Syntheses and Antiinflammatory Actions of 1,5,6,7-Tetrahydroindazole-5-carboxylicAcids Masahiko Nagakura.* Tomio Ota. S o h o r u Shiniidzu. liiyoshi l i a n a m u r a . Yoshinori Eto. and Yasushi IVada Tok?,o Rescarch Laborntoric.\. Koic a
('onipari?,
I,td
,
Hian\hitnurn?nmn. Tok?'n.Japan. Rcc,cirtd .Va> .YO. 1978
.A novel se r i e i ( 1 1' 1 -a r >.I - -1. .i.t ,(i,7-I e t r u h y ti r ( I - 2 if indazole-3-cart)tixylic acid5 were s y n t hesizeti \.ia condenhatioii betwveeii a phenylhydrazine and a .'-(hydroxy~ i ~ e t h y l e n e i c y c l c ~ h e s a n o n e - ~ - c ~ ~ and r l i ~ the ~ ~ yantiint'lanimatciry l~~te. activity \vas determined. I n the carrageenan edema test. l-aryl-.~.;,.6.7-tetrah!.drc,-lH - i n t i a z c ~ l e - ~ - c ~ i r I ~acids i ~ ~ y exhibited lic fairly high antiinflammatory activity. However. the ?-aryl koniers w r e l'ar less active t h a n t h e t'ciriner. T h e most active compound of' the series was 1 - ~ ~ h e n y l - 4 . . ~ . 6 . 7 - t e t r a t i yI ~~l ~r o-- i n d a z i ~ l e - ~ - arid, c ~ i \vhich ~ l ~ ~ had ~ ~ a~n~ ED-), l i ~ ~value ( 1 1 ~:1.3 m g kg,
Xntiinflammatory. analgesic. antipyretic. and antirheumatic activity has heen reported f'or acidic pyrazole derivatives.'.' One ( i f these derivatives. 2 - i 1 -phenylpyrazol-3-y1)propionic acid i l i.' has heen shown t o tw r-
Jy.
Scheme I ,-
-2'd1u1-Y-? ?
a;
c ,; ,:
3
4 , rlriir;
-ti:-
7t ,',
dc
.. .>
4
:
4a, R~ = M e
3a, R. Me b, Rr= E t ~~
0 1
q)
b, R .
Et
\
i
1
F
2
clinically active in the treatment of' rheumatic. disorders. In addition. it has been reported that pyrazole corticoids'.' are more active than parent corticoids. One of' these derivatives, 17it 2 1-dihydrosy-20-oxo~)regn-3-eno[ 3.2--(,] "-(l-fluoropheiyl)p?-razole (2Ia4has been used clinically as a topical antiinflammatory agent. These reports led us to synthesize acidic 4.ri.6.;-tetrahydrc)indazole-3-carl,tlic acids and related compounds. Chemistry. T h e novel -1.;5,6.;-tt.trahydroi~idazole-3carboxylic acids and related compounds were synthesized by a modified Auwers's method" (Scheme I ) and are collected in Table I. 2-( Hydroxymethy1ene)cyclohexanone-4-carboxylate ( 4 ) \ o1)taint.d t i ? formylation
I 7 .
9
8
R
aryl. benzyl
of' cyclohexanone-3-carboxvlate ( 3 under conditions using Ai n s !vi irt h' s method. ii T h e appropriate su hs t i t (1t ed h y drazine 5 was cyclized with 4 to t ~ v oisomers, 1-substituted I . ~ ~ . 6 . ~ - t e t r a h y d r o - l ~ - i n d a z o l e - 5 - c a r ~ ~6~ and ~ x y l2ate substituted 1,5,r;,;-tetrahydrt,-'H-iiidazole-5-carb~x~late 7 . which could be separated by column chromatography or f'ractional recrystallization. Hydrolysis of' 6 and 7 af-
Journal of Medicinal ChernistrJ,,1979, Vol. 22, N o . 1 49
4,5,6,7-Tetrahydroindazole-5-carboxJlie Acids
Hoocm Hoocm,81 '
Table I. Physical Properties a n d Pharmacological Activities of 4,5,6,7-Tetrahydroindazole-5-carboxylic Acid Derivatives I
OO
I
C
N;NI
9a-i
Ri
m
Rl
8a-m
15a-d inhibitory act. o n carrageenan paw edema
R,
c o m p d no.
yield:
mp, " c
%
formulab
recrystn solvent
10 2.5 25 10 25 25 25 25
8a
C6H;
85.7
181-182
Me,CO
8b
4-C1C,H4
77.2
192.5-194
MeOH
8c 8d 8e 8f 8g 8h 8i
3-FC6H4 4-MeC6H, 2-MeC6H, 4-MeOC,H4 4-HOC,H4 3-CF 3C,H, 2-C,H4N 4-C \H,N 1-C,3H,,f C,H,CH, 4-C6H,CH,OC,H, C,H, 4-C1C,H4 4-MeC H, 2 -M eC H, 4-M e 0 C H, 3-CF3C,H4 2-C H4N 1-C I H, C,H,CH, C,H, 4-C1C,H4 4-MeC6H, 3-CF,C6H,
62.5 55.7 74.0 80.5 86.2d 57.6 73.8 51.5 58.4 87.9 92.5
157-158 177-178.5 171-172 167-170 263-265 145-146.5 163-164 263-264 171.5-1 7 2 . 5 160-161 168-169
EtOH-n-hexane EtOH-n-hexane E tOH-n-hexane E tO H--n-hexane MeOH i-Pr OH-E t O H E t OH--n-hexane MeOH EtOH MeOH MeOH
74.1
165.5-167 203-204 199.5-200.5 152-154 173-174 128-129.5 171-172 192-193 181.5-183 277 dec 278 dec 266 dec 2 6 3 dec
EtOH-n-hexane EtOH MeOH EtOH-n-hexane MeOH i-PrOH--n-hexane Me,CO EtOH-n-hexane MeOH dioxane MeOH dioxane dioxane
8j
8k 81
8m 9a 9b 9c 9d 9e 9f 9g 9h 9i 15a 15b 15c 15d phenylbutazone indomethacin
81.0
75.0 75.4 90.0 59.0 89.8 70.4 67.9 84.5 97.0 quant quant
(,
dose, mg/kg - PO .
100
25 25 25 25 25 NT'
--____-
100 100
100 100
100 100 100 25 100 100
100 100 100
50 3
76
inhibn' 72.6*** 40.6** 60.0*** 39.4** 38.2* 38.7* 0 9.8 14.7 35.6* 57.9** 13.4 13.1 15.9 36.4* 17.9 10.8 38.0* 6.0 14.8 11.5 0 3.7 0 0 0 0 43.4** 35.5*
All new compounds were analyzed for C, H, and N . ' Significant difference The yield from hydrolysis of the ester. The yield from the catalytic hydrogenation of the benzyl comfrom control: * p < 0 . 0 5 , * * < 0 . 0 1 , ***p < 0 . 0 0 1 , pound. ' N T = n o t tested. !Naphthyl.
-
a
Scheme I1 "2
1
I
RI
-
NHN=CCOOEt
NONO* AcCHZcooEt
- 1 R,
B~~
I
AC
11
10
4-
~
r+c.cve
NHY=CCOOE'
I RI
13
/ Br
-
forded 1-substituted 4,,5,6.7-tetrahydro-lH-indazole-5carboxylic acid 8 and "substituted 4.5,6,7-tetrahydro2H-indazole-5-carboxylicacid 9. respectively. In the case of cyclization, the use of free base 5 (method A) preferentially gave 7 . However. when 5 was used as an HC1 salt (method B), the main product was 6 with only a trace of 7 . T h e structure of 8 was confirmed by preparing 8 according to Scheme I1 (method C). Incidentally, the structure of the other isomer could be confirmed as 7 . Ethyl cx-bromoglyoxylate substituted hydrazone 12 was prepared from aniline derivatives 10 under conditions using Sharp's method.; 12 was cyclized with methyl 1morpholinocyclohexene-4-carboxylate(13) to methyl 1substituted 3-carbethoxy-4.5,6.'i-tetrahydro-lH-indazole-5-carboxylate (14) according to a modified method.R Alkaline hydrolysis of 14 afforded 1-substituted 4,5,6,7tetrahydro-lH-indazoIe-3,S-dicarboxylic acid (13), which was converted into 8 by decarboxylation. T h e physical properties of 8 obtained as shown in Scheme I1 were identical with those obtained via Scheme I. The physical properties of intermediates 6. 7 , and 14 are shown in Table 11.
MecncDy 12
CCGEt
N'
RI
14 HOOC
I1
I
Rl
R1
15
8
R,= aryl
Pharmacology and Structure-Activity Relation-
ships. T h e test compounds were first subjected to the
I
-
7a-I 14a-d
6a-0 yield,
R,
compd n o 6a
R
method
%
Et
A B B
14.4 88.9 71.7 31.3 37.8 52.9 9.3 32.0 32.0 8.1 14.1 65.5 19.8 35.1 59.0 36.8 53.8 17.1 '40.7 9.9
6b 6c
CfY 1 ('IC II
Me
6d 6e
1 CIC,H, 1 MeC, H,
Me Et
6f 6g 6h 6i 6j 6!i 61 6m 6n 60 7a
3-CF
