biological actions important in the
homeostasis of organisms and in pathophysiological conditions. The
main sources of TNF-.alpha. are monocytes-macrophages,
T-lymphocytes and mastocytes.
[0004] The discovery that anti-TNF-.alpha. antibodies (cA2) have an
action in treating patients with rheumatoid arthritis (RA) (Elliott
M et al., Lancet, 1994, 344:1105-1 1 10) led to an increased
interest in finding novel TNF-.alpha. inhibitors as possible potent
drugs for RA. Rheumatoid arthritis is an autoimmune chronic
inflammatory disease characterized by irreversible pathological
changes in the joints. Besides in RA, TNF-.alpha. antagonists may
also be used in numerous pathological conditions and diseases such
as spondylitis, osteoarthritis, gout and other arthritic
conditions, sepsis, septic shock, toxic shock syndrom, atopic
dermatitis, contact dermatitis, psoriasis, glomerulonephritis,
lupus erythematosus, scleroderma, asthma, cachexia, chronic
obstructive lung disease, congestive cardiac arrest, insulin
resistance, lung fibrosis, multiple sclerosis, Crohn's disease,
ulcerative colitis, viral infections and AIDS.
[0005] Evidence for the biological importance of TNF-.alpha. was
obtained by in vivo experiments in mice, in which mice gens for
TNF-.alpha. or its receptor were inactivated. Such animals are
resistant to collagen-induced arthritis (Mori L et al., et al., J.
Immunol., 1996, 157:3178-3182) and to endotoxin-caused shock
(Pfeffer K et al., Cell, 1993, 73:457-467). In animal assays where
TNF-.alpha. level was increased, a chronic inflammatory
polyarthritis occured (Georgopoulos S et al., J. Inflamm., 1996,
46:86-97; Keffer J et al., EMBO J., 1991, 10:4025-4031) and its
pathological picture was alleviated by inhibitors of TNF-.alpha.
production. The treatment of such inflammatory and pathological
conditions usually includes the application of non-steroid
antiinflammatory drugs and, in more severe cases, gold salts,
D-penicillinamine or methotrexate are administered. Said drugs act
symptomatically, but they do not stop the pathological process.
Novel approaches in the therapy of rheumatoid arthritis are based
upon drugs such as tenidap, leflunomide, cyclosporin, FK-506 and
upon biomolecules neutralizing the TNF-.alpha. action. At present
there are commercially available etanercept (Enbrel,
Immunex/Wyeth), a fusion protein of the soluble TNF-.alpha.
receptor, and infliximab (Remicade, Centocor), a chimeric
monoclonal human and mouse antibody. Besides in RA therapy,
etanercept and infliximab are also registered for the therapy of
Crohn's disease (Exp. Opin. Invest. Drugs, 2000, 9:103).
[0006] In RA therapy, besides inhibition of TNF-.alpha. secretion,
also the inhibition of IL-1 secretion is very important since IL-1
is an important cytokin in cell regulation and immunoregulation as
well as in pathophysiological conditions such as inflammation
(Dinarello C A et al., Rev. Infect. Disease, 1984, 6:51).
Well-known biological activities of IL-1 are: activation of
T-cells, induction of elevated temperature, stimulation of
secretion of prostaglandine or collagenase, chemotaxia of
neutrophils and reduction of iron level in plasma (Dinarello C A,
J. Clinical Immunology, 1985, 5:287). Two receptors to which IL-1
may bind are well-known: IL-1RI and IL-1RII. Whereas IL-1RI
transfers a signal intracellularly, IL-1RII is situated on the cell
surface and does not transfer a signal inside the cell. Since
IL1-RII binds IL-1 as well as IL1-RI, it may act as a negative
regulator of IL-1 action. Besides this mechanism of signal transfer
regulation, another natural antagonist of IL-1 receptor (IL-1ra) is
present in cells. This protein binds to IL-1RI but does not
transfer any signal. However, its potency in stopping the signal
transfer is not high and its concentration has to be 500 times
higher than that of IL-1 in order to achieve a break in the signal
transfer. Recombinant human IL-Ira (Amgen) was clinically tested
(Bresnihan B et al., Arthrit. Rheum., 1996, 39:73) and the obtained
results indicated an improvement of the clinical picture in 472 RA
patients over an placebo. These results indicate the importance of
the inhibition of IL-1 action in treating diseases such as RA where
IL-1 production is disturbed. Since there exists a synergistic
action of TNF-.alpha. and IL-1, benzonaphthoazulenes may be used in
treating conditions and diseases related to an enhanced secretion
of TNF-.alpha. and IL-1.
[0007] Inventive Solution
[0008] The present invention relates to benzonaphthoazulenes of the
formula I 1
[0009] wherein
[0010] X may be CH.sub.2 or a hetero atom such as O, S, S(.dbd.O),
S(.dbd.O).sub.2, or NR.sup.a, wherein R.sup.a is hydrogen or a
protecting group;
[0011] Y and Z independently from each other denote one or more
identical or different substituents linked to any available carbon
atom, and may be halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkinyl, trifluoromethyl,
halo-C.sub.1-C.sub.4 alkyl, hydroxy, C.sub.1-C.sub.4 alkoxy,
trifluoromethoxy, C.sub.1-C.sub.4 alkanoyl, amino,
amino-C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylamino,
N--(C.sub.1-C.sub.4-alkyl)amino,
N,N-di(C.sub.1-C.sub.4-alkyl)amino, thiol, C.sub.1-C.sub.4
alkylthio, sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.4 alkylsulfinyl, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, nitro;
[0012] G.sub.A or G.sub.B: 2
[0013] independently from each other denote one or more identical
or different substituents linked to any available carbon atom, and
may be halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkinyl, trifluoromethyl, halo-C.sub.1-C.sub.4
alkyl, hydroxy, C.sub.1-C.sub.4 alkoxy, trifluoromethoxy,
C.sub.1-C.sub.4 alkanoyl, amino, amino-C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkylamino, N--(C.sub.1-C.sub.4-alkyl)amino,
N;N-di(C.sub.1-C.sub.4-alkyl)amino, thiol, C.sub.1-C.sub.4
alkylthio, sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.4 alkylsulfinyl, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, nitro;
[0014] R.sup.1 may be halogen, an optionally substituted
C.sub.1-C.sub.7 alkyl or C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkinyl, an optionally substituted aryl or heteroaryl and a
heterocycle, hydroxy, hydroxy-C.sub.2-C.sub.7 alkenyl,
hydroxy-C.sub.2-C.sub.7 alkinyl, C.sub.1-C.sub.7 alkoxy, thiol,
thio-C.sub.2-C.sub.7 alkenyl, thio-C.sub.2-C.sub.7 alkinyl,
C.sub.1-C.sub.7 alkylthio, amino-C.sub.1-C.sub.7 alkyl,
amino-C.sub.2-C.sub.7 alkenyl, amino-C.sub.2-C.sub.7 alkinyl,
amino-C.sub.1-C.sub.7 alkoxy, C.sub.1-C.sub.7 alkanoyl, aroyl,
oxo-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkanoyloxy, carboxy, an
optionally substituted C.sub.1-C.sub.7 alkyloxycarbonyl or
aryloxycarbonyl, carbamoyl, N--(C.sub.1-C.sub.7-alkyl)carbamoyl,
N,N-di(C.sub.1-C.sub.7-alkyl)carbamo- yl, cyano-C.sub.1-C.sub.7
alkyl, sulfonyl, C.sub.1-C.sub.7 alkylsulfonyl, sulfinyl,
C.sub.1-C.sub.7 alkylsulfinyl, nitro, or a substituent of the
formula II 3
[0015] wherein
[0016] R.sup.2 and R.sup.3 simultaneously or independently from
each other may be hydrogen, C.sub.1-C.sub.4 alkyl, aryl or together
with N have the meaning of an optionally substituted heterocycle or
heteroaryl;
[0017] n represents an integer from 0 to 3;
[0018] m represents an integer from 1 to 3;
[0019] Q.sub.1 and Q.sub.2 represent, independently from each
other, oxygen, sulfur or groups: 4
[0020] wherein the substituents
[0021] y.sub.1 and y.sub.2 independently from each other may be
hydrogen, halogen, an optionally substituted C.sub.1-C.sub.4 alkyl
or aryl, hydroxy, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkanoyl,
thiol, C.sub.1-C.sub.4 alkylthio, sulfonyl, C.sub.1-C.sub.4
alkylsulfonyl, sulfinyl, C.sub.1-C.sub.4 alkylsulfinyl, nitro or
together form carbonyl or imino group;
[0022] as well as to pharmacologically acceptable salts and
solvates thereof.
[0023] The term "halo", "hal" or "halogen" relates to a halogen
atom which may be fluorine, chlorine, bromine or iodine.
[0024] The term "alkyl" relates to alkyl groups with the meaning of
alkanes wherefrom radicals are derived, which radicals may be
straight, branched or cyclic or a combination of straight and
cyclic ones and branched and cyclic ones. The preferred straight or
branched alkyls are e.g. methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl and tert-butyl. The preferred cyclic alkyls are e.g.
cyclopentyl or cyclohexyl.
[0025] The term "haloalkyl" relates to alkyl groups which must be
substituted with at least one halogen atom. The most frequent
haloalkyls are e.g. chloromethyl, dichloromethyl, trifluoromethyl
or 1,2-dichloropropyl.
[0026] The term "alkenyl" relates to alkenyl groups having the
meaning of hydrocarbon radicals, which may be straight, branched or
cyclic or are a combination of straight and cyclic ones or branched
and cyclic ones, but having at least one carbon-carbon double bond.
The most frequent alkenyls are ethenyl, propenyl, butenyl or
cyclohexenyl.
[0027] The term "alkinyl" relates to alkinyl groups having the
meaning of hydrocarbon radicals, which are straight or branched and
contain at least one and at most two carbon-carbon triple bonds.
The most frequent alkinyls are e.g. ethinyl, propinyl or
butinyl.
[0028] The term "alkoxy" relates to straight or branched chains of
alkoxy group. Examples of such groups are methoxy, propoxy,
prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.
[0029] The term "aryl" relates to groups having the meaning of an
aromatic ring, e.g. phenyl, as well as to fused aromatic rings.
Aryl contains one ring with at least 6 carbon atoms or two rings
with totally 10 carbon atoms and with alternating double (resonant)
bonds between carbon atoms. The most freqently used aryls are e.g.
phenyl or naphthyl. In general, aryl groups may be linked to the
rest of the molecule by any available carbon atom via a direct bond
or via a C.sub.1-C.sub.4 alkylene group such as methylene or
ethylene.
[0030] The term "heteroaryl" relates to groups having the meaning
of aromatic and partially aromatic groups of a monocyclic or
bicyclic ring with 4 to 12 carbon atoms, at least one of them being
a hetero atom such as O, S or N, and the available nitrogen atom or
carbon atom is the binding site of the group to the rest of the
molecule either via a direct bond or via a C.sub.1-C.sub.4 alkylene
group defined earlier. Examples of this type are thiophenyl,
pyrrolyl, imidazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl,
tetrazolyl, pirimidinyl, pyrazinyl, quinolinyl or triazinyl.
[0031] The term "heterocycle" relates to five-member or six-member,
fully saturated or partly unsaturated heterocyclic groups
containing at least one hetero atom such as O, S or N, and the
available nitrogen atom or carbon atom is the binding site of the
group to the rest of the molecule either via a direct bond or via a
C.sub.1-C.sub.4 alkylene group defined earlier. The most frequent
examples are morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl,
pirazinyl or imidazolyl.
[0032] The term "alkanoyl" group relates to straight chains of acyl
group such as formyl, acetyl or propanoyl.
[0033] The term "aroyl" group relates to aromatic acyl groups such
as benzoyl.
[0034] The term "optionally substituted alkyl" relates to alkyl
groups which may be optionally additionally substituted with one,
two, three or more substituents. Such substituents may be halogen
atom (preferably fluorine or chlorine), hydroxy, C.sub.1-C.sub.4
alkoxy (preferably methoxy or ethoxy), thiol, C.sub.1-C.sub.4
alkylthio (preferably methylthio or ethylthio), amino,
N--(C.sub.1-C.sub.4) alkylamino (preferably N-methylamino or
N-ethylamino), N,N-di(C.sub.1-C.sub.4-alkyl)- -amino (preferably
dimethylamino or diethylamino), sulfonyl, C.sub.1-C.sub.4
alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl),
sulfinyl, C.sub.1-C.sub.4 alkylsulfinyl (preferably
methylsulfinyl).
[0035] The term "optionally substituted alkenyl" relates to alkenyl
groups optionally additionally substituted with one, two or three
halogen atoms. Such substituents may be e.g. 2-chloroethenyl,
1,2-dichloroethenyl or 2-bromo-propene-1-yl.
[0036] The term "optionally substituted aryl, heteroaryl or
heterocycle" relates to aryl, heteroaryl or heterocyclic groups
which may be optionally additionally substituted with one or two
substituents. The substituents may be halogen (preferably chlorine
or fluorine), C.sub.1-C.sub.4 alkyl (preferably methyl, ethyl or
isopropyl), cyano, nitro, hydroxy, C.sub.1-C.sub.4 alkoxy
(preferably methoxy or ethoxy), thiol, C.sub.1-C.sub.4 alkylthio
(preferably methylthio or ethylthio), amino, N--(C.sub.1-C.sub.4)
alkylamino (preferably N-methylamino or N-ethylamino),
N)N-di(C.sub.1-C.sub.4-alkyl)-amino (preferably N,N-dimethylamino
or NN-diethylamino), sulfonyl, C.sub.1-C.sub.4 alkylsulfonyl
(preferably methylsulfonyl or ethylsulfonyl), sulfinyl,
C.sub.1-C.sub.4 alkylsulfinyl (preferably methylsulfinyl).
[0037] When X has the meaning of NR.sup.a and R.sup.a has the
meaning of a protecting group, then R.sup.a relates to groups such
as alkyl (preferably methyl or ethyl), alkanoyl (preferably
acetyl), alkoxycarbonyl (preferably methoxycarbonyl or
tert-butoxycarbonyl), arylmethoxycarbonyl (preferably
benzyloxycarbonyl), aroyl (preferably benzoyl), arylalkyl
(preferably benzyl), alkylsilyl (preferably trimethylsilyl) or
alkylsilylalkoxyalkyl (preferably trimethylsilylethoxymethyl).
[0038] When R.sup.2 and R.sup.3 together with N have the meaning of
heteroaryl or heterocycle, this means that such heteroaryls or
heterocycles have at least one carbon atom replaced by a nitrogen
atom through which the groups are linked to the rest of the
molecule. Examples of such groups are morpholine-4-yl,
piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-yl or
piperazine-1-yl.
[0039] The term "pharmaceutically suitable salts" relates to salts
of the compounds of the formula I and include e.g. salts with
C.sub.1-C.sub.4 alkylhalides (preferably methyl bromide, methyl
chloride) (quaternary ammonium salts), with inorganic acids
(hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric or
sulfuric acids) or with organic acids (tartaric, acetic, citric,
maleic, lactic, fumaric, benzoic, succinic, methane sulfonic
orp-toluene sulfonic acids).
[0040] Some compounds of the formula I may form salts with organic
or inorganic acids or bases and these are also included in the
present invention.
[0041] Solvates (most frequently hydrates) which may form compounds
of the formula I or salts thereof are also an object of the present
invention.
[0042] Depending upon the nature of particular substituents, the
compounds of the formula I may have geometric isomers and one or
more chiral centres so that there can exist enantiomers or
diastereoisomers. The present invention also relates to such
isomers and mixtures thereof, including racemates.
[0043] The present invention also relates to all possible
tautomeric forms of particular compounds of the formula I.
[0044] A further object of the present invention relates to the
preparation of compounds of the formula I according to processes
comprising
[0045] a) for compounds of the formula I, wherein R.sup.1 is
alkyloxycarbonyl,
[0046] a cyclisation of the compound of the formula III 5
[0047] with esters of mercaptoacetic acid;
[0048] b) for compounds of the formula I, wherein Q.sub.1 has the
meaning of --O--,
[0049] a reaction of alcohols of the formula V 6
[0050] with compounds of the formula IV 7
[0051] wherein R.sup.4 has a meaning of a leaving group;
[0052] c) for the compounds of the formula I, wherein Q.sub.1 has a
meaning of --O--, --NH--, --S-- or --C.ident.C--,
[0053] a reaction of the compounds of the formula Va 8
[0054] wherein L has a meaning of a leaving group,
[0055] with compounds of the formula IVa 9
[0056] d) for the compounds of the formula I, wherein Q.sub.1 has a
meaning of a hetero atom --O--, --NH-- or --S--,
[0057] a reaction of the compounds of the formula Vb 10
[0058] with the compounds of the formula IV, wherein R.sup.4 has a
meaning of a leaving group;
[0059] e) for the compounds of the formula I, wherein Q.sub.1 has a
meaning of --C.dbd.C--, a reaction of the compounds of the formula
Vb, wherein Q.sub.1 has a meaning of carbonyl, with phosphorous
ylides.
[0060] Preparation Methods:
[0061] a) Cyclization of the compounds of the formula III with
ethyl mercaptoacetate is carried out by methods disclosed for the
preparation of analogous compounds. The reaction is carried out in
the presence of organic bases (preferably pyridine) at the boiling
point during 1 to 5 hours. The obtained tetracyclic products may be
isolated by column chromatography or by recrystallization from an
appropriate solvent.
[0062] The starting substances for the preparation of the compounds
of the formula III, ketones of the formula VI, 11
[0063] are already known or are prepared by methods disclosed for
the preparation of analogous compounds. Thus e.g. the compounds of
the formula VI may be obtained starting from compounds of the
formula VIII 12
[0064] wherein R.sup.5 has a meaning of a CO.sub.2H group, in such
a way that by suitable chemical transformations there is obtained a
compound of the formula VIII wherein R.sup.5 has the meaning of
CH.sub.2CO.sub.2H. By the action of polyphosphoric acid,
cyclization and formation of a ketone of the formula VI occur. A
similar reaction sequence has been disclosed earlier in Protiva M
et al. (CS 163583, Collect. Czech. Chem. Commun., 1975,
40:1960-1965 and Collect. Czech. Chem. Commun., 1974,
39:3147-3152). Alternatively, the compound of the formula VIII,
wherein R.sup.5 has the meaning of CH.sub.2CO.sub.2H, may be
prepared by reacting the compound of the formula VIII, wherein
R.sup.5 is COCH.sub.3, with sulfur and morpholine and by
hydrolyzing thioamide thus obtained (Ueda I et al., Chem. Pharm.
Bull., 1975, 23:2223-2231). By the action of Vilsmeier-Haack
reagent upon the corresponding ketones of the formula VI, compounds
of the formula III (Tsuji K et al., Chem. Pharm. Bull., 1998,
46:279-286) are prepared.
[0065] b) Compounds of the formula I according to the present
process may be prepared by reaction of alcohols of the formula V
and compounds of the formula IV, wherein R.sup.4 has the meaning of
a leaving group, which may be a halogen atom (most frequently
bromine, iodine or chlorine) or sulfonyloxy group (most frequently
trifluoromethylsulfonyloxy or p-toluenesulfonyloxy). The reaction
of condensation may be carried out according to methods disclosed
for the preparation of analogous compounds (Menozzi G et al., J.
Heterocyclic Chem., 1997, 34:963-968 or WO 01/87890). The reaction
is carried out at a temperature from 20.degree. C. to 100.degree.
C. during 1 to 24 hours in a two-phase system (preferably with 50%
NaOH/toluene) in the presence of a phase transfer catalyst
(preferably benzyl triethyl ammonium chloride, benzyl triethyl
ammonium bromide, cetyl trimethyl bromide). After treating the
reaction mixture, the products formed are isolated by
recrystallization or chromatography on a silica gel column.
[0066] The starting substances, alcohols of the formula V, may be
prepared from the compounds of the formula I, wherein R.sup.1 has
the meaning of a suitable functional group. Thus e.g. alcohols of
the formula V may be obtained by the reduction of alkyloxycarbonyl
group (e.g. ethyloxycarbonyl) by using metal hydrides such as
lithium aluminum hydride or sodium borohydride. Further, alcohols
of the formula V may be prepared by hydrolysis of the corresponding
esters in an alkaline or acidic medium.
[0067] The starting compounds of the formula IV are already known
or are prepared according to methods disclosed for the preparation
of analogous compounds.
[0068] c) Compounds of the formula I according to the present
process may be prepared by reacting compounds of the formula Va,
wherein L has the meaning of a leaving group defined earlier for
R.sup.4, and compounds of the formula IVa, wherein Q.sub.1 has the
meaning of oxygen, nitrogen, sulfur or --C.ident.C--. The most
suitable condensation reactions are reactions of nucleophilic
substitution on a saturated carbon atom as disclosed in the
literature.
[0069] The starting compounds of the formula Va (most frequently
halides) may be obtained by halogenation (e.g. bromination or
chlorination) of alcohols of the formula V with the usual
halogenating agents (e.g. hydrobromic acid, PBr.sub.3, SOCi.sub.2
or PCl.sub.5) by processes as disclosed in the literature. The
obtained compounds may be isolated or may be used without isolation
as suitable intermediates for the preparation of the compounds of
the formula I.
[0070] The starting compounds of the formula IVa are already known
or are prepared according to methods disclosed for the preparation
of analogous compounds.
[0071] d) The compounds of the formula I, wherein Q.sub.1 has a
meaning of --O--, --NH-- or --S--, may be prepared by condensation
of the compounds of the formula Vb and of compounds of the formula
IV, wherein R.sup.4 has the meaning of a leaving group defined
earlier. The reaction may be carried out at reaction conditions
disclosed in method b) or by reactions of nucleophilic substitution
disclosed in the literature. The starting alcohols, amines and
thiols may be obtained by a reaction of water, ammonia or hydrogen
sulfide with compounds Va according to processes disclosed in the
literature.
[0072] e) The alcohols of the structure V may be oxidized to
corresponding compounds of the formula Vb, wherein Q.sub.1 has the
meaning of carbonyl and which may further, by reaction with
corresponding ylide reagents, result in a prolongation of the chain
and in the formation of an alkenyl substituent with carbonyl or
ester groups as disclosed in HR patent application No.
20000310.
[0073] Besides the reactions mentioned above, the compounds of the
formula I may be prepared by transforming other compounds of the
formula I and it is to be understood that the present invention
also comprises such compounds and processes. A special example of a
change of a functional group is the reaction of the aldehyde group
with chosen phosphorous ylides resulting in a prolongation of the
chain and the formation of an alkenyl substituent with carbonyl or
ester groups as disclosed in HR patent application No. 20000310.
These reactions are carried out in solvents such as benzene,
toluene or hexane at elevated temperature (most frequently at
boiling temperature).
[0074] By reacting the compounds of the formula Va with 1-alkyne in
an alkaline medium (such as sodium amide in ammonia) the compounds
of the formula I, wherein Q.sub.1 is --C.ident.C--, are obtained.
The reaction conditions of this process are disclosed in the
literature. At similar reaction conditions (nucleophilic
substitution) various ether, thioether or amine derivatives may be
prepared.
[0075] The formylation of the compounds of the formula I by
processes such as e.g. Vilsmeier acylation or reaction of n-BuLi
and N,N-dimethylformamide is a further general example of a
transformation. The reaction conditions of these processes are
well-known in the literature.
[0076] By hydrolysis of the compounds of the formula I having
nitrile, amide or ester groups, there may be prepared compounds
with a carboxyl group, which are suitable intermediates for the
preparation of other compounds with novel functional groups such as
e.g. esters, amides, halides, anhydrides, alcohols or amines.
[0077] Oxidation or reduction reactions are a further possibility
of the change of substituents in the compounds of the formula I.
Most frequently used oxidation agents are peroxides (hydrogen
peroxide, m-chloroperbenzoic acid or benzoyl peroxide) or
permanganate, chromate or perchlorate ions. Thus e.g. by the
oxidation of an alcohol group by pyridinyl dichromate or pyridinyl
chlorochromate, an aldehyde group is formed, which group may be
converted to a carboxyl group by further oxidation. By oxidation of
the compounds of the formula I, wherein R.sup.1 has the meaning of
alkyl, with lead tetraacetate in acetic acid or with
N-bromosuccinimide using a catalytic amount of benzoyl peroxide, a
corresponding carbonyl derivative is obtained.
[0078] By a selective oxidation of alkylthio group, alkylsulfinyl
or alkylsulfonyl groups may be prepared.
[0079] By the reduction of the compounds with a nitro group, the
preparation of amino compounds is made possible. The reaction is
carried out under usual conditions of catalytic hydrogenation or
electrochemically. By catalytic hydrogenation using palladium on
carbon, alkenyl substituents may be converted to alkyl ones or
nitrile group can be converted to aminoalkyl.
[0080] Various substituents of the aromatic structure in the
compounds of the formula I may be introduced by standard
substituion reactions or by usual changes of individual functional
groups. Examples of such reactions are aromatic substitutions,
alkylations, halogenation, hydroxylation as well as oxidation or
reduction of substituents. Reagents and reaction conditions are
known from the literature. Thus e.g. by aromatic substitution a
nitro group is introduced in the presence of concentrated nitric
acid and sulfuric acid. By using acyl halides or alkyl halides, the
introduction of an acyl group or an alkyl group is made possible.
The reaction is carried out in the presence of Lewis acids such as
aluminum- or iron-trichloride in conditions of Friedel-Crafts
reaction. By the reduction of the nitro group, an amino group is
obtained, which is by the reaction of diazotizing converted to a
suitable starting group, which may be replaced with one of the
following groups: H, CN, OH, Hal.
[0081] In order to prevent undesired interaction in chemical
reactions, it is often necessary to protect certain groups such as
e.g. hydroxy, amino, thio or carboxy. For this purpose a great
number of protecting groups may be used (Green T W, Wuts P G H,
Protective Groups in Organic Synthesis, John Wiley and Sons, 1999)
and the choice, use and elimination thereof are conventional
methods in chemical synthesis.
[0082] A convenient protection for amino or alkylamino groups are
groups such as e.g. alkanoyl (acetyl), alkoxycarbonyl
(methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl);
arylmethoxycarbonyl (benzyloxycarbonyl), aroyl (benzoyl) or
alkylsilyl (trimethylsilyl or trimethylsilylethoxymethyl) groups.
The conditions of removing a protecting group depend upon the
choice and the characteristics of this group. Thus e.g. acyl groups
such as alkanoyl, alkoxycarbonyl or aroyl may be eliminated by
hydrolysis in the presence of a base (sodium hydroxide or potassium
hydroxide), tert-butoxycarbonyl or alkylsilyl (trimethylsilyl) may
be eliminated by treatment with a suitable acid (hydrochloric,
sulfuric, phosphoric or trifluoroacetic acid), whereas
arylmethoxycarbonyl group (benzyloxycarbonyl) may be eliminated by
hydrogenation using a catalyst such as palladium on carbon.
[0083] Salts of the compounds of the formula I may be prepared by
generally known processes such as e.g. by reacting the compounds of
the formula I with a corresponding base or acid in an appropriate
solvent or solvent mixture e.g. ethers (diethylether) or alcohols
(ethanol, propanol or isopropanol).
[0084] Another object of the present invention concerns the use of
the present compounds in the therapy of inflammatory diseases and
conditions, especially all diseases and conditions induced by
excessive TNF-.alpha. and IL-1 secretion.
[0085] Inhibitors of production of cytokins or inflammation
mediators, which are the object of the present invention, or
pharmacologically acceptable salts thereof may be used in
production of drugs for the treatment and prophylaxis of any
pathological condition or disease induced by excessive unregulated
production of cytokins or inflammation mediators, which drugs
should contain an effective dose of said inhibitors.
[0086] The present invention specifically relates to an effective
dose of TNF-.alpha. inhibitor, which may be determined by usual
methods.
[0087] Further, the present invention relates to a pharmaceutical
formulation containing an effective non-toxic dosis of the present
compounds as well as pharmaceutically acceptable carriers or
solvents.
[0088] The preparation of pharmaceutical formulations may include
blending, granulating, tabletting and dissolving ingredients.
Chemical carriers may be solid or liquid. Solid carriers may be
lactose, sucrose, talcum, gelatine, agar, pectin, magnesium
stearate, fatty acids etc. Liquid carriers may be syrups, oils such
as olive oil, sunflower oil or soya bean oil, water etc. Similarly,
the carrier may also contain a component for a sustained release of
the active component such as e.g. glyceryl monostearate or glyceryl
distearate. Various forms of pharmaceutical formulations may be
used. Thus, if a solid carrier is used, these forms may be tablets,
hard gelatine capsules, powder or granules, which may be
administered in capsules per os. The amount of the solid carrier
may vary, but it is mainly from 25 mg to 1 g. If a liquid carrier
is used, the formulation would be in the form of a syrup, emulsion,
soft gelatine capsules, sterile injectable liquids such as ampoules
or non-aqueous liquid suspensions.
[0089] Compounds according to the present invention may be applied
per os, parenterally, locally, intranasally, intrarectally and
intravaginally. The parenteral route herein means intravenous,
intramuscular and subcutaneous applications. Appropriate
formulations of the present compounds may be used in the
prophylaxis as well as in the treatment of various diseases and
pathological inflammatory conditions induced by an excessive
unregulated production of cytokins or inflammation mediators,
primarily TNF-.alpha.. They comprise rheumatoid arthritis,
rheumatoid spondylitis, osteoarthritis and other arthritic
pathological conditions and diseases, eczemas, psoriasis and other
inflammatory skin conditions such as burns induced by UV radiation
(sun rays and similar UV sources), inflammatory eye diseases,
Crohn's disease, ulcerative colitis and asthma.
[0090] The inhibitory action of the present compounds upon
TNF-.alpha. and IL-1 secretion was determined by the following in
vitro and in vivo experiments:
[0091] Determination of TNF-.alpha. and IL-1 Secretion in Human
Peripheral Blood Mononuclear Cells In Vitro
[0092] Human peripheral blood mononuclear cells (PBMC) were
prepared from heparinized whole blood after separating PBMC on
Ficoll-Paque.TM. Plus (Amersham-Pharmacia). To determine the
TNF-.alpha. level, 3.5-5.times.10.sup.4 cells were cultivated in a
total volume of 200 pi for 18 to 24 hours on microtitre plates with
a flat bottom (96 wells, Falcon) in RPMI 1640 medium, into which
there were added 10% FBS (Fetal Bovine Serum, Biowhittaker)
previously inactivated at 54.degree. C./30 min, 100 units/ml of
penicillin, 100 mg/ml of streptomycin and 20 mM HEPES (GIBCO). The
cells were incubated at 37.degree. C. in an atmosphere with 5%
CO.sub.2 and 90% humidity. In a negative control the cells were
cultivated only in the medium (NC), whereas in a positive control
TNF-.alpha. secretion was triggered by adding 1 ng/ml of
lipopolysaccharides (LPS, E. coli serotype 0111 :B4, SIGMA) (PC).
The effect of the tested substances upon TNF-.alpha. secretion was
investigated after adding them into cultures of cells stimulated by
LPS (TS). The TNF-.alpha. level in the cell supernatant was
determined by ELISA procedure according to the suggestions of the
producer (R&D Systems). The test sensitivity was <3 pg/ml
TNF-.alpha.. The IL-1 level was determined in an assay under the
same conditions and with the same number of cells and the same
concentration of the stimulus by ELISA procedure (R&D Systems).
The percentage of inhibition of TNF-.alpha. or IL-1 production was
calculated by the equation:
% inhibition=[1=(TS-NC)/(PC-NC)]*100.
[0093] The IC-50 value was defined as the substance concentration,
at which 50% of TNF-.alpha. production were inhibited.
[0094] Compounds showing IC-50 with 20 .mu.M or lower
concentrations are active.
[0095] Determination of TNF-.alpha. and IL-1 Secretion in Mouse
Peritoneal Macrophages In Vitro
[0096] In order to obtain peritoneal macrophages, Balb/C mouse
strain males, age 8 to 12 weeks, were injected i.p. with 300 .mu.g
of zymosan (SIGMA) dissolved in a phosphate buffer (PBS) in a total
volume of 0.1 ml/mouse. After 24 hours the mice were euthanized
according to the Laboratory Animal Welfare Act. The peritoneal
cavity was washed with a sterile physiological solution (5 ml). The
obtained peritoneal macrophages were washed twice with a sterile
physiological solution and, after the last centrifugation (350 g/10
min), resuspended in RPMI 1640, into which 10% of FBS portion were
added. In order to determine TNF-.alpha. secretion,
5.times.10.sup.4 cells/well were cultivated in a total volume of
200 .mu.l for 18 to 24 hours on microtitre plates with a flat
bottom (96 wells, Falcon) in RPMI 1640 medium, into which 10% FBS
(Fetal Bovine Serum, Biowhittaker) inactivated by heat, 100
units/ml of penicillin, 100 mg/ml of streptomycin, 20 mM HEPES and
50 .mu.M 2-mercaptoethanol (all of GIBCO) were added. The cells
were incubated at 37.degree. C. in an atmosphere with 5% CO.sub.2
and 90% humidity. In a negative control the cells were cultivated
only in a medium (NC), whereas in a positive control the
TNF-.alpha. secretion was triggered by adding 10 ng/ml of
lipopolysaccharides (LPS, E. coli serotype 0111:B4, SIGMA) (PC).
The effect of the substances upon the TNF-.alpha. secretion was
investigated after adding them into cultures of cells stimulated
with LPS (TS). The TNF-.alpha. level in the cell supernatant was
determined by ELISA procedure (R&D Systems, Biosource). The
IL-1 level was determined in an assay identical to the assay for
TNF-.alpha. by ELISA procedure (R&D Systems). The percentage of
inhibition of TNF-.alpha. or IL-1 production was calculated by the
equation:
% inhibition=[1-(TS-NC)/(PC-NC)]*100.
[0097] The IC-50 value was defined as the substance concentration,
at which 50% of TNF-.alpha. production were inhibited.
[0098] Compounds showing IC-50 with 10 .mu.M or lower
concentrations are active.
[0099] In Vivo Model of LPS-Induced Excessive TNF-.alpha. or IL-1
Secretion in Mice
[0100] TNF-.alpha. or IL-1 secretion in mice was induced according
to the already disclosed method (Badger A M et al., J. Pharmac.
Env. Therap., 1996, 279:1453-1461). Balb/C males, age 8 to 12
weeks, in groups of 6 to 10 animals were used. The animals were
treated p.o. either with a solvent only (in negative and in
positive controls) or with solutions of substances 30 minutes prior
to i.p. treatment with LPS (E. coli serotype 0111:B4, Sigma) in a
dosis of 25 .mu.g/animal. Two hours later the animals were
euthanized by means of i.p. Roumpun (Bayer) and Ketanest
(Parke-Davis) injection. A blood sample of each animal was taken
into a Vacutainer tube (Becton Dickinson) and the plasma was
separated according to the producer's instructions. The TNF-.alpha.
level in the plasma was determined by ELISA procedure (Biosource,
R&D Systems) according to the producer's instructions. The test
sensitivity was <3 pg/ml TNF-.alpha.. The IL-1 level was
determined by ELISA procedure (R&D Systems). The percentage of
inhibition of TNF-.alpha. or IL-1 production was calculated by the
equation:
% inhibition=[1-(TS-NC)/(PC-NC)]*100.
[0101] Active are the compounds showing 30% or more inhibition of
TNF-.alpha. production at a dosis of 10 mg/kg.
[0102] Writhing Assay for Analgetic Activity
[0103] In this assay pain is induced by the injection of an
irritant, most frequently acetic acid, into the peritoneal cavity
of mice. Animals react with characteristic writhings, which has
given the name of the assay (Collier HOJ et al., Pharmac.
Chemother., 1968, 32:295-310; Fukawa K et al., J. Pharmacol. Meth
., 1980, 4:251-259; Schweizer A et al., Agents Actions, 1988,
23:29-31). The assay is convenient for the determination of
analgetic activity of compounds. Procedure: male Balb/C mice
(Charles River, Italy), age 8 to 12 weeks, were used. A control
group received methyl cellulose p.o. 30 minutes prior to i.p.
application of acetic acid in a concentration of 0.6%, whereas test
groups received standard (acetylsalicylic acid) or test substances
in methyl cellulose p.o. 30 minutes prior to i.p. application of
0.6% acetic acid (volume 0.1 ml/10 g). The mice were placed
individually under glass funnels and the number of writhings was
registered for 20 minutes for each animal. The percentage of
writhing inhibition was calculated according to the equation:
% inhibition=(mean value of number of writhings in the control
group-number of writhings in the test group)/number of writhings in
the control group*100.
[0104] Active are the compounds showing such analgetic activity as
acetylsalicylic acid or better.
[0105] In Vivo Model of LPS-Induced Shock in Mice
[0106] Male Balb/C mice (Charles River, Italy), age 8 to 12 weks,
were used. LPS isolated from Serratie marcessans (Sigma, L-6136)
was diluted in sterile physiological solution. The first LPS
injection was administered intradermally in a dosis of 4
.mu.g/mouse. 18 to 24 hours later, LPS was administered i.v. in a
dosis of 200 ag/mouse. A control group received two LPS injections
as disclosed above. The test groups received substances p.o. half
an hour prior to each LPS application. Survival after 24 hours was
observed.
[0107] Active are the substances at which the survival at a dosis
of 30 mg/kg was 40% or more.
[0108] Compounds from Examples 6 and 7 show activity in at least
two investigated assays though these results only represent an
illustration of biological activity of compounds and should not
limit the invention in any way.
PREPARATION PROCESSES WITH EXAMPLES
[0109] The present invention is illustrated by the following
Examples which are in no way a limitation thereof.
Example 1
8-Oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid ethyl
ester (48; Table 1)
[0110] Ethyl-2-mercaptoacetate (0.005 mole) and triethyl amine (1.0
ml) were added to a pyridine solution of the compound 41 (0.005
mole in 10 ml) and the mixture was refluxed under stirring for 3
hours. Then pyridine was removed under reduced pressure. Water and
ethyl acetate were added to the residue, the layers were separated
and the aqueous layer was twice more extracted with ethyl acetate.
The organic layer was dried on sodium sulfate and evaporated. There
remained a crude product, which was purified by recrystallization
or column chromatography to give a pure product in the form of a
white solid.
[0111] According to the above process, starting from compounds
42-47 there were prepared and isolated:
[0112] 1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic acid
ethyl ester;
[0113] 3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-carboxylic acid
ethyl ester;
[0114] 10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-carboxylic
acid ethyl ester;
[0115]
11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-carboxylic
acid ethyl ester;
[0116]
6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ca-
rboxylic acid ethyl ester;
[0117]
10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-
-carboxylic acid ethyl ester (Table 1, compounds 49-54)
Example 2
(8-Oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol (55;
Table 1)
[0118] An ether solution of ester 48 (1.5 mmole in 20 ml) was added
dropwise to a suspension of LiAIH4 in ether (5.0 mmole in 10 ml).
The reaction mixture was stirred at room temperature for 2 hours.
After the completion of reaction the excess of LiAIH.sub.4 was
decomposed by addition of ether and water. The obtained precipitate
was filtered off and the filtrate was evaporated under reduced
pressure. A crude product was purified by recrystallization to
obtain a pure product in the form of white crystals.
[0119] According to the above process, starting from compounds
49-54 there were prepared and isolated:
[0120]
(1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methanol;
[0121] (3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-yl)
-methanol;
[0122]
(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-yl)-methanol;
[0123]
(11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-yl)-methan-
ol;
[0124]
(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-y-
l)-methanol;
[0125]
(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene--
2-yl)-methanol,
[0126] (Table 1; compounds 56-61).
1TABLE 1 Compounds of the structure I wherein Y = Z = H 13 MS comp.
X G.sub.A G.sub.B R.sup.1 (m/z) .sup.1H NMR (ppm) 48 O G.sub.1
CO.sub.2Et -- 1.36 (t, 3H); 4.38 (q, 2H); 7.32 (m, 1H); 7.45-7.60
(m, 4H); 7.77 (d, 1H); 7.95 (d, 1H); 7.99 (s, 1H); 8.04 (d, 1H);
8.22 (s, 1H); 8.27 (s, 1H) (DMSO-d.sub.6) 49 S G.sub.1 CO.sub.2Et
-- 1.43 (t, 3H); 4.42 (q, 2H); 7.30-7.56 (m, 5H); 7.70 (d, 1H);
7.82 (m, 2H); 8.01 (s, 1H); 8.04 (s, 1H); 8.17 (s, 1H) (CDCl.sub.3)
50 S G.sub.1 CO.sub.2Et -- 1.34 (t, 3H); 4.20 (q, 2H); 7.10-8.10
(m, 10H); 9.20 (d, 1H); (CDCl.sub.3) 51 O G.sub.1 CO.sub.2Et --
1.43 (t, 3H); 4.42 (q, 2H); 7.21-7.73 (m, 8 H); 7.85 (d, 1H); 8.09
(s, 1H); 8.67 (d, 1H) (CDCl.sub.3) 52 O G.sub.2 CO.sub.2Et 403 1.36
(t, 3H); 3.90 (s, 3H); 4.37 (q, 2H); 7.18 (dd, 1H); 7.29-
(MH.sup.+) 7.36 (m, 2H); 7.46-7.50 (m, 2H); 7.76 (d, 1H); 7.86 (s,
1H); 7.95 (d, 1H); 8.18 (s, 1H), 8.20 (s, 1H) (CDCl.sub.3) 53 O
G.sub.3 CO.sub.2Et 377 1.34 (t, 3H); 1.74 (m, 2H); 1.80 (m, 2H);
2.74 (m, 2H); 3.06 (MH.sup.+) (m, 2H); 4.35 (q, 2H); 7.02 (d, 1H);
7.28-7.44 (m, 4H); 7.72 (d, 1H); 8.14 (s, 1H) (DMSO-d.sub.6) 54 O
G.sub.3 CO.sub.2Et 377 1.34 (t, 3H); 1.71 (bs, 4H); 2.73 (m, 4H);
4.35 (q, 2H); 7.16 (MH.sup.+) (s, 1H); 7.27-7.31 (m, 2H); 7.37-7.46
(m, 2H); 7.70 (d, 1H); 8.15 (s, 1H) (DMSO-d.sub.6) 55 O G.sub.1
CH.sub.2OH -- 4.76 (d, 2H); 5.74 (t, 1H); 7.27-7.62 (m, 7H); 7.92
(m, 1H); 7.93 (s, 1H); 8.00 (m, 1H); 8.05 (s, 1H) (DMSO-d.sub.6) 56
S G.sub.1 CH.sub.2OH -- 1.70 (bs, 1H), 4.95 (s, 2H); 7.25-7.51 (m,
6H); 7.70 (d, 1H); 7.81 (m, 2H); 7.98 (s, 1H); 8.16 (s, 1H)
(CDCl.sub.3) 57 S G.sub.1 CH.sub.2OH -- 1.58 (bs, 1H); 5.00 (s,
2H); 7.20-7.90 (m, 10H); 9.09 (d, 1H) (CDCl.sub.3) 58 O G.sub.1
CH.sub.2OH -- 1.69 (bs, 1H); 4.94 (s, 2H); 7.18-7.67 (m, 9H); 7.83
(d, 1H); 8.66 (d, 1H) (CDCl.sub.3) 59 O G.sub.2 CH.sub.2OH 361 --
(MH.sup.+) 60 O G.sub.1 CH.sub.2OH 334 1.72 (m, 2H); 1.81 (m, 2H);
2.73 (t, 2H); 3.05 (t, 2H); 4.71 (M.sup.+) (d, 2H); 5.64 (t, 1H);
6.96 (d, 1H); 7.16 (d, 1H); 7.26 (m, 1H); 7.32 (s, 1H); 7.36-7.40
(m, 2H); 7.56 (d, 1H) (DMSO-d.sub.6) 61 O G.sub.3 CH.sub.2OH 334
1.71 (bs, 4H); 2.71 (m, 4H); 4.71 (d, 2H); 5.65 (t, 1H); 7.09
(M.sup.+) (s, 1H); 7.11 (s, 1H); 7.22-7.41 (m, 4H); 7.54 (d, 1H)
(DMSO-d.sub.6)
Example 3
a)
Dimethyl-[2-(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-et-
hyl]-amine
[0127] To a solution of 2-dimethylaminoethyl chloride hydrochloride
(3.0 mmole) in 50% sodium hydroxide (5 ml), a catalytic amount of
benzyltriethylammonium chloride and a solution of alcohol 55 (0.3
mmole) in toluene (5 ml) were added. The reaction mixture was
heated under reflux and vigorous stirring for 4 hours. Then it was
cooled to room temperature, diluted with water and extracted with
dichloromethane. After purifying by column chromatography, a yellow
oily product was isolated.
[0128] .sup.1H NMR (ppm, CDCl.sub.3): 2.31 (s, 6H); 2.60 (t, 2H);
3.68 (t, 2H); 4.78 (s, 2H); 7.18-7.50 (m, 7H); 7.73 (s, 1H); 7.80
(m, 2H); 7.90 (s, 1H); MS (m/z): 402 (MH.sup.+).
b)
Dimethyl-[3-(8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-pr-
opyl]-amine
[0129] By the reaction of alcohol 55 (0.2 mmole) and
3-dimethylaminopropyl chloride hydrochloride (2.0 mmole), a yellow
oily product was obtained.
[0130] .sup.1H NMR (ppm, CDCl.sub.3): 2.01 (m, 2H); 2.50 (s, 6H);
2.75 (t, 2H); 3.68 (t, 2H); 4.75 (s, 2H); 7.18-7.73 (m, 7H); 7.73
(s, 1H); 7.80 (m, 2H); 7.90 (s, 1H); MS (m/z): 416 (MH.sup.+).
c)
3-(8-Oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propylamine
[0131] By the reaction of alcohol 55 (0.3 mmole) and 3-aminopropyl
chloride hydrochloride (3.0 mmole), a yellow oily product was
obtained.
[0132] .sup.1H NMR (ppm, CD.sub.3COCD.sub.3): 1.90 (m, 2H); 2.86
(b, 2H); 3.30 (t, 2H); 3.68 (t, 2H); 4.78 (s, 2H); 7.25-7,65 (m,
7H); 7.89 (s, 1H); 7.90-8.00 (m, 2H); 8.04 (s, 1H); MS (m/z): 388
(MH.sup.+).
Example 4
Dimethyl-[3-(1,8-dithia-benzo[e]naphtho[3,2-h]azulene-2-ylmethoxy)-propyl]-
-amine
[0133] To a solution of 2-dimethylaminopropyl chloride
hydrochloride (8.0 mmole) in 50% sodium hydroxide (10 ml), a
catalytic amount of benzyltriethylammonium chloride and a solution
of alcohol 56 (0.6 mmole) in toluene (10 ml) were added. The
reaction mixture was heated under reflux and vigorous stirring for
4 hours. Then it was cooled to room temperature, diluted with water
and extracted with dichloromethane. After purifying by column
chromatography, a yellow oily product was isolated.
[0134] .sup.1H NMR (ppm, CDCl.sub.3): 1.90 (m, 2H); 2.31 (s, 6H);
2.49 (t, 2H); 3.67 (t, 2H); 4.76 (s, 2H); 7.23 (s, 1H); 7.29-7.52
(m, 5H); 7.70 (d, 1H); 7.81 (m, 2H); 7.99 (s, 1H); 8.16 (s,1H).
Example 5
a)
Dimethyl-[2-(3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-eth-
yl]-amine
[0135] To a solution of 2-dimethylaminoethyl chloride hydrochloride
(10.0 mmole) in 50% sodium hydroxide (10 ml), a solution of alcohol
57 (0.7 mmole) in toluene (10 ml) was added. The reaction mixture
was heated under reflux and vigorous stirring for 4 hours. Then it
was cooled to room temperature, diluted with water and extracted
with dichloromethane. After purifying by column chromatography, a
yellow oily product was isolated.
[0136] .sup.1H NMR (ppm, CDCl.sub.3): 2.33 (s, 6H); 2.63 (t, 2H);
3.73 (t, 2H); 4.82 (s, 2H); 7.15-7.80 (m, 10H); 9.02 (d, 1H).
b)
Dimethyl-[3-(3,10-dithia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-pro-
pyl]-amine
[0137] By the reaction of alcohol 57 and 3-dimethylaminopropyl
chloride, a yellow oily product was obtained; .sup.1H NMR (ppm,
CDCl.sub.3): 1.87 (m, 2H); 2.27 (s, 6H); 2.45 (t, 2H); 3.68 (t,
2H); 4.78 (s, 2H); 7.20-7.83 (m, 1OH); 9.02 (d, 1H); MS (m/z): 432
(MH.sup.+).
Example 6
a)
Dimethyl-[2-(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-e-
thyl]-amine
[0138] To a solution of 2-dimethylaminoethyl chloride hydrochloride
(5.0 mmole) in 50% sodium hydroxide (5 ml), a toluene solution of
alcohol 58 (0.5 mmole) was added. The reaction mixture was heated
under reflux and vigorous stirring for 3 hours. Then it was cooled
to room temperature, diluted with water and extracted with
dichloromethane. After purifying by column chromatography, a yellow
oily product was isolated.
[0139] .sup.1H NMR (ppm, CDCl.sub.3): 2.36 (s, 6H); 2.65 (t, 2H);
3.72 (t, 2H); 4.79 (s, 2H); 7.18-7.67 (m, 9H); 7.83 (d, 1H); 8.66
(d, 1H); MS (m/z): 402 (MH.sup.+).
b)
Dimethyl-[3-(10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-p-
ropyl]-amine
[0140] By the reaction of alcohol 58 and 3-dimethylaminopropyl
chloride hydrochloride, a yellow oily product was obtained.
[0141] .sup.1H NMR (ppm, CDCl.sub.3): 1.91 (m, 2H); 2.35 (s, 6H);
2.55 (t, 2H); 3.65 (t, 2H); 4.75 (s, 2H); 7.20-7.67 (m, 9H); 7.83
(d, 1H); 8.66 (d, 1H); MS (m/z): 416 (MH.sup.+).
Example 7
Dimethyl-[3-(11-methoxy-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-2-ylmet-
hoxy)-propyl]-amine
[0142] To a solution of 3-dimethylaminopropyl chloride
hydrochloride (3.0 mmole) in 50% sodium hydroxide (5 ml), a
catalytic amount of benzyltriethylammonium chloride and a solution
of alcohol 59 (0.3 mmole) in toluene (5 ml) were added. The
reaction mixture was heated under reflux and vigorous stirring for
6 hours. Then it was cooled to room temperature, diluted with water
and extracted with dichloromethane. After purifying by column
chromatography, a yellow product was isolated, which crystallized
upon standing.
[0143] .sup.1H NMR (ppm, CDCl.sub.3): 1.86 (p, 2H); 2.25 (s, 6H);
2.41 (t, 2H); 3.64 (t, 2H); 3.92 (s, 3H); 4.74 (s, 2H); 7.07-7.49
(m, 7H); 7.63 (s, 1H); 7.71 (d, 1H); 7.83 (s, 1H MS (m/z): 446
(MH.sup.+).
Example 8
a)
Dimethyl-[2-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azu-
lene-2-ylmethoxy)-ethyl]-amine
[0144] To a solution of 2-dimethylaminoethyl chloride hydrochloride
(6.0 mmole) in 50% sodium hydroxide (10 ml), a solution of alcohol
60 (0.6 mmole) in toluene (10 ml) was added. The reaction mixture
was heated under reflux and vigorous stirring for 3 hours. Then it
was cooled to room temperature, diluted with water and extracted
with dichloromethane. After purifying by column chromatography, a
yellow oily product was isolated.
[0145] .sup.1H NMR (ppm, CDCl.sub.3): 1.79 (m, 2H); 1.86 (m, 2H);
2.43 (s, 6H); 2.73 (m, 2H); 2.77 (t, 2H); 3.12 (t, 2H); 3.75 (t,
2H); 4.75 (s, 2H); 6.90 (d, 1H); 7.14-7.35 (m, 5H); 7.45 (d, 1H);
MS (m/z): 406 (MH.sup.+).
b)
Dimethyl-[3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azu-
lene-2-ylmethoxy)-propyl]-amine
[0146] By the reaction of alcohol 60 and 3-dimethylaminopropyl
chloride hydrochloride, a yellow oily product was obtained.
[0147] .sup.1H NMR (ppm, CDCl.sub.3): 1.80 (m, 2H); 1.88 (m, 2H);
2.02 (m, 2H); 2.51 (s, 6H); 2.75 (m, 2H); 2.79 (t, 2H); 3.14 (t,
2H); 3.67 (t, 2H); 4.73 (s, 2H); 6.89 (d, 1H); 7.15-7.36 (m, 5H);
7.45 (d, 1H); MS (m/z): 420 (MH.sup.+).
c)
3-(6,7,8,9-Tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylm-
ethoxy)-propylamine
[0148] By the reaction of alcohol 60 and 3-aminopropyl chloride
hydrochloride, a yellowish oily product was obtained.
[0149] .sup.1H NMR (ppm, CDCl.sub.3): 1.41 (s, 2H); 1.75-1.87 (m,
6H); 2.77 (t, 2H); 2.85 (t, 2H); 3.12 (t, 2H); 3.64 (t, 2H); 4.71
(s, 2H); 6.89 (d, 1H); 7.14-7.36 (m, 5H); 7.45 (d, 1H); MS (m/z):
414 (M+Na.sup.+).
Example 9
Methyl-[3-(6,7,8,9-tetrahydro-10-oxa-3-thia-benzo[e]naphtho[1,2-h]azulene--
2-ylmethoxy)-propyl]-amine
[0150] To a methanolic solution of dimethyl-[3-(6,
7,8,9-tetrahydro-10-oxa-
-3-thia-benzo[e]naphtho[1,2-h]azulene-2-ylmethoxy)-propyl]-amine
prepared as in Example 8b (1.0 mmole in 30 ml), sodium acetate
trihydrate (5.4 mmole) and iodine (1.13 mmole) were added. The
reaction mixture was illuminated with a 500 W lamp and stirred at
ambient temperature for 5 hours. After the completion of the
reaction, a 10% aqueous sodium thiosulfate solution was added to
the reaction mixture. The solvent was evaporated under reduced
pressure and the residue was extracted with ethyl acetate. A crude
product was purified by column chromatography to obtain a pure
product in the form of a yellow oil.
[0151] .sup.1H NMR (ppm, CDCl.sub.3): 1.76-1.91 (m, 4H); 2.00 (m,
2H); 2.59 (s, 3H); 2.77 (m, 2H); 2.96 (t, 2H); 3.12 (t, 2H); 3.70
(t, 2H); 4.4-4.7 (b, 1H); 4.74 (s, 2H); 6.89 (d, 1H); 7.15-7.36 (m,
5H); 7.45 (d, 1H); MS (m/z): 406 (MH.sup.+).
Example 10
a)
Dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]-
azulene-2-ylmethoxy)-ethyl]-amine
[0152] To a solution of 2-dimethylaminoethyl chloride hydrochloride
(6.0 mmole) in 50% sodium hydroxide (10 ml), a solution of alcohol
61 (0.6 mmole) in toluene (10 ml) was added. The reaction mixture
was heated under reflux and vigorous stirring for 3 hours. Then it
was cooled to room temperature, diluted with water and extracted
with dichloromethane. After purifying by column chromatography, a
yellow oily product was isolated.
[0153] .sup.1H NMR (ppm, CDCl.sub.3): 1.77 (m, 4H); 2.38 (s, 6H);
2.67 (m, 2H); 2.75 (m, 4H); 3.71 (t, 2H); 4.75 (s, 2H); 7.01 (s,
1H); 7.12 (s, 1H); 7.14-7.45 (m, 5H); MS (m/z): 406 (MH.sup.+).
b)
Dimethyl-[3-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]-
azulene-2-ylmethoxy)-propyl]-amine
[0154] By the reaction of alcohol 61 and 3-dimethylaminopropyl
chloride hydrochloride, a yellow oily product was obtained.
[0155] .sup.1H NMR (ppm, CDCl.sub.3): 1.78 (m, 4H); 1.99 (m, 2H);
2.49 (s, 6H); 2.70-2.80 (m, 6H); 3.65 (t, 2H); 4.71 (s, 2H); 7.01
(s, 1H); 7.12 (s, 1H); 7.14-7.45 (m, 5H); MS (m/z): 420
(MH.sup.+).
c)
4-[2-(10,11,12,13-Tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-
-2-ylmethoxy)-ethyl]-morpholine
[0156] By the reaction of alcohol 61 and
4-(2-chloroethyl)morpholine hydrochloride, a yellow oily product
was obtained.
[0157] .sup.1H NMR (ppm, CDCl.sub.3): 1.77 (m, 4H); 2.53 (b, 4H);
2.66 (m, 2H); 2.75 (m, 4H); 3.70-3.75 (m, 6H); 4.75 (s, 2H); 7.01
(s, 1H); 7.11 (s, 1H); 7.14-7.44 (m, 5H); MS (m/z): 448
(MH.sup.+).
d)
1-[2-(10,11,12,13-Tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-
-2-ylmethoxy)-ethyl]-piperidine
[0158] By the reaction of alcohol 61 and
1-(2-chloroethyl)piperidine hydrochloride, a yellow oily product
was obtained.
[0159] .sup.1H NMR (ppm, CDCl.sub.3): 1.45 (m, 2H); 1.65 (m, 4H);
1.77 (m, 4H); 2.52 (m, 4H); 2.66 (m, 2H); 2.75 (m, 4H); 3.73 (t,
2H); 4.74 (s, 2H); 7.01 (s, 1H); 7.12 (s, 1H); 7.14-7.44 (m, 5H);
MS (m/z): 446 (MH.sup.+).
e)
1-[2-(10,11,12,13-Tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]azulene-
-2-ylmethoxy)-ethyl]-pyrrolidine
[0160] By the reaction of alcohol 61 and
1-(2-chloroethyl)pyrrolidine hydrochloride, a yellow oily product
was obtained.
[0161] .sup.1H NMR (ppm, CDCl.sub.3): 1.78 (m, 4H); 1.92 (b, 4H);
2.74-2.94 (m, 10H); 3.84 (b, 2H); 4.76 (s, 2H); 7.01 (s, 1H); 7.12
(s, 1H); 7.15-7.45 (m, 5H); MS (n/z): 432 (MH.sup.+).
f)
Dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,2-h]-
azulene-2-ylmethoxy)-propyl]-amine
Dimethyl-[1-methyl-(10,11,12,13-tefrahydro-8-oxa-1-thia-benzo[e]naphtho[3,-
2-h]azulene-2-ylmethoxy)-ethyl]-amine
[0162] By the reaction of alcohol 61 and 1-dimethylamino-2-propyl
chloride hydrochloride, two products were obtained, which were
separated and purified by column chromatography to give yellow oily
substances, namely:
[0163]
dimethyl-[2-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]naphtho[3,-
2-h]azulene-2-ylmethoxy)-propyl]-amine;
[0164] .sup.1H NMR (ppm, CDCl.sub.3): 1.25 (d, 3H); 1.77 (m, 4H);
2.36 (s, 6H); 2.40 (m, 1H); 2.60 (m, 1H); 2.75 (m, 4H); 3.90 (b,
1H); 4.80 (m, 2H); 7.00 (s, 1H); 7.12 (s, 1H); 7.14-7.45 (m, 5H);
MS (m/z): 420 (MH.sup.+), and
[0165]
dimethyl-[1-methyl-(10,11,12,13-tetrahydro-8-oxa-1-thia-benzo[e]nap-
htho[3,2-h]azulene-2-ylmethoxy)-ethyl]-amine;
[0166] .sup.1H NMR (ppm, CDCl.sub.3): 1.04 (d, 3H); 1.77 (m, 4H);
2.33 (s, 6H); 2.75 (m, 4H); 2.85 (m, 1H); 3.45 (m, 1H); 3.59 (m,
1H); 4.74 (s, 2H); 7.01 (s, 1H); 7.12 (s, 1H); 7.14-7.44 (m, 5H);
MS (m/z): 420 (MH.sup.+).
[0167] Preparation of Starting Substances
[0168] Process A
1-[2-(Naphthalene-2-yloxy)-phenyl]-ethanone (1; Table 2)
[0169] A mixture of 2-naphthol (0.035 mole), 2-chloroacetophenone
(0.026 mole), potassium carbonate (0.040 mole) and CuCl (100 mg) in
isoamyl alcohol (3 ml) was refluxed overnight. Then the reaction
mixture was filtered and the precipitate was washed a few times
with ethyl acetate and then the filtrate was washed with a 10%
aqueous sodium hydroxide solution and water. The solvent was
removed by evaporation under reduced pressure and the residue was
distilled under high vacuum to give a pure product in the form of a
light yellow liquid.
[0170] Process B
1-Morpholine-4-yl-2-[2-(naphthalene-2-yloxy)-phenyl]-ethanethione
(2; Table 2)
[0171] A mixture of the compound 1 (0.058 mole), morpholine (0.08
mole) and sulfur (0.087 mole) was refluxed for about 3 hours. After
the completion of the reaction the mixture was poured into hot
ethanol, wherefrom the product was precipitated by cooling.
[0172] Process C1
2-(Naphthalene-2-ylsulfanyl)-benzoic acid (3; Table 2)
[0173] 2-Naphthalenethiol (0.06 mole), 2-iodobenzoic acid (0.60
mole) and Cu powder (1 g) were added to an aqueous potassium
hydroxide solution (0.21 mole in 110 ml). The reaction mixture was
refluxed for 8 hours and then filtered. Concentrated HCl was added
drop by drop to the filtrate up to an acidic reaction. The
separated white crystals were sucked off, washed a few times with
water and dried.
[0174] According to the same process, starting from 2-iodobenzoic
acid and 1-naphthalenethiol, also
2-(naphthalene-1-ylsulfanyl)-benzoic acid (Table 2; compound 4) was
obtained.
[0175] Process C2
2-(Naphthalene-1-yloxy)-benzoic acid (5; Table 2)
[0176] A mixture of 1-naphthol (0.03 mole), 2-iodobenzoic acid
(0.03 mole), potassium carbonate (0.045 mole) and Cu powder (150
mg) in nitrobenzene or xylene (10 ml) was heated at 140.degree. C.
for about 1 hour. After the completion of the reaction water (100
ml) was added to the cooled reaction mixture, the organic layer was
separated and concentrated HCl was addedd to the aqueous layer drop
by drop up to an acidic reaction. The separated product was
extracted with ethyl acetate.
[0177] According to the same procedure, starting from 2-iodobenzoic
acid and
[0178] 7-methoxy-2-naphthol;
[0179] 5,6,7,8-tetrahydro-1-naphthol;
[0180] 5,6,7,8-tetrahydro-2-naphthol;
[0181] there were obtained the following compounds:
[0182] 2-(7-methoxy-naphthalene-2-yloxy)-benzoic acid;
[0183] 2-(5,6,7,8-tetrahydro-naphthalene-1-yloxy)-benzoic acid;
[0184] 2-(5,6,7,8-tetrahydro-naphthalene-2-yloxy)-benzoic acid
[0185] (Table 2; compounds 6-8)
[0186] Process D
[2-(Naphthalene-2-ylsulfanyl)-phenyl]-methanol (9; Table 2)
[0187] To a suspension of LiALH.sub.4 in diethyl ether (0.1 mole in
100 ml), acid 3 (0.06 mole) was added step by step. After 2 hours
of stirring the reaction mixture at room temperature, the excess of
LiAlH.sub.4 was decomposed by adding ether and water. The obtained
precipitate was filtered and the filtrate was evaporated under
reduced pressure to give a crude product, which was purified by
column chromatography.
[0188] According to the same procedure, starting from compounds 4-8
the following compounds were obtained:
[0189] [2-(naphthalene-1-ylsulfanyl)-phenyll-methanol;
[0190] [2-(naphthalene-1-yloxy)-phenyl]-methanol;
[0191] [2-(7-methoxy-naphthalene-2-yloxy)-phenyl]-methanol;
[0192]
[2-(5,6,7,8-tetrahydro-naphthalene-1-yloxy)-phenyl]-methanol;
[0193]
[2-(5,6,7,8-tetrahydro-naphthalene-2-yloxy)-phenyl]-methanol
[0194] (Table 2; compounds 10-14)
[0195] Process E
2-(2-Bromomethyl-phenylsulfanyl)-naphthalene (15; Table 2)
[0196] To a dichloromethane solution of alcohol 9 (0.057 mole in
200 ml) cooled to 0.degree. C., PBr.sub.3 (0.019 mole) was added
stepwise drop by drop and the mixture was stirred at the same
temperature for about 30 minutes. After the completion of the
reaction the mixture was poured to cool water (100 ml), the organic
layer was separated and the aqueous layer was extracted twice with
dichloromethane. The dichloromethane layer was shaken once with a
saturated sodium hydrogen carbonate solution, dried on
Na.sub.2SO.sub.4 and evaporated under reduced pressure to leave a
crude product, which was purified by column chromatography.
[0197] According to the same procedure, starting from the compounds
10-14 the following compounds were obtained:
[0198] 1-(2-bromomethyl-phenylsulfanyl)-naphthalene;
[0199] 1-(2-bromomethyl-phenoxy)-naphthalene;
[0200] 2-(2-bromomethyl-phenoxy)-7-methoxy-naphthalene;
[0201]
5-(2-bromomethyl-phenoxy)-1,2,3,4-tetrahydro-naphthalene;
[0202] 6-(2-bromomethyl-phenoxy)-1,2,
3,4-tetrahydro-naphthalene
[0203] (Table 2; compounds 16-20)
[0204] Process F
[2-(Naphthalene-2-ylsulfanyl)-phenyl]-acetonitrile (21; Table
2)
[0205] To an ethanolic solution of bromide 15 (0.05 mole in 60 ml)
NaCN (0.063 mole) was added and the reaction mixture was refluxed
for 3 hours. After the completion of the reaction ethanol was
eliminated under reduced pressure and water (80 ml) and ethyl
acetate (80m1) were added to the residue. The layers were separated
and the aqueous layer was extracted two more times with ethyl
acetate. The combined organic layers were washed with water, dried
on Na.sub.2SO.sub.4 and evaporated under reduced pressure to leave
a crude product, which was purified by column chromatography.
[0206] According to the same procedure, starting from compounds
16-20 the following compounds were obtained:
[0207] [2-(naphthalene-1-ylsulfanyl)-phenyl]-acetonitrile;
[0208] [2-(naphthalene-1-yloxy)-phenyl]-acetonitrile;
[0209] [2-(7-methoxy-naphthalene-2-yloxy)-phenyl]-acetonitrile;
[0210]
[2-(5,6,7,8-tetrahydro-naphthalene-1-yloxy)-phenyl]-acetonitrile;
[0211]
[2-(5,6,7,8-tetrahydro-naphthalene-2-yloxy)-phenyl]-acetonitrile
[0212] (Table 2; compounds 22-26)
[0213] Process G
[2-(Naphthalene-2-yloxy)-phenyl]acetic acid (27; Table 2)
[0214] A mixture of 2 (0.04 mole), acetic acid (10 ml) and 50%
sulfuric acid (4.5 ml) was stirred under reflux for about 5 hours.
After the completion of the reaction the reaction mixture was
poured into water (10 ml). The separated crystals were sucked off,
dissolved in a 10% aqueous NaOH solution and the solution was
extracted twice with dichloromethane. The aqueous layer was
acidified with concentrated HCl up to an acidic reaction. The
separated crystals were filtered and dried.
[0215] Process H
[2-(Naphthalene-2-ylsulfanyl)-phenyl]acetic acid (28; Table 2)
[0216] An aqueous KOH solution (0.15 mole in 15 ml) was aded to an
ethanolic solution of nitrile 21 (0.045 mole in 60 ml). The
reaction mixture was stirred under reflux for about 10 hours and
then ethanol was evaporated under reduced pressure. The residue was
diluted with water and shaken once with ethyl acetate. The aqueous
layer was acidified to an acidic reaction in order to separate the
product.
[0217] According to the same procedure, starting from the compounds
22-26 the following compounds were obtained:
[0218] [2-(naphthalene-1-ylsulfanyl)-phenyl]acetic acid;
[0219] [2-(naphthalene-1-yloxy)-phenyl]acetic acid;
[0220] [2-(7-methoxy-naphthalene-2-yloxy)-phenyl]acetic acid;
[0221] [2-(5,6,37,8-tetrahydro-naphthalene-1-yloxy)-phenyl]acetic
acid;
[0222] [2-(5, 6,7,8-tetrahydro-naphthalene-2-yloxy)-phenyl]acetic
acid
[0223] (Table 2; compounds 29-33)
2TABLE 2 Compounds of the structure VIII wherein Y = Z = H 14 MS
comp. X G.sub.A G.sub.B R.sup.5 (m/z) .sup.1H NMR (ppm) 1 O G.sub.1
COMe 263 (MH.sup.+) 2.68 (s, 3H); 6.96-7.97 (m, 11H) (CDCl.sub.3) 2
O G.sub.1 15 364 (MH.sup.+) -- 3 S G.sub.1 CO.sub.2H -- 6.77-8.23
(m, 11H); 13.50 (b, 1H) (DMSO-d.sub.6) 4 S G.sub.1 CO.sub.2H --
4.10 (b, 1H); 6.48 (m, 1H); 7.11 (m, 2H); 7.53 (m, 3H); 7.90-8.32
(m, 5H) (CDCl.sub.3) 5 O G.sub.1 CO.sub.2H 265 (MH.sup.+) 6.77-8.20
(m, 11H); 12.98 (b, 1H) (DMSO-d.sub.6) 6 O G.sub.2 CO.sub.2H --
3.82 (s, 3H); 6.88-8.14 (m, 10H); 12.93 (bs, 1H) (DMSO-d.sub.6) 7 O
G.sub.3 CO.sub.2H -- 1.72 (bs, 4H); 2.61 (bs, 2H); 2.75 (bs, 2H);
6.52 (d, 1H); 6.81-6.88 (m, 2H); 7.06 (t, 1H); 7.20 (m, 1H); 7.49
(t, 1H); 7.79 (m, 1H); 12.83 (bs, 1H) (DMSO-d.sub.6) 8 O G.sub.3
CO.sub.2H -- 1.71 (m, 4H); 2.66 (bs, 4H); 6.62-7.88 (m, 7H);
12.5-13.0 (b, 1H) (DMSO-d.sub.6) 9 S G.sub.1 CH.sub.2OH -- 1.92
(bs, 1H); 4.86 (s, 2H); 7.28-7.90 (m, 11H) (CDCl.sub.3) 10 S
G.sub.1 CH.sub.2OH -- 1.79 (bs, 1H); 4.87 (s, 2H); 7.05-7.55 (m,
8H); 7.79-7.90 (m, 2H); 8.31 (m, 1H) (CDCl.sub.3) 11 O G.sub.1
CH.sub.2OH 250 (M.sup.+) 4.61 (d, 2H); 5.22 (t, 1H); 6.78-8.18 (m,
11H) (DMSO-d.sub.6) 12 O G.sub.2 CH.sub.2OH -- 3.81 (s, 3H); 4.52
(d, 2H); 5.18 (t, 1H); 6.95-7.86 (m, 10H) (DMSO-d.sub.6) 13 O
G.sub.3 CH.sub.2OH -- 1.71 (bs, 4H); 2.59 (bs, 2H); 2.75 (bs, 2H);
4.56 (d, 2H); 5.16 (t, 1H); 6.51-7.60 (m, 7H) (DMSO-d.sub.6) 14 O
G.sub.3 CH.sub.2OH -- 1.71 (m, 4H); 2.66 (m, 4H); 4.52 (d, 2H);
5.14 (t, 1H); 6.60- 6.67 (m, 2H); 6.79 (d, 1H); 7.02 (d, 1H);
7.12-7.26 (m, 2H); 7.52 (m, 1H) (DMSO-d.sub.6) 15 S G.sub.1
CH.sub.2Br -- 4.80 (s, 2H); 7.24-7.87 (m, 11H) (CDCl.sub.3) 16 S
G.sub.1 CH.sub.2Br -- 4.81 (s, 2H); 6.89-7.21 (m, 3H); 7.40-7.61
(m, 5H); 7.86- 7.91 (m, 2H); 8.35 (m, 1H) (CDCl.sub.3) 17 O G.sub.1
CH.sub.2Br 312;314 4.69 (s, 2H); 6.73-8.27 (m, 11H) (CDCl.sub.3)
(M.sup.+) 18 O G.sub.2 CH.sub.2Br 342;344 3.83 (s, 3H); 4.73 (s,
2H); 6.93-7.90 (m, 10H) (DMSO-d.sub.6) (M.sup.+) 19 O G.sub.3
CH.sub.2Br 316;318 1.71 (bs, 4H); 2.61 (bs, 2H); 2.76 (bs, 2H);
4.74 (d, 2H); (M.sup.+) 6.58 (d, 1H); 6.68 (d, 1H); 6.93 (d, 1H);
7.02-7.36 (m, 3H), 7.53 (d, 1H) (DMSO-d.sub.6) 20 O G.sub.3
CH.sub.2Br 316;318 1.72 (m, 4H); 2.69 (bs, 4H); 4.70 (s, 2H);
6.72-6.80 (m, (M.sup.+) 3H); 7.06-7.12 (m, 2H); 7.30 (m, 1H); 7.53
(d, 1H) (DMSO d.sub.6) 21 S G.sub.1 CH.sub.2CN 276 -- (MH.sup.+) 22
S G.sub.1 CH.sub.2CN 276 -- (MH.sup.+) 23 O G.sub.1 CH.sub.2CN 259
3.87 (s, 2H); 6.73-8.28 (m, 11H) (CDCl.sub.3) (M.sup.+) 24 O
G.sub.2 CH.sub.2CN 290 3.84 (s, 3H); 4.02 (s, 2H); 6.96-7.91 (m,
10H) (DMSO-d.sub.6) (MH.sup.+) 25 O G.sub.3 CH.sub.2CN -- 1.71 (bs,
4H); 2.59 (bs, 2H); 2.77 (bs, 2H); 4.00 (s, 2H); 6.54-6.70 (m, 2H);
6.95 (d, 1H); 7.03-7.31 (m, 3H); 7.47 (d, 1H) (DMSO-d.sub.6) 26 O
G.sub.3 CH.sub.2CN 264 1.72 (m, 4H); 2.67 (m, 4H); 3.96 (s, 2H);
6.61-7.49 (m, 7H) (MH.sup.+) (DMSO-d.sub.6) 27 O G.sub.1
CH.sub.2CO.sub.2H -- 3.63 (s, 2H); 6.92-7.97 (m, 11H); 12.25 (bs,
1H) (DMSO-d.sub.6) 28 S G.sub.1 CH.sub.2CO.sub.2H -- 3.91 (s, 2H);
7.28-7.82 (m, 11H) (DMSO-d.sub.6) 29 S G.sub.1 CH.sub.2CO.sub.2H --
3.90 (s, 2H); 6.97 (d, 1H); 7.18-7.69 (m, 7H); 8.01-8.10 (m, 2H);
8.24 (m, 1H); 12.60 (b, 1H) (DMSO-d.sub.6) 30 O G.sub.1
CH.sub.2CO.sub.2H -- 3.68 (s, 2H); 6.71-8.13 (m, 11H); 12.32 (bs,
1H) (DMSO- d.sub.6) 31 O G.sub.2 CH.sub.2CO.sub.2H 309 3.60 (s,
2H); 3.82 (s, 3H); 6.93-7.42 (m, 8H); 7.78-7.86 (m, (MH.sup.+) 2H);
12.14 (bs, 1H) (DMSO-d.sub.6) 32 O G.sub.3 CH.sub.2CO.sub.2H --
1.71 (bs, 4H); 2.58 (bs, 2H); 2.75 (bs, 2H); 3.59 (s, 2H);
6.55-6.63 (m, 2H); 6.88 (d, 1H); 7.01-7.34 (m, 4H) (DMSO d.sub.6)
33 O G.sub.3 CH.sub.2CO.sub.2H -- 1.71 (m, 4H); 2.66 (m, 4H); 3.58
(s, 2H); 6.63-7.35 (m, 7H) 12.17 (bs, 1H) (DMSO-d.sub.6)
[0224] Process I
13H-5-Oxa-benzo[4,5]cyclohepta[1,2-b]naphthalene-12-one (34; Table
3)
[0225] A mixture of an acid 27 and polyphosphoric acid (PPA; 3.0 g
in 30 g) was vigorously sitrred at 100.degree. C. for about 2
hours. The reaction mixture was then poured into water and
extracted three times with dichloromethane. The dichloromethane
layer was dried on Na.sub.2SO.sub.4 and evaporated under reduced
pressure to leave a crude product, which may be purified by column
chromatography or recrystallization.
[0226] According to the same procedure, starting from the compounds
28-33 following compounds were obtained:
[0227] 13H-5-thia-benzo[4,
5]cyclohepta[1,2-b]naphthalene-12-one;
[0228] 8H-13-thia-benzo[5,6]cyclohepta[1,2-b]naphthalene-7-one;
[0229] 8H-13-oxa-benzo[5, 6]cyclohepta[1,2-a]naphthalene-7-one;
[0230] 8-methoxy-13H-S-oxa-benzo[4,
S]cyclohepta[1,2-b]naphthalene-12-one;
[0231]
1,2,3,4-tetrahydro-8H-13-oxa-benzo[5,6]cyclohepta[1,2-a]naphthalene-
-7-one;
[0232]
7,8,9,10-tetrahydro-13H-5-oxa-benzo[4,5]cyclohepta[1,2-b]naphthalen-
e-12-one
[0233] (Table 3; compounds 35-40)
3TABLE 3 Compounds of the formula VI wherein Y = Z = H 16 MS comp.
X G.sub.A G.sub.B (m/z) .sup.1H NMR (ppm) 34 O G.sub.1 261 4.22 (s,
2H); 7.12-7.99 (m, 9H); 8.66 (s, 1H) (CDCl.sub.3) (MH.sup.+) 35 S
G.sub.1 -- 4.55 (s, 2H); 7.19-7.93 (m, 8H); 8.11 (s, 1H); 8.78 (s,
1H) (CDCl.sub.3) 36 S G.sub.1 -- 4.55 (s, 2H); 7.06-8.32 (m, 9H);
8.91 (m, 1H) (CDCl.sub.3) 37 O G.sub.1 261 4.20 (s, 2H); 7.15-7.84
(m, 8H); 8.04 (d, 1H); 8.77 (m, 1H) (MH.sup.+) (CDCl.sub.3) 38 O
G.sub.2 291 3.94 (s, 3H); 4.19 (s, 2H); 7.07-7.35 (m, 6H); 7.66 (s,
1H); 7.79 (MH.sup.+) (d, 1H); 8.57 (s, 1H) (DMSO-d.sub.6) 39 O
G.sub.3 265 1.70-1.90 (m, 4H); 2.78 (m, 2H); 3.04 (m, 2H); 4.08 (s,
2H); 6.97 (MH.sup.+) (d, 1H), 7.22-7.44 (m, 4H); 7.66 (d, 1H)
(DMSO-d.sub.6) 40 O G.sub.3 265 1.72 (m, 4H); 2.71 (bs, 2H); 2.80
(bs, 2H); 4.08 (s, 2H); 7.18 (s, (MH.sup.+) 1H); 7.20-7.43 (m, 4H);
7.61 (s, 1H) (DMSO-d.sub.6)
[0234] Process J
12-Chloro-5-oxa-benzo[4,5]cyclohepta[1,2-b]naphthalene-13-carbaldehyde
(41; Table 4)
[0235] A trichloroethene solution of the compound 34 (0.008 mole in
5 ml) was added drop by drop to a solution of Vilsmeier-Hack
reagent in trichloroethene (0.01 mole in 5 ml). The reaction
mixture was then refluxed for about 6 hours, whereupon it was
cooled and 20 ml of a 50% aqueous sodium acetate solution were
added stepwise drop by drop thereto. The layers were separated and
the aqueous layer was extracted three times with dichloromethane.
The dichloromethane layers dried on Na.sub.2SO.sub.4 were
evaporated under reduced pressure to leave a crude product, which
may be purified by recrystallization or column chromatography.
[0236] According to the same procedure, starting from the compounds
35-40 the following compounds were obtained:
[0237]
12-chloro-5-thia-benzo[4,5]cyclohepta[1,2-b]naphthalene-13-carbalde-
hyde;
[0238]
7-chloro-13-thia-benzo[5,6]cyclohepta[1,2-a]naphthalene-8-carbaldeh-
yde;
[0239] 7-chloro-1
3-oxa-benzo[5,6]cyclohepta[1,2-a]naphthalene-8-carbaldeh- yde;
[0240]
12-chloro-8-methoxy-5-oxa-benzo[4,5]cyclohepta[1,2-b]naphthalene-13-
-carbaldehyde;
[0241]
7chloro-1,2,3,4-tetrahydro-13-oxa-benzo[5,6]cyclohepta[1,2-a]naphth-
alene-8-carbaldehyde;
[0242]
12-chloro-7,8,9,10-tetrahydro-5-oxa-benzo[4,5]cyclohepta[1,2-b]naph-
thalene-13-carbaldehyde
[0243] (Table 4; compounds 42-47)
4TABLE 4 Compounds of the formula III wherein Y = Z = H 17 MS comp.
X G.sub.A G.sub.B (m/z) .sup.1H NMR (ppm) 41 O G.sub.1 -- 7.19-7.94
(m, 9H); 8.38 (s, 1H); 10.73 (s, 1H) (CDCl.sub.3) 42 S G.sub.1 --
7.18-7.91 (m, 8H); 8.07 (s, 1H); 8.32 (s, 1H); 10.75 (s, 1H)
(CDCl.sub.3) 43 S G.sub.1 -- 7.03-8.25 (m, 9H); 8.94 (m, 1H); 10.79
(s, 1H) (CDCl.sub.3) 44 O G.sub.1 307 7.18-7.87 (m, 9H); 8.65 (d,
1H); 10.73 (s, 1H) (CDCl.sub.3) (MH.sup.+) 45 O G.sub.2 337 3.91
(s, 3H); 7.20-7.49 (m, 6H); 7.82 (s, 1H); 8.04 (d, 1H); 8.48 (s,
(MH.sup.+) 1H); 10.73 (s, 1H) (DMSO-d.sub.6) 46 O G.sub.3 311
1.65-1.85 (m, 4H); 2.76 (m, 2H), 3.02 (bs, 2H); 7.11 (d, 1H); 7.23-
(MH.sup.+) 7.47 (m, 4H); 7.56 (d, 1H); 10.51 (s, 1H) (DMSO-d.sub.6)
47 O G.sub.3 311 1.71 (m, 4H); 2.70-2.77 (m, 4H); 7.14 (s, 1H);
7.21-7.47 (m, 4H); 7.52 (MH.sup.+) (s, 1H); 10.52 (s, 1H)
(DMSO-d.sub.6)
* * * * *