Cyclic anthranilic acid acetic acid derivatives and process for the preparation

Cyclic anthranilic acid acetic acid derivatives of the following formula, ##STR1## wherein R.sup.1 and R.sup.2 each independently indicate a hydrogen atom, lower alkyl group having 1 to 3 carbon atoms; their acid or alkali salts thereof are useful as drugs treat autoimmune diseases, antirheumatic agents and therapeutic or prophylactic agents to treat metabolic bone diseases.

DETAILED DESCRIPTION OF THE INVENTION 
This invention is concerned with certain novel cyclic anthranilic acid 
acetic acid derivatives, their acid and alkali salts thereof and the 
process for their preparation thereof. This invention is also concerned 
with the use of these novel compounds as antirheumatic agents, drugs for 
treating autoimmune diseases, and drugs which have both therapeutic and 
prophylactic effects on metabolic bone diseases. 
Chronic diseases related to immune responses include rheumatoid arthritis 
and other autoimmune diseases (systemic lupus erythematosus, psoriatic 
arthritis, atopic dermatitis, ankylosing spondylitis). These diseases are 
considered to be caused by bacteria, virus or autoantigens or by an 
aberration in cytokine regulation of T cells. Especially, patients with 
rheumatoid arthritis demonstrate various immune abnormalities including 
reduced functions of suppressor T cells and hyperactivity of B cells. 
Non-steroidal antiinflammatory drugs are widely used as first choice drugs 
in the therapy of rheumatoid arthritis and other diseases due to 
immunological disorders. While these drugs offer symptomatic relief for 
patients with these diseases, they fail to alter the underlying 
immunological dysfunction or the overall course of the disease process. 
Furthermore, serious side effects from prolonged use of these drugs have 
also been well documented. 
On the other hand, second choice antirheumatic drugs, such as gold salt and 
D-penicillamine have little acute antiinflammatory effects, but they 
appear to show or halt the tissue destruction and more especially the 
progression of articular damage. They also have immunomodulatory effects. 
However, it is necessary to improve the safety and other aspects of these 
drugs, because of the higher incidence of side effects that have been 
observed in 40-50% of the patients treated with these drugs. 
Metabolic bone diseases as generic term include osteoporosis, osteomalacia 
and ostetic fibrous. In patients with these diseases, there are morbid 
changes in weight, constitution and structure of bone as a result of the 
failure of the systemic bone formation and resorption process. This is 
caused by abnormalities in the somatological regulatory system due to 
various hormones or vitamins and by congenital or acquired abnormalities 
of the functions of the osteocytes. It is also associated with abnormal 
calcium and phosphorus metabolism. Vitamin D, calcium, calcitonin and 
phosphorus are used as therapeutic drugs, but their effectiveness has not 
been clearly proven and development of a superior drug has been strongly 
desired. 
As a result of our research into the development of an antirheumatic agent, 
we have found that novel cyclic anthranilic acid acetic acid derivatives 
represented by a general formula (I) and their acid and alkali salts 
thereof, have potent therapeutic effects upon rheumatic arthritis without 
inhibiting cyclooxygenase activity. We have proved the superiority in the 
safety as well as in the effectiveness of these compounds. We have also 
found that these compounds of this invention have inhibitory effects on 
bone damage. 
##STR2## 
wherein R.sup.1 and R.sup.2 each independently indicate a hydrogen atom, 
lower alkyl group having 1 to 3 carbon atoms. 
The compounds which structurally resemble the compounds represented by a 
general formula (I) have been published in Japan Kokai Sho 58-116466 
(Nippon Zoki Pharmaceutical Co., Ltd.), and in U.S. Pat. No. 3,778,511 
(Ciba-Geigy Corporation). The compounds in these literatures have been 
described to have antiinflammatory action, but the potency of such 
compounds are not satisfactory. Moreover, any claim of these patents never 
include the compounds of this invention. 
We have published the compounds represented by a following general formula 
in EP-A-0 310 096, 
##STR3## 
wherein R.sup.1, R.sup.2 and R.sup.3 each independently indicate a 
hydrogen atom, a halogen atom, lower alkyl group having 1 to 3 carbon 
atoms, lower alkoxy group having 1 to 3 carbon atoms, amino group, nitro 
group, hydroxy group, sulfonamide group, trifluoromethyl group, cyano 
group, carboxyl group, carbamoyl group, acetyl group, benzoylmethyl group 
which may be substituted, methylthio group, phenylethynyl group which may 
be substituted, ethynyl group which may be substitute, alkanoylamino group 
having 1 to 3 carbon atoms, benzoylamino group which may be substituted, 
alkylsulfonylamino group having 1 to 3 carbon atoms or phenylsulfonylamino 
group which may be substituted; R.sup.4 and R.sup.5 each independently 
indicate a hydrogen atom, lower alkyl group having 1 to 3 carbon atoms, 
cyano group, carboxyl group, hydroxymethyl group, phenyl group which may 
be substituted or benzyl group; R.sup.6 indicates a hydrogen atom, lower 
alkyl group having 1 to 3 carbon atoms or benzyl group; X indicates a 
methylene group, oxygen atom, sulfur atom, sulfinyl group or sulfonyl 
group. The compounds of this invention, however, have not been included in 
above patent and have unexpectedly higher potency. 
Next, we will describe the process for their preparation of the compounds 
of this invention. 
Cyclic anthranilic acids that amino groups looped benzene rings have been 
synthesized by oxidizing 1,7-trimethyleneisatins with hydrogen peroxide in 
aqueous alkali medium (E. Ziegler et al., Monatsh. Chem., 94, 698 (1963), 
ibid 95, 59 (1964)), or by reducing quinoline-8-carboxylic acid (C. 
Satyendranath et al, J. Annamalai Univ., 2, 227 (1933)). 
But, all of the literatures have included the very limited compounds and no 
mentions have been made on pharmacological activity. 
According to the invention, the compounds represented by the general 
formula (I) are prepared from the compounds represented by the general 
formula (II) by hydrolysing and then by decarbonylation. Moreover, they 
can be prepared by the compounds represented by the general formula (II) 
to hydrolyse with a little excess mole of suitable alkali solution such 
as, for example, sodium hydroxide or potassium hydroxide, in a suitable 
solvent such as, for example, water or aqueous alcohol and followed by 
oxidization with more than equal mole of a mild oxidant such as, for 
example, hydrogen peroxide solution or acetic peracid. Preferably, 
reaction temperature is 0.degree. to 50.degree. C. and reaction time is 
0.5 to 3 hours. 
##STR4## 
wherein R, R.sup.1 and R.sup.2 each independently indicate a hydrogen 
atom, lower alkyl group having 1 to 3 carbon atoms. 
The compounds in the general formula (II), which are intermediates of this 
preparation method, are also novel and can be prepared from the compounds 
represented by the general formula (III) according to the known method 
(Japan Kokai No. 60-243088). 
##STR5## 
wherein R, R.sup.1 and R.sup.2 have the same meanings described above. 
Moreover, the compounds represented by the general formula (I) can be 
converted to the corresponding salts by the treatment with acid or alkali. 
The acid may be an inorganic acid such as, for example hydrochloric acid, 
sulfuric acid or phosphoric acid, or an organic acid such as, for example 
methanesulfonic acid, lactic acid, acetic acid, citric acid or tartaric 
acid. The alkali may be an alkali metal such as, for example, sodium or 
potassium.

The invention will be illustrated based on concrete examples, but the 
invention is not confined to following examples. 
EXAMPLE 1 
Ethyl 5,6-dihydro-1,2-dioxo-4H-pyrrolo[3,2,1-ij]quinolin-8-ylacetate 
To the refluxing mixture of oxalyl chloride (0.3 ml) in dry tetrahydrofuran 
(THF; 15 ml) was added ethyl 1,2,3,4-tetrahydroquinolin-6-ylacetate (500 
mg) in dry THF (5 ml) dropwise. The mixture was refluxed for 4 hours after 
addition was completed, then cooled to room temperature and concentrated 
under reduced pressure. The residue was dissolved in carbon disulfide (20 
ml) and added aluminum chloride (610 mg) portionwise. The mixture was 
refluxed for 4 hours and allowed to stand for overnight at room 
temperature. After decantation of the solvent, ice water (20 ml) was added 
to the residue. The mixture was extracted with chloroform and dried over 
anhydrous sodium sulfate. Evaporation of chloroform afforded the title 
compound. The compound was recrystallized from acetonitrile to give 490 mg 
(75%) of dark red needles, mp 124.degree.-125.degree. C. 
Analysis (%) for C.sub.15 H.sub.15 NO.sub.4, Calcd. (Found): C, 65.92 
(65.83); H, 5.53 (5.52); N, 5.13 (5.12). 
EXAMPLE 2 
8-Carboxy-1,2,3,4-tetrahydroquinolin-6-ylacetic acid 
To a solution of ethyl 
5,6-dihydro-1,2-dioxo-4H-pyrrolo[3,2,1-ij]quinolin-8-ylacetate (21.5 g) 
and sodium hydroxide (18.5 g) in water (1 litter) was added 35% hydrogen 
peroxide solution (10 ml) and stirred for 3 hours at room temperature. The 
mixture was acidified at pH 2 with concentrated hydrochloric acid, 
resulting precipitate was collected by filtration, washed with water and 
dried to yield 17.6 g (95.1%) of the title compound. The compound was 
recrystallized from ethanol to give pale yellow needles, mp 
210.degree.-211.degree. C. 
Analysis (%) for C.sub.12 H.sub.13 NO.sub.4, Calcd. (Found): C, 61.27 
(61.21); H, 5.57 (5.62); N, 5.95 (5.90). 
Further, the following experiments will illustrate the effectiveness of the 
compound of the present invention. 
EXPERIMENT 1 
Therapeutic Effect on Adjuvant Arthritis in Sprague Dowley Rats 
Adjuvant arthritis was induced by intradermal injection of heat-killed 
Mycobacterium butyricum (0.6 mg/rat) suspended in liquid paraffin into the 
right hind foot pad of female rats (8 week of age). The compound of this 
invention suspended in 0.3% carboxymethylcellulose solution was orally 
administered once a day for 7 days during days 14 to 20 after adjuvant 
injection. Left hind paw volume was measured by the water immersion 
method. 
As shown in Table 1, administration of the Example 2 compound reduced the 
swelling of left (uninjected) hind paw. 
TABLE 1 
______________________________________ 
Dose Increase in left hind paw.sup.1) 
Compound (mg/kg) N Day 17 Day 21 
______________________________________ 
control -- 8 1.54 .+-. 0.21 
1.35 .+-. 0.16 
(adjuvant) 
Example 2 10 8 0.96 .+-. 0.29 
1.03 .+-. 0.31 
Example 2 50 8 1.22 .+-. 0.25 
1.15 .+-. 0.32 
______________________________________ 
.sup.1) volume (ml), Mean .+-. S.E. 
EXPERIMENT 2 
Inhibition of Bone Damage in Adjuvant Arthritis 
Adjuvant arthritis was induced by the same manner as Experiment 1. The 
schedule of administration was also same in Experiment 1. On day 27, all 
rats was killed and radiographs of hind paws were taken using a soft X-ray 
apparatus. The degree of bone damage was assessed blindly on a scale 
(grades 1 through 4) based on the "cotton wool appearance" surrounding the 
distal limb joints. 
As shown in Table 2, the Example 2 compound significantly inhibited the 
progression of bone damage induced in the adjuvant arthritis. 
TABLE 2 
______________________________________ 
Bone damage score on -Dose Day 27 (Mean .+-. S.E.) 
Compound 
(mg/kg) N Non-injected paw 
Injected paw 
______________________________________ 
control -- 8 1.63 .+-. 0.38 
3.38 .+-. 0.26 
(adjuvant) 
Example 2 
5 6 1.33 .+-. 0.49 
3.33 .+-. 0.33 
Example 2 
10 8 1.00 .+-. 0.33 
2.25 .+-. 0.37* 
______________________________________ 
*Significantly different from adjuvant control, P &lt;0.05.