CA1237442A - 4-amino-tetrahydro-2-naphthoic acid derivatives - Google Patents

Abstract

YO-1-34888C/NK/84.

ABSTRACT
4-Amino-1,2,3,4-tetrahydro-2-naphthoic acid derivative of the formula:

Description

7~

S P E C I ~ I C A T I O N
4-AMI~-0 T~TRAHYDRO-2-NAPHT~OIC ACID DERIVATIVES

Technical Field And Disclosure Of Invention This invention~relates to novel and therapeutical-ly useful 4-amino-1,2,3,4-tetrahydro-2-naphtho~c acid derivatives of the formula:

N~R

Xn ~55 ~ COR
and salts thereof, wherein X is halogen atom, i~e~
fluorine, chlorine, bromine or iodine; n is l or 2; R
is hydroxy group, lower alkoxy group, e g. methoxy~
lo ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.
or amino group; and R is hydrogen atom, lower alkanoyl group, a.g. acetyl, propionyl, isopropionyl~ butyryl, isobutyryl, etc. or carbamoyl group.
Japanese Patent Publication No. 43-22097 (19683~
Chem. Pharm. Bull.~ 14, 324 (1966) and J. Med. Chem.,

2 , 1105 (1978) make ~lention of co~lpounds ~seful as an intermediate for the synthesis of a certain ki~d of analgesics, which compounds are represented by the formula:

. ~

~3~

1' ' `
COR

wherein X' is hydrogen atom or methoxy group, Rl is hydroxy group or lower alkoxy group, and R is hydrogen or lower alkanoyl group.
The present inventors ha~e synthesi~ed a variety of the derivatives having gamma-aminobutyric acid (hereinafter abbreviated as GABA) moiety in their structure and investigated into their usefullnass.
As a result, this invention has bee~ accomplished on the basis of the new finding that the compounds of the 10 invention unexpectedly have potent diUretic and blood pressure lowering actions~ although they show little protecting effects on the functions in which only the - central ner~ous system participates such as convuLsions or fatal convulsions induced by a GABA antagonist such 15 as bicuculline or picrotoxin.
To the contrary, with the aforementioned known ~- ~ea~
compounds these actions are extremely ~e~ or substan-tially ara not found.

The compounds of ~ormula (I) wherein R i5 20 hydrogen can be produced for example by the following Methods 1 to 3:

Method 1 .

, ~ lethod of reducing an o.~ime compound of the formula:

NOH

~ CORl (II) - wherein ~ n and Rl are the same as defined above.
Preferably, catalytic reduction is carried out in the presence of a metallic catalyst such as Rarley nickelg platinum oxide or palladium carbon in an inert solvent, preferably a lower alkanol such as methanol~ ethanol or the like or a lower alkanoic acid such as acetic acid, if desired in the presence of ammonia for prevention of possible polymerization~at a t~mperature of room tempe-ra~ure to 150 C, preferably 50 to 100 C-under normal - pressure or 50 to 150 atm of hydro~en. Here, hydrogen or hydrazine may be used as a hydrogen source.
Otherwise, the reduction may be carried out by the u9e of metallic sodium in liquid ammonia containing methanol or by the use of both hydrochloric acid or acetic acid and zinc or tin.
plethod 2 ~lethod of subjecting a compound of the formulao xn~l COEl

3'7 to ammonolysis iII water or lower alkanol~ wherein X~ n and Rl are the same as defined above, and Y is halogen atom, methylsulfonyloxy group, p-toiyls~lfonyloxy group or the like of the reactive residue.
Method 3 Method of subjecting a compound of the formula:
o Xn ~ (IV) to Leukart reaction~ wherein ~ n and Rl are the same as defined above~ That is, a compound of formula (IV) and urea, ammonium formate or the like undergo fusion reaction in the presence of formic acid at 150 - 200 C
and the resulting product is hydrolyzed to give the intended compounds~
The compounds of formula (I) wharein R is hydrogen are allowed to react with a reactive deri~ative of lower alkanic acid such as acid halide, acid anhydride or the like to give the compounds of ~ormula (I) wherein R i5 lower alkanoyl group. They are allowed to react with pot~ssium cyanate or sodium cyanate in an a~ueous lower alkanol to giv~ the compounds of formula ~I) wherein R
is carbamoyl.
The compoun~ of formula ~I) wherein Rl is hydroxy group are allowed to e~terify with a lower alkanol in the presence of mineral acid such as hydrochloric acid . ,i ~3~

or sUlfu~ic acid to give the compounds of formula (I) wherein R is lower aLkoxy. The ester compounds thus obtained or their free carboxylic acids are allowed to react with ammonia to give the compounds of for~ula (I) wherein R is amino.
The N-lower alkanoyl compounds and the estex compounds or the amido compounds each of *ormula (I) are subjected to hydrolysis to give, reversely, the amino compounds and the free carboxylic acids of formula (~), respecti~ely.
The compounds of formula (I) of this in~ention produced in this way are present in the form of dia-stereoisomers, with their tetralin ring containing asymmetric carbon atoms at the 2- and 4-positions.
When the mixture of the diastereoisomers is fused under heatirg at 60 to 200 C~ preferably 100 to 140 ~C~
the 2,4-cis isomer (simply referred to as "cis-isomer") causes ring closure to form 1,4-me~hano-2-benzazepin-3 one derivative of the formula :

Xn ~,,`~L (v) wherein X and n are the same as above.
Since the compound of formula (V) is neutral, the 2,4-trans isomer (simply referred to as "trans-isomer") ~an be isolated by the extraction with acid or alkali . . .

~L2 3~ d The compounds of ~ormula (Y) can be converted, upon hydrolysis by acid or alkali, into the cis-isomer of amino-acid.
The cis-isomer and the trans-isomer thus separated are respective ra^emates~ and the racemates can be separated into respective optically active isomers, for example by optically resolving the ester compounds with an optically active cabroxylic acid~ e.g. tartaric acid, dibenzoyltartaric acid, camphorsulfonic acid, diacetyltartaric acid, phenylsuccinic acid, mandelic acid, malic acid, lactic acid, etc. or the amino-protected carboxylic acid compound with an optically active base (e.g. natural alkaloid such as brucine, quinine, cinchonidine, etc., optically active a-phenethyl-amine, a-amino acid ester, etc.).
Where a carboxylic acid compound of formula ~II), (III) or (IV) optically active at the 2-position is used, respective optical isomers can be obtained only through the foregoing proced~re of separation into the cis-isomer and the trans-isomer.
The compounds (I) of the invention may be~ if desired, treated with acid (e.g. inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or organic acid such as acetic acid3 oxalic acid, maleic acid, fumaric acid, lactic acid, citric acid7 etc.) or with inorganic base (e.g. sodium hydroxide, so~ium bicarbonate, potassium hydroxide~ calciunl hydroxide, . "

etc.) to form their acid or base adducts.
As ~ill be apparent from the description above~
the compounds (I) of this invention include all of the diastereoisomers, cis-isomers, transisomers and optically active isomers and salts of them.
The diuretic activity of the compounds ~I~ accordi~g to this invention will be shown hereinbelow. The trans-i(somers have more potent activity than the cis-isomers.
Test Method ~ccording to the method of Lipschitz et al (W. L.
Lipschit~, ~. Haddian, A. Kerpsser : J. Pharmacol. Exp.
Therap., 7~, 97 (1943)), groups each of 6 male ~istar rats (weighing 180 to 220 g) were used. In precondi-tioning, they were not fed witll any food for 18 hours 15 and further with any food and water for 3 hours.
Test group o* the rats was orally administered with solution or suspension of the test compounds of this invention in isotonic saline at a dosagè of 25 m~/kg and was placed in metabolism cagss, and urine of them 20 was collected in the course of 6 hours.
The diuretic activity is calculated by the following equation in terms of increment percentaga of the test group to control group:

jAverage urine amount~ ~Aver~ge urine amount~
'f test group / ~of control group __ _ -- _ x 1 0 0 (A~erage urine amount of control group) - = increment percentage :~37~

Results ,. ~
Compound Increment (Example No.) (~) l(a) 737 . 2 410 3 . ~00 ~0 . 7 362 14 ~25 !1~ 354 ,_ 19 241 _ I
Under the same test conditions above, 4-amino-1,2, 3,4-tetrahydro-2-naphthoic acid hydrochloride, methyl trans-4-amino-1,2,3,4-tetrahydro-2-naphthoate hydro-chloride, ethyl trans-4-amino-6,7-dimethoxy-1~2~3,4-tetrahydro-2-napllthoate hydrochloride dis not sho-~ any results significantly different from the control group.
With G~BA per se, the diuretic activity could not be found even at a high dosage of 1000 mg~kg.
- Blood pressure lowering action due to the compound of Example la ~lich is typical of this invention is shown in the folLowing:
.Test ~lethod (1) Experiment with Spontaneous ~Iypertensive Rats (SHR) Spontaneous hypertensive male rats (SHR) of 28 to 30 weeks age were used for the experiment and blood press~re was measured according to tail compressi~g methvd~ These rats were preliminarily divided into ~3~4~;~

control group and test group (six rats/one group) so that both the groups have the same mean blood pressure.
A suspension of the test compound in 0,5 ~ methyl~
cellulose solution was administered orally to ths test group at a dosage of 2 m~/kg and after 1~ 5, 7 and 9 hours blood pressure was measured, Dosage required for lowering the blood pressure value before the administ-ration by 20 mm Hg was determined.
(2) Experiment with DOCA ~ypertensive Rats 10 According to the method of Willard, male Wistar rats o~ 8 weeks age were made DOC~ ~deoxycorticoste-rone acetate) hypertensive rats by operation and among them, rats whose blood pressure values a~ter 6 weeks had reached upward of 150 mm Hg were used as test animal, The experiment was carried out in the ~ame conditions as thoAe of SHR above.

Results SHR DOCA
ED20 (mg/kg, p.o.) 6~5 In both the Experiments, the blood pressure lowering action was gra~ually and slowly exhibited and its maximum effect was exerted 7 to 9 hour after the administration of the test compound.
The compounds of formula (I) of this invention can be administered orally or parenterally as pharma-ceutical composition by the co-rlbination with a suitable, conventional pharmac~utically acceptable carrierO

~ 10 - ~37~

The pharmaceutical composition may be the form of tablets, capsules, granules, powders, injectable solutions or the like.
The daily dose of the compounds (I) for human adults ranges usually f rom about 10 mg to about 500 ~g f or oral administration in single dose or multiple doses~ b-lt may vary depending on the age~ weight and/
or conditions of disease to be treated and response to the medication.
The in~ention will be hereinafter described more concretely by the following examples; but they are not to be construed as limiting the invention.
Example 1 ~à) A solution of 265 g of ethyl 7,8-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate (m.p. 133 - 135 C) i~ 1 ~ of ethanol is charged into 3~-autoclave and 130 m~ of 12 ~ ethanolic ammonia and 27 g of Raney nickel are added thereto to reduce with hydrogen under pressure of 65 atm at an inner temperature of 75 C.
The hydrogen upta~e is completed in about 3 hours, and then the whole is allowed to cool. The catalyst i~
filtered o~f and the filtrate is concentrated. Ethyl acetate is added to the residue and cooled. Crystals are deposited and collected by filtration to give 75 g of 6,7-dichloro-1,4-methano-2,3,4,5-tetrahydro-1}~-2 benzazepin-3-one, m.p. 1~6 - 200 C, which is ring-closure product of t~e foregoing cis-isomer. The filtrate solution is washed with water once, dried and concentrated under heating on oil-bath at 130 C for 3 hours. After cooling, ethyl acetate is added and the deposited crystals are collected by filtration to recover an additional 14 g of the ring-closure isomer.
The filtrate solution is diluted with 1 ~ of ethyl acetate and 1~0 m~ of 20 ~ a~ueous hydrochloric acid is added with stirring, whereupon white needles separate out. The crystals are collected by suction filtration to give 76 g of crude ethyl trans-4-amino-7,8-dichloro-1~2,3,4-tetrahydro-2-naphthoate hydro-chloride. The aqueous layer of the filtrate`solution is separated, the organic layer is extracted with water several times and the aqueous layers combined are saturated with sodium chloride. -An additional 23 g of crystalline product is recovered. The product, when recrystallized from ethanol, sho~s a m. p. of 249 - 251 C (decomposition).
(b) Ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2~naphthoate, when opticall~ resolved by di- -benzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid, affords optically activo dextro- and lovo-iSomerS 9 respectivelyO
Hydrochloride of dextro-isomer Z5 m.p. 209 - 213 C ~a3D = ~ 38.~ (1 ,o~ methanol) ~Iydrochloride of levo-i~omer m.p. 2~8 - 213 C ~a ~D = ~ 37 . 4 ( 1 ~, methanol) ~ , . .
.

~74~2 - 12 _ Example 2 A suspension of 29 g of 6,7-dichloro-1,4-methano-2,3,4,5-tetrahydro-lH-2-benzazepin-3-one in 300 m~ o~
20 ~ hydrochloric acid is hydroly~ed by heating with stirring for 40 hours. After cooling~ crystals are precipitated and collected by filtration to give 32 g of crude cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride. To the crude product is added 500 m~ of ethanol, and dry hydrochloric acid gas is introduced gently with stirring under reflu~
for 8 hours. After cooling, crystals are deposited~
separated by filtration and recrystallized from 95 ~
ethanol to give 2~ g of ethyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-napllthoate hydrochl~ride having a m. p. of 239 - 245 C (decon~position) a~ white needles.
~xample 3 A solution of 60 g of methyL 6,7-dichloro-4-~ hydroxyimino-l,Z,3,4-tetrahydro-2-naphthoate in 300 m~
of methanol and 300 m~ of 10 ~ ammonia-methanol is hydrogenated at 60 atm of hydro~en in the presence of Reney nickel. Ile~ting is conducted at 70 ~ 80 C with stirring for 7 hours. After cooling, the catalyst is filtered off and the solven~ is distilled off. Acetone is added to t~le semi~solid residue and cooled. The precipitated crystals are collected by filtration to give 17 g of 7,8-dichloro-1~4-lnethallo-~,3,4,5-tetra-~: .

~3~4~

hydro~ 2-benzaZepin-3-one~ m.p. 215 - 217 C.
The mother liquor is concentrated~ heated at 110 -120 C for 2 hours and cooled followed by crystalliza-tion from acetone. Upon filtration, additional 3 g of ring-closure product is obtained. The mother liquor is concentrated, and ethyl acetate and 100 m~ of 10 aqueous hydrochloric acid are added and stirred well.
White needles are deposited and collected by filtra-tion to gi~e 10 g of methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride in the crystalline form. From the mother liquor~ a further 3 g of the product i9 recovered. The product, upon recrystallization from methanol, gives white needles having a ~I.p. of 262 - 263 C (decompositio~).
Example 4 Into a solution of 3. G g of methyl trans-4-amino-6,7-dichloro-1,~,3,4-tetrahydro-2-naphthoate hyd~o-chloride in 50 m~ of methanol and 15 ~ o~ 28 ~ aqueous ammonia, ammonia gas is blew at 30 - 40 C for 8 hours.

The solvent is distilled off and water is added. The precipitated crystals are separated by filtration and dissolved in methanol and to -the solution i9 added methanolic hydrochloric acid. Crystals are deposited, separated by suction filtration and recrystallized from methanol to give 1.6 g of trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthalene carboxamlde hydrochloride hav~ng a In . p . of above 280 C.

3~ 2 - 14 ~

Example 5 To a solution of 1.5 g of methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate in 20 m~
of pyridine is added 10 m~ of acetic anhydride under ice-cooling, and the reactant is allowed to stand overnight. The reaction solution is concentrated and to the resulting residue is added water. Deposited crystals are separated by suction filtration and recrystallized from ethanol to gi~e 1.5 g of methyl trans-4-acetamide-6,7-dichloro-1~2,3,4-tetrahydro-2-naphthoate~ m.p. 182 - 184 CC.
Example 6 Into 100 m~ of 50 ~ methanol~ 3.1 g of methyl trans-4-6,7-dichloro-1,2,3,4-tetrahydro-Z-naphthoate hydrochloride is dissolved under warming~ and to the solution is added dropwise a solution of l.Z g of potassium cyanate in 10 m~ o~ water. After the drop~
wise addition~ the system is made to react at ~0 C
for 2 hours and cooled with ice. Deposite~ crystals are separated by filtration, washed with water, and recrystallized from a ~lixture of methanol and acetone to give 1.7 e of methyl trans-~7-dichloro-4-ureido-1,2,3,4-tetrahydro-2-naphthoate h~ving a ~.p~ of 227 -229 C.
The fo110wing compounds are produced in a similar manner to E~amples 1 to 6.
7. ~lethyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-~2379c~

naphthoate hydrochloride, m.p 229 - 231 C
8. Methyl cis-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride 1/2 hydrate, m.p. 218 -219 C (decomposition) 9. Cis-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride, m.p. 269 - 271 C (deco~position) 10. Ethyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphtho~te hydrochloride~ m.p. 199 - 200 C
11. Trans-4-amino-6-chloro-1,2~3~4-tetrahydro-2-naphthoic acid hydrochloride, m.p~ 283 - 285 C
12. Methyl trans-4-amino-7-chloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride~ m.p. 215 - 218 C
13. Cis-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoic acid hydrochloride~ m.p. 2j6 - 257 C
15 14. Trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoic acid llydrochloride~ m.p. 283 285 C
15. ~thyl cis-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride, m.p. 222 - 223 C
16. Ethyl trans-4-amino-6,7-dichloro-1~2~3,4-tetra-20 hydro-2-na~htho~te hydrochloride, m.p. 234 - 236 C
17. Methyl trans-4-amino-7,8-dichloro-1,2,3~4-tetra-hydro-2-naphthoate hydrochloride, m.p. 247 - 250 C
(decomposition~
18. ~lethyl cis-4-amino-7 9 8-dichloro-1,2,3~4-tetrahydro-25 2-naphthoate hydrochloride~ m.p 240 - 242 C
(decomposition) 19. Bu~yl trans-4-amino-7,8-dichloro-1,2,314-tetrahydro-~3791~2 - 16 _ 2-naphthoate hydrochloride, m.p. 163 - 167 C
20. Ethyl trans-4-amino-6-fluoro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride, m.p. 211 - 213 C
21. Ethyl trans-4-amino-6-bromo-1~2,3~4-tetrahydro-2-naphthoate The invention has been fully e~plained in the description and examples given above, but any ~aria-tions and modifications of it may be made without departing from the spirit and scope of the invention.

Claims (48)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for producing 4-amino-1,2,3,4-tetra-hydro-2-naphthoic acid derivatives of the general formula (I) (I) and the pharmaceutically acceptable salts thereof;
wherein X is a halogen atom;
n is 1 or 2;
R1 is selected from the group consisting of a hydroxy group, a lower alkoxy group, and an amino group;
and R2 is selected from the group consisting of a hydrogen atom, a lower alkanoyl group and a carbamoyl group;
which comprises selecting a process from the group of processes consisting of:
(a) reducing an oxime of the general formula (II) (II) wherein X, n and R1 are defined hereinbefore;

Claim 1 continued (b) subjecting a compound of the general formula (III) (III) wherein X, n and R1 are defined hereinbefore, Y is a reactive residue, to ammonolysis;
(c) subjecting a compound of the general formula (IV);

(IV) wherein X, n and R1 are defined hereinbefore, to Reukart reaction;

(d) for producing compounds of the general formula (I) wherein R2 is a lower alkanoyl group, reacting a compound of the general formula (I) wherein R is hydrogen with a reactive lower alkanoic-acid derivative;

(e) for producing compounds of the general formula (I) wherein R2 is a carbamoyl group, reacting a compound of the general formula (I) wherein R2 is hydrogen, with potassium cyanate or sodium cyanate;
1. Claim 1 continued (f) for producing compounds of the general formula (I) wherein R1 is a lower alkoxy group, esterifying compounds of the general formula (I) wherein R1 is a hydroxy group;
   
   (g) for producing compounds of the general formula (I) wherein R1 is amino, reacting a compound of the general formula (I) wherein R1 is a hydroxy group or a lower alkoxy group, with ammonia;
   
   (h) for producing compounds of the general formula (I) wherein R2 is hydrogen, hydrolyzing a compound of the general formula (I) wherein R2 is a lower alkanoyl group;
   
   (i) for producing compounds of the general formula (I) wherein R1 is a hydroxy group, hydrolyzing a compound of the general formula (I) wherein R1 is a lower alkoxy or amino group; and (j) hydrolyzing a compound of the general formula (V) (V) wherein X and n are defined hereinbefore.
2. 2. A process as claimed in claim 1(a).
3. 3. A process as claimed in claim 1(b).
4. 4. A process as claimed in claim 1(c).
5. 5. A process as claimed in claim 1(d).
6. 6. A process as claimed in claim 1(e).
7. 7. A process as claimed in claim 1(f).
8. 8. A process as claimed in claim 1(g).
9. 9. A process as claimed in claim 1(h).
10. 10. A process as claimed in claim 1(i).
11. 11. A process as claimed in claim 1(j).
12. 12. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof, whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
13. 13. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof, whenever prepared by a process as claimed in claims 2 or 3 or an obvious chemical equivalent thereof.
14. 14. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof, whenever prepared by a process as claimed in claims 4 or 11 or an obvious chemical equivalent thereof.
15. 15. Compounds of the general formula (I) as defined in claim 1 wherein R2 is a lower alkanoyl group and the pharmaceutically acceptable salts thereof, whenever prepared by a process as claimed in claim 5 or an obvious chemical equivalent thereof.
16. 16. Compounds of the general formula (I) as defined in claim 1 wherein R2 is a carbamoyl group whenever prepared by a process as claimed in claim 6 or an obvious chemical equivalent thereof.
17. 17. Compounds of the general formula (I) as defined in claim 1 wherein R1 is a lower alkoxy group whenever prepared by a process as claimed in claim 7 or an obvious chemical equivalent thereof.
18. 18. Compounds of the general formula (I) as defined in claim 1 wherein R1 is an amino whenever prepared by a process as claimed in claim 8 or an obvious chemical equivalent thereof.
19. 19. Compounds of the general formula (I) as defined in claim 1 wherein R2 is hydrogen,whenever prepared by a process as claimed in claim 9 or an obvious chemical equivalent thereof.
20. 20. Compounds of the general formula (I) as defined in claim 1 wherein R1 is a hydroxy group, whenever prepared by a process as claimed in claim 10 or an obvious chemical equivalent thereof.
21. 21. A process as claimed in claim 1 for producing ethyl trans-4-amino-7,8-dichloro-1,2,3,4 tetrahydro-2-naphthoate which comprises reducing ethyl 7,8-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate.
22. 22. Ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate whenever prepared by a process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. 23. A process as claimed in claim 1 for producing ethyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate which comprise hydrolyzing 6,7-dichloro-1, 4-methane-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.
24. 24. Ethyl cis-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate whenever prepared by a process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. 25. A process as claimed in claim 1 for producing methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate which comprises reducing methyl 6,7-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate.
26. 26. Methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate whenever prepared by a process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. 27. A process as claimed in claim 1 for producing methyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoate which comprises reducing methyl 6-chloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate.
28. 28. Methyl trans-4-amino-6-chloro-1,2,3,4-tetra-hydro-2-naphthoate whenever prepared by a process as claim-ed in claim 27 or an obvious chemical equivalent thereof.
29. 29. A process as claimed in claim 1 for producing ethyl trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate which comprises reducing ethyl 6,7-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate.
30. 30. Ethyl trans-4-amino-6,7-dichloro-1,2,3,4-tetra-hydro-2-naphthoate whenever prepared by a process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. 31. A process as claimed in claim 1 for producing methyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naphthoate which comprises reducing methyl 7,8-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate.
32. 32. Methyl trans-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate whenever prepared by a process as claimed in claim 31 or an obvious chemical eqwivalent thereof.
33. 33. A process as claimed in claim 1 for preparing methyl cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-2-naph-thoate which comprises hydrolyzing 6,7-dichloro-1,4-methano-2, 3,4,5-tetrahydro-1H-2-benzazepin-3-one.
34. 34. Methyl cis-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate whenever prepared by a process as claimed in claim 33 or an obvious chemical equivalent thereof.
    
    35. 4-Amino-1,2,3,4-tetrahydro-2-naphthoic acid derivatives of the general formula (I) (I) and the pharmaceutically acceptable salts thereof;
35. Claim 35 continued...
    wherein X is a halogen atom;
    n is 1 or 2;
    R1 is selected from the group consisting of a hydroxy group, a lower alkoxy group, and an amino group; and R2 is selected from the group consisting of a hydrogen atom, a lower alkanoyl group and a carbamoyl group.
36. 36. Compounds of the general formula (I) as defined in claim 35 wherein R2 is a lower alkanoyl group and the pharmaceutically acceptable salts thereof.
37. 37. Compounds of the general formula (I) as defined in claim 35 wherein R2 is a carbamoyl group and the pharmaceutically acceptable salts thereof.
38. 38. Compounds of the general formula (I) as defined in claim 35 wherein R1 is a lower alkanoyl group and the pharmaceutically acceptable salts thereof.
39. 39. Compounds of the general formula (I) as defined in claim 35 wherein R1 is an amino and the pharmaceutically acceptable salts thereof.
40. 40. Compounds of the general formula (I) as defined in claim 35 wherein R2 is hydrogen and the pharmaceutically acceptable salts thereof.
41. 41. Compounds of the general formula (I) as defined in claim 35 wherein R1 is a hydroxy group and the pharmaceutically acceptable salts thereof.
42. 42. Ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate.
43. 43. Ethyl cis-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate.
44. 44. Methyl trans-4-amino-6,7-dichloro-1,2,3,4-tetra-hydro-2-naphthoate.
45. 45. Methyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoate.
46. 46. Ethyl trans-4-amino-6,7-dichloro-1,2,3,4-tetra-hydro-2-naphthoate.
47. 47. Methyl trans-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate.
48. 48. Methyl cis-4-amino-7,8-dichloro-1,2,3,4-tetra-hydro-2-naphthoate.