WO1995003053A1

WO1995003053A1 - Oxophthalazines for treating cachexia

Info

Publication number: WO1995003053A1
Application number: PCT/JP1994/001179
Authority: WO
Inventors: Fumihiko Sakai; Nobuchika Yamamoto; Kunio Nakahara; Harumi Yamazaki; Yoshitada Notsu; Yoshio Kawai; Hitoshi Yamazaki; Yoshito Abe; Teruo Oku
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1993-07-26
Filing date: 1994-07-18
Publication date: 1995-02-02
Anticipated expiration: 1996-01-26
Also published as: AU7195594A; JPH09506068A

Abstract

This invention relates to a new use of the oxophthalazine compounds or pharmaceutically acceptable salts thereof as the prophylactic and/or therapeutic treatment of cachexia and the like, wherein oxophthalazine compounds can be represented by general formula (I), wherein R1 is ar(lower)alkyl which may have one or more suitable substituent(s), and R2 is carboxy(lower)alkyl or protected carboxy(lower)alkyl.

Description

_ _χ _

OXOPHTHALAZINES FOR TREATING CACHEXIA

DESCRIPTION

TECHNICAL FIELD The present invention relates to a new use of the oxophthalazine compounds or pharmaceutically acceptable salts thereof. The present invention is useful for the medical care.

BACKGROUND ART

The oxophthalazine compounds to be used in the present invention may include the novel and known ones disclosed in the publications such as Japanese Patent Application laid-open No. 54-95582, or the like; and the like.

But up to now, it is not known said oxophthalazine compounds are useful for the therapeutic treatment of cachexia, and the like.

DISCLOSURE OF INVENTION

The present invention relates to a new use of the oxophthalazine compounds or pharmaceutically acceptable salts thereof.

More particularly, it relates to the utility of the oxophthalazine compounds for the prophylactic and/or therapeutic treatment of cachexia (e.g. oligotropha, anorexia, syntexis, etc.) such as cancer cachexia [e.g. alimentary cancer cachexia (e.g. cancer cachexia of stomach, cancer cachexia of pancreas, etc.)]; cachexia in case of chronic infectious diseases (e.g. AIDS, trypanosoma infection, etc.); shock (e.g. septic shock, hemorrhagic shock, burn shock, anaphylactic shock, etc.); disseminated intravascular coagulation (DIC); hypertriglycemia; hyperglyce ia; arteriosclerosis; osteoporosis; degradation of bone and cartilage in case of rheumatoid arthritis, osteoarthritis, etc.; rejection by transplantation; asthma; specific autoimmune diseases (e.g. aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, etc.); systemic lupus erythematosus; egener granulamotosis; chronic active hepatitis; myasthenia gravis; psoriasis; idiopathic sprue; multiple sclerosis; primary biliary cirrhosis; juvenile diabetes (diabetes ellitus type I); Reiter's syndrome; thrombosis and the like in a human being or an animal.

Accordingly, one object of the present invention is to provide a pharmaceutical composition for the prophylactic and/or therapeutic treatment of above- mentioned diseases in a human being or an animal comprising, as an active ingredient, the oxophthalazine compounds or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal which comprises administering the oxophthalazine compounds to a human being or an animal.

A further object of the present invention is to provide a use of the oxophthalazine compounds for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal.

An additional object of the present invention is to provide a use of the oxophthalazine compounds for the prophylactic and/or therapeutic treatment of above- mentioned diseases in a human being or an animal.

The inventors of the present invention have found the oxophthalazine compounds and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal and have completed the present inventio .

The oxophthalazine compounds used in the present invention can be represented by following general formula

(I)

wherein R^ is ar(lower)alkyl which may have one or more suitable substituent(s) , and R^ is carboxy(lower)alkyl or protected carboxy(lower)alkyl, or a pharmaceutically acceptable salt thereof.

The oxophthalazine compounds to be used in the present invention may include the novel and known ones disclosed in the publications such as Japanese laid-open No. 54-95582, or the like; and the like.

The novel oxophthalazine compound (I) can be prepared, for example, according to the procedures disclosed in Preparations and Examples as mentioned later in the present specification.

Suitable pharmaceutically acceptable salts of the oxophthalazine compound (I) to be used in the present invention are conventional ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid - 4 -

salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like.

In the above and following descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.

Suitable example of "ar(lower)alkyl" may include mono-(or di- or tri-)phenyl(lower)alky1 (e.g. benzyl, phenethy1, 2-phenylpropyl, 4-phenylbuty1, 2-pheny1-1,1- dimethylethyl, 1-phenylpentyl, 6-phenylhexyl, benzhydryl, trityl, etc.) and the like, in which the preferred one may be phenyl(Cι-C4)alkyl and the most preferred one may be benzyl.

Suitable example of "Suitable substituent(s)" in the term of "ar(lower)alkyl which may have one or more suitable substituent(s) " may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), halogen (e.g. chloro, bromo, fluoro, iodo), mono-(or di- or tri-)halo(lower)alkyl (e.g. trifluoromethyl, 2-iodoethyl, 2,2,2-trichloroethyl, etc.). Suitable number of the substituent(s) on said "ar(lower)alkyl" may be 1 to 3, preferably 2.

Suitable example of "carboxy(lower)alkyl" may include carboxymethyl, 1-carbσxyethyl, 2-carboxypropyl, l-(carboxymethyl)ethyl, 4-carboxybutyl, 3-carboxyρentyl, 2-carboxyhexyl, etc., in which the preferred one may be carboxy(C1-C4)alkyl and the more preferred one may be carboxymethyl.

Suitable example of "protected carboxy" in the term of "protected carboxy(lower)alkyl" may be an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.] which may have suitable substituent(s) , for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxymethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.], mono-(or di- or tri-)halo(lower)alkyl ester [e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc. ]; lower alkenyl ester [e.g. vinyl ester, allyl ester, etc. ] ; lower alkynyl ester [e.g. ethynyl ester, propynyl ester, etc. ] ; ar(lower)alkyl ester which may have suitable substituent(s) [e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)meth l ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert- butylbenzyl ester, etc.]; aryl ester which may have suitable substituent(s) [e.g. phenyl ester, 4-chlσrophenyl ester, tolyl ester, 4-tert- butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.]; or the like.

In said "protected carbox (lower)alkyl", the preferred one may be lower alkoxycarbonyl(lower)alkyl, the more preferred one may be (C1-C4)alkoxycarbonyl(C1-C4)- alkyl and the most preferred one may be ethoxycarbonylmethyl.

In the oxophthalazine compound (I) as explained above, i) the preferred one may be the compound (I) wherein R* is phenyl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, halogen and tri- halo(lower)alkyl, and R^ is carboxy(lower)alkyl or esterified carboxy(lower)alkyl; ii) the more preferred one may be the compound (I) wherein R¹ is phenyl(lower)alkyl which may have 1 to 3 halogen, and R^ is carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl; iii) the much more preferred one may be the compound (I) wherein R^ is phenyl(Cι~C4)alkyl having 2 halogen, and R^ is carboxy(C1-C4)alkyl; iv) the most preferred one may be 2-[3-(2-fluoro-4- bromobenzyl)-3,4-dihydro-4-oxophthalazin-l-yl]acetic acid.

The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the oxophthalazine compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.

The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.

The oxophthalazine compound (I) or pharmaceutical acceptable salts thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the diseases.

The pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention.

For applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation.

While the dosage of therapeutically effective amount of the oxophthalazine compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-100 g of the oxophthalazine compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.01-100 mg of the oxophthalazine compound (I) per kg weight of a human being or an animal, in case of oral administration, a daily dose of 0.01-200 mg of the oxophthalazine compound (I) per kg weight of a human being or an animal is generally given for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal.

In order to show the usefulness of the oxophthalazine compound to be used in the present invention for the prophylactic and therapeutic treatment of above-mentioned diseases in a human being or an animal, the pharmacological test data of the representative compound thereof are shown in the following.

Test Compound

2-[3-(2-Fluoro-4-bromobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid. (This compound is disclosed in Example 7 of Japanese Patent Application laid-open No. 54-95582.) [hereinafter referred to as Test Compound (I) ]

Test 1 in vitro activity :

(a) Inhibitory activity on the production of interleukin-1 (IL-1)

1. Test method

Purified human peripheral blood monocyte were stimulated with bacterial lipopolysaccharide (LPS) (1 μg/lO^* cells) in the absence or presence of appropriately diluted test compound for 18 hours at 37°C in a humidified 5% CO2 atmosphere culture supernatants were tested for IL-1 enzyme-linked immunoadsorbent assay (ELISA) assay. Test compound was dissolved in absolute DMSO (dimethyl sulfoxide) to achieve 10 mM stock solutions and was subsequently diluted in serum free RPMI1640.

IL-1 levels were quantified by a commercial ELISA kit (prepared by Ohtuka assay, Japan) using a sandwich technique. The sensitivity levels for the detection of IL-lβ were 20 pg/ml.

The inhibitory concentration that caused a 50% inhibition (IC50) ^was calculated by regression analysis of the dose-response data.

Test result

Test Compound IC₅₀ (M)

(1) 2.9 x 10^-6

This result apparently shows the inhibitory activity of the oxophthalazine compound (I) on the production of interleukin-1 (IL-1).

(b) Increase on LPL activity in 3T3-L^ adipocytes

1. Test method and result

3T3-L^ adipocytes were induced by the method of (J. Biolo. Che ., 253 (20), 7570 (1978)) and the fully differentiated 3T3-L^ adipocytes showed lipoprotein lipase (LPL) activity. The LPL activity was suppressed more than 80% by the addition of rabbit serum injected with LPS to 3T3-L^ adipocytes. However, when test compound (1) was added at concentration of 1.6 μg/ml, the increase of intracellular lipids accumulation and a two times increase in LPL activity compared with that incubated in the presence of LPS injected rabbit serum only were observed. LPL activity were determined by the method of (J. Lipid Res., 17,536 (1976)) with minor modification. This result apparently shows the increase on lipoprotein lipase (LPL) because of the oxophthalazine compound (I).

Test 2 in vivo activity :

(a) LPS-induced shock in rabbits

1. Test method

The rabbit model was prepared according to the methods of (FASEB J., 5 (3), 338-343 (1991)) with minor modification. Female New Zealand White (3 kg) were housed for a minimum of a week in the animal care facilities were free of infections. The rabbits were anesthetized with 1% halothane. Catheters were placed in the abdominal aorta from the left femoral artery, to continuously record mean arterial pressure. LPS were resuspended with 10 ml of sterile saline, and then infused into the left femoral vena cava for 20 minutes beginning to 0 minute. The saline-treated (vehicle-matched) control received saline intravenous injection as a 10 ml bolus 15 minutes before LPS infusion, then continuous infusion at a constant rate (3 ml/hr) for 4 hours. Test compound treated group received test compound intravenous injection as a 10 ml bolus (3.2 mg/kg) at 15 minutes before LPS infusion, followed by a constant rate (3.2 mg/kg/hr) for 4 hours. 2. Test result

hour 0 4

Vehicle 100 54.0 ± 2.8

Test Compound (1) 100 81.2 ± 4.4*

* : P<0.05 Student's t test

Data were presented as the mean ± S.E. percent of initial mean arterial pressure.

(b) Adipose tissue LPL activity in mice

1. Test method

Male C3H/HeN mice were fasted and replaced with a solution of 25% sucrose in water before the experiment. And then test compound (1) was suspended in 0.5% carboxymethylcellulose and administered orally at a dosage of from 32 to 100 mg/kg. After 16 hours, the LPL activity in the epididymal fat pads were determined by the method of (J. Lipid Res., 17,536 (1976) with minor modification.

2. Test result

Control 100 mg/kg

% of LPL activity 100 ± 26.4 189.6 ± 5.2*

* : p<0.05 Student's t test

Data were presented as the mean ± S.E. of percent activity in five animals for each dose compared with those of control receiving placebo.

(c) Adipose tissue weight loss in an experimental mouse model of cancer cachexia

1. Test method

Mouse cancer cachexia model is induced by intraperitoneal injection of B16 mice melanoma 1.5 x 10" cells/head into female C57BL/6 mice. In this model, food intake, epididymal fat pad weight and body weight were significantly decreased. This situation is similar to that observed in cancer patients. Epididymal fat pad weight started to decrease approximately 7 days after transplantation. After 10-12 days the epididymal fat pad weight loss were measured. Test compound (1) was suspended in 0.5% carboxymethylcellulose and administered orally for 10-12 days at dosage rate of from 3.2 to 10 mg/kg/day.

2. Test result

N.T. Control 10 mg/kg

fat pad weight 287+28* 180+29 293±37* (mg) (105.5%)

* : p<0.05 Student's t test

Data were presented as the mean ± S.E. for eight mice.

(d) Prolonged survival in B16 melanoma tumor bearing mice

1. Test method This tumor bearing mice is induced by intraperitoneal injection of B16 melanoma 10^ cells/head into female C57 BL/6 mice. Test compound (I) was suspended in 0.5% carboxymethyl cellulose and administered orally at dosage of 32 mg/kg/day.

2. Test result

days after tumor implantation survival

14 15 16 17 18

control group 10 10 8 5 1 test group* 10 10 10 10 5

* : p<0.05 Wilcoxon test

This result apparently shows the effect of the oxophthalazine compound (I) on the prolonged survival.

(e) Hypoglycemic effect in db/db obese mice

1. Test method

Female db/db mice (7 weeks old) were administered orally test compound (I) at dosage of 100 mg/kg/day for 12 days before measurement. Blood sample were collected from the heart, were obtained to measure plasma glucose and free fatty acid for 6 hours after the last administration. The plasma glucose and free fatty acid were markedly decreased in treated mice. - 14 -

2. Test result

db/db mice

+/+ mice (normal mice) control 100 mg/kg

Glycemia (mg/dl) 158.3+ 9.4*** 595.5+ 30.3 158.7±30.0*** Free Fatty Acid 792.4+60.4*** 1777.6+189.2 962.8+61.9** (μ Eq/1)

** p<0.01, *** p<0.001 Student's t test

This result apparently shows the hypoglycemic effect of the oxophthalazine compound (I) .

The results of above-mentioned test apparently shows the utility of the oxophthalazine compound (I) for the prophylactic and/or therapeutic treatment of cachexia (e.g. oligotrophia, anorexia, syntexis, etc.) such as cancer cachexia [e.g. alimentary cancer cachexia (e.g. cancer cachexia of stomach, cancer cachexia of pancreas, etc.)]; cachexia in case of chronic infectious disease (e.g. AIDS, trypanosoma infection, etc.); shock (e.g. septic shock, hemorrhagic shock, burn shock, anaphylactic shock, etc.); disseminated intravascular coagulation (DIC); hypertriglycemia; hyperglycemia; arteriosclerosis; osteoporosis; degradation of bone and cartilage in case of rheumatoid arthritis, osteoarthritis, etc.; rejection by transplantation; asthma; specific autoimmune diseases (e.g. aplastic anaemia, pure red cell anaemia, idiopathic thrombocytopenia, etc.); systemic lupus erythematosus; Wegener granulomatosis; chronic active hepatitis; myasthenia gravis; psoriasis; idiopathic sprue; multiple sclerosis; primary biliary cirrhosis; juvenile diabetes (diabetes mellitus type I); Reiter's syndrome; thrombosis and the like in a human being or an animal. Particularly, the oxophthalazine compound (I) is useful for the prophylactic and/or therapeutic treatment of cachexia and shock.

In the following, the preparations of the novel oxophthalazine compounds (I) are explained by Preparations and Examples.

Preparation 1

Sodium hydride (88 mg) was added to a solution of ethyl 2-(3,4-dihydro-4-oxophthalazin-l-yl)acetate (464 mg) in N,N-dimethylformamide (4.6 ml) with ice cooling. The mixture was stirred for 30 minutes and then, to the mixture was added 2,4-bis(trifluromethyl)benzyl bromide (675 mg) . The mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added water (15 ml) and the separated oil was extracted with ethyl acetate. The extract was washed with 0.2N-hydrochloric acid and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained crude crystal was recrystallized from diisopropyl ether to give ethyl 2-[3-{2,4- bis(trifluoromethyl)benzyl}-3,4-dihydro-4-oxophthalazin-l- yl]acetate (865 mg) .

NMR (CDC1₃, δ) : 1.22 (3H, t, J=6Hz), 3.98 (2H, s), 4.19 (2H, q, J=6Hz), 5.70 (2H, s), 7.22 (IH, d, J=9Hz), 7.62-8.00 (5H, m) , 8.50 (IH, dd, J=9Hz and 2Hz)

Preparation 2

The following compound was prepared according to a similar manner to that of Preparation 1. Ethyl 2-[3-(4-bromo-2-methylbenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetate

NMR (CDCL3, δ) : 1.22 (3H, t, J=6Hz), 2.46 (3H, s), 3.96 (2H, s), 4.18 (2H, q, J=6Hz), 5.35 (2H, s), 7.12 (IH, d, J=9Hz), 7.25 (IH, dd, J=2Hz and

9Hz), 7.33 (IH, d, J=2Hz), 7.68-7.88 (3H, m), 8.48 (IH, m)

Preparation 3 The following compound was prepared according to a similar manner to that of Preparation 1.

Ethyl 2-[3-(2,4-dibromobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetate NMR (CDC1₃, δ) : 1.22 (3H, t, J=6Hz), 3.97 (2H, s),

4.19 (2H, q, J=6Hz), 5.47 (2H, s), 6.95 (IH, d, J=9Hz), 7.32 (IH, dd, J=2Hz and 9Hz), 7.70-7.88 (4H, m), 8.50 (IH, m)

Preparation 4

The following compound was prepared according to a similar manner to that of Preparation 1.

Ethyl 2-[3-(4-bromo-2-chlorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetate

NMR (CDCI3, δ) : 1.23 (3H, t, J=6Hz), 3.98 (2H, s), 4.19 (2H, q, J=6Hz), 5.48 (2H, s), 7.00 (IH, d, J=9Hz), 7.30 (IH, dd, J=2Hz and 9Hz) , 7.56 (IH, d, J=2Hz), 7.70-7.90 (3H, m), 8.50 (IH, m)

Example 1

A solution of ethyl 2-[3-{2,4-bis(trifluromethyl)- benzyl}-3,4-dihydro-4-oxophthalazin-l-yl]acetate (550 mg) and IN-aqueous sodium hydroxide (1.32 ml) in ethanol (5.5 ml) was stirred at 60°C for 1.5 hours. The reaction mixture was neutralized with IN hydrochloric acid and diluted with water. The separated solid was collected, washed with water and dried to give 2-[3-{2,4- bis(trifluoromethyl)benzyl}-3,4-dihydro-4-oxophthalazin-l- yl]acetic acid (464 mg). mp : 181-182°C

NMR (CDCI3-CD3OD, δ) : 3.99 (2H, s), 5.70 (2H, s), 7.22 (IH, d, J=9Hz), 7.69 (IH, d, J=9Hz), 7.78- 8.00 (4H, m), 8.50 (IH, d, J=9Hz)

Example 2

The following compound was obtained according to a similar manner to that of Example 1.

2-[3-(4-Bromo-2-methylbenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid mp : 191-192°C

NMR (DMS0-d₆, δ) : 2.40 (3H, s), 4.00 (2H, s), 5.29 (2H, s), 6.94 (IH, d, J=9Hz) , 7.30 (IH, dd, J=2Hz and 9Hz) , 7.44 (IH, d, J=2Hz), 7.85-8.02

(3H, m), 8.32 (IH, d, J=2Hz)

Example 3

2-[3-(2,4-Dibromobenzyl)-3,4-dihydro-4-oxophthalazin- 1-yl]acetic acid mp : 187-189°C NMR (DMS0-d₆, δ) : 3.99 (2H, s), 5.33 (2H, s), 6.94

(IH, d, J=9Hz), 7.53 (IH, dd, J=2Hz and 9Hz), 7.88-8.06 (4H, ) , 8.33 (IH, d, J=9Hz)

Example 4 The following compound was obtained according to a similar manner to that of Example 1.

2-[3-(4-Bromo-2-chlorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid mp : 194-196°C

NMR (DMSO-dg, 6) : 4.00 (2H, s), 5.39 (2H, s), 7.01 (IH, d, J=9Hz), 7.50 (IH, dd, J=2Hz and 9Hz), 7.79 (IH, d, J=2Hz), 7.86-8.05 (3H, m), 8.32 (IH, d, J=9Hz)

The following compounds in Example 5 to 19 were obtained according to a similar manner to that of Example or any process known in the field of the art for preparing structurally analogous compounds thereto.

Example 5

2-[3-(2,4-Dichlorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid mp : 190-191°C NMR (CDC1₃:CD₃0D = 9:1, δ) : 3.99 (2H, s), 5.50 (2H, s), 7.06 (IH, d, J=8Hz), 7.15 (IH, d, J=8Hz), 7.40 (IH, s), 7.75-7.90 (3H, m), 8.48 (IH, d, J=7Hz)

Example 6

2-[3,4-Dihydro-4-oxo-3-(4-trifluoromethylbenzyl)- phthalazin-1-yl]acetic acid mp : 158-159°C

NMR (CDC1₃:CD₃0D = 9:1, δ) : 3.99 (2H, s), 5.45 (2H, s), 7.58 (4H, s), 7.75-7.90 (3H, ) , 8.44 (IH, d, J=7Hz)

Example 7

2-[3-(2-Bromo-4-fluorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid mp : 164-166°C

NMR (DMSO-dg, δ) : 4.00 (2H, s), 5.34 (2H, s), 7.06 (IH, t, J=8Hz), 7.20 (IH, dt, J=2Hz and 8Hz) , 7.66 (IH, dd, J=2Hz and 8Hz), 7.85-8.04 (3H, m), 8.32 (IH, d, J=8Hz)

Example 8

2-[3,4-Dihydro-4-oxo-3-(2-trifluoromethylbenzyl)- phthalazin-1-yl]acetic acid mp : 156-159°C

NMR (DMS0-d₆, δ) : 4.01 (2H, s), 5.43 (2H, s), 7.51 (2H, d, J=8Hz), 7.70 (2H, d, J=8Hz), 7.85-8.00 (3H, ), 8.32 (IH, m)

Example 9

2-{3-[1-(4-Bromophenyl)ethyl]-3,4-dihydro-4- oxophthalazin-l-yl}acetic acid mp : 139-141°C

NMR (CDC1₃, δ) : 1.79 (3H, d, J=7Hz), 4.04 (2H, s), 6.38 (IH, q, J=7Hz), 7.30-7.45 (4H, m), 7.69

(IH, m), 7.73-7.87 (2H, m) , 8.47 (IH, m)

Example 10

2-[3-(4-Bromo-2-nitrobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetic acid mp : 188-190°C

NMR (DMSO-d₆, δ) : 3.98 (2H, s), 5.58 (2H, s), 7.18 (IH, d, J=8Hz), 7.83-8.04 (4H, m) , 8.26-8.33 (2H, m)

Example 11

2-[3-(4-Bromo-2-fluorobenzyl)-1,4-dihydro-4- oxocinnolin-1-yl]acetic acid mp : 209-210°C NMR (CDCI3-CD3OD, δ) : 4.12 (2H, s), 5.09 (2H, s). 7.13-7.36 (4H, m) , 7.42 (IH, t, J=8Hz), 7.71 (IH, dt, J=8Hz and 1Hz), 8.31 (IH, dd, J=8Hz and 1Hz)

Example 12

2-[3-(4-Bromobenzyl)-3,4-dihydro-4-oxophthalazin-l- yl]acetic acid mp : 181-183°C

NMR (DMSO-dg, δ) : 3.99 (2H, s), 5.29 (2H, s), 7.29 (2H, d, J=7.5Hz), 7.53 (2H, d, J=7.5Hz), 7.85-

8.02 (3H, m), 8.31 (IH, m)

Example 13

2-[3-(4-Bromo-2-fluorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]acetonitrile mp : 148-150°C

NMR (CDC1₃, δ) : 4.02 (2H, s), 5.42 (2H, s), 7.20- 7.35 (3H, ), 7.77 (IH, J=7Hz), 7.80-7.95 (2H, m), 8.50 (IH, d, J=7Hz)

Example 14

2-[3-(4-Bromo-2-fluorobenzyl)-3,4-dihydro-4- oxophthalazin-l-yl]propionic acid mp : 179-181°C NMR (DMSO-dg, δ) : 1.45 (3H, d, J=9Hz), 4.41 (IH, q,

J=7.5Hz), 5.29 and 5.49 (2H, ABq, J=14Hz), 7.25 (IH, t, J=9Hz), 7.39 (IH, dd, J=7.5Hz and 1.5Hz), 7.59 (IH, dd, J=9Hz and 1.5Hz), 7.85-

8.03 (3H, ), 8.33 (IH, d, J=7.5Hz)

Example 15

3-(4-Bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-l-(1H- tetrazol-5-ylmethyl)phthalazine mp : 219-222°C NMR (DMSO-dg, δ) : 4.68 (2H, s), 5.29 (2H, s), 7.19 (IH, t, J=8Hz), 7.33 (IH, d, J=8Hz) , 7.54 (IH, d, J=8Hz), 7.80-8.05 (3H, m) , 8.31 (IH, d, J=7Hz)

Example 16

Isopropyl 2-[3-(4-bromo-2-fluorobenzyl)-3,4-dihydro- 4-oxophthalazin-l-yl]acetate mp : 112-115°C

NMR (CDC1₃, δ) : 1.20 (6H, d, J=6Hz), 3.93 (2H, s), 5.05 (IH, m), 5.42 (2H, s), 7.17-7.28 (3H, ) ,

7.69-7.88 (3H, m), 8.49 (IH, dd, J=7.5Hz and 1.5Hz)

Example 17 Ethyl 2-[3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]propionate mp : 110-112°C

NMR (CDCI3, δ) : 1.15 (3H, t, J=7.5Hz), 1.60 (3H, d, J=6Hz), 4.07-4.28 (3H, m) , 5.42 (2H, s), 7.18- 7.29 (3H, m), 7.72-7.83 (3H, m) , 8.48 (IH, dd,

J=7.5Hz and 1.5Hz)

Example 18

Ethyl 4-[3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]-3-oxobutyrate mp : 153-154°C

NMR (CDCI3, 6) : 1.26 (3H, t, J=7Hz), 3.58 (2H, s), 4.18 (2H, q, J=7Hz) , 4.20 (2H, s), 5.40 (2H, s), 7.18-7.30 (3H, m) , 7.65-7.90 (3H, m) , 8.47 (IH, d, J=7Hz)

Example 19

[3-(4-Bromo-2-fluorobenzyl)-3,4-dihydro-4- oxophthalazin-1-yl]carbaldehyde oxime mp : 230-233°C NMR (DMSO-dg, δ) : 5.40 (2H, s), 7.25 (IH, t,

J=8Hz), 7.40 (IH, dd, J=2Hz and 8Hz) , 7.60 (IH, dd, J=2Hz and 8Hz), 7.85-8.05 (2H, ), 8.15 (IH, s), 8.35 (IH, dd, J=2Hz and 8Hz), 8.85 (IH, d, J=8Hz)

Claims

A pharmaceutical composition for the prophylactic and/or therapeutic treatment of cachexia which comprises, as an active ingredient, an oxophthalazine compound of the following formula :

wherein R* is ar(lower)alkyl which may have one or more suitable substituent(s), and R^ is carboxy(lower)alkyl or protected carboxy(lower)alkyl, or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or excipient.

2. Use of an oxophthalazine compound of the following formula :

R2

o

wherein R¹ is ar(lower)alkyl which may have one or more suitable substituent(s) , and R^ is carbox (lower)alkyl or protected - 24 -

carboxy(lower)alkyl, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of cachexia.

A method for the prophylactic and/or therapeutic treatment of cachexia, which comprises administering an oxophthalazine compound of the following formula :

wherein R¹ is ar(lower)alkyl which may have one or more suitable substituent(s) , and R^ is carboxy(lower)alkyl or protected carboxy(lower)alkyl, or a pharmaceutically acceptable salt thereof to a human being or an animal.

4. A pharmaceutical composition of claim 1, use of claim 2 or a method of claim 3, wherein a oxophthalazine compound is the compound of the following formula :

o

wherein R^ is phenyl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, halogen and tri-halo(lower)alkyl, and R^ is carboxy(lower)alkyl or esterified carboxy(lower)alkyl.

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