AU3171293A - Use of renin inhibitors for the treatment of glaucoma - Google Patents

Use of renin inhibitors for the treatment of glaucoma

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Publication number
AU3171293A
AU3171293A AU31712/93A AU3171293A AU3171293A AU 3171293 A AU3171293 A AU 3171293A AU 31712/93 A AU31712/93 A AU 31712/93A AU 3171293 A AU3171293 A AU 3171293A AU 3171293 A AU3171293 A AU 3171293A
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alkyl
acyl
lower alkyl
group
hydrogen
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AU661748B2 (en
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Takehisa Hata
Akira Kagayama
Yoko Tanaka
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/553—Renin inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

DESCRIPTION
USE OF RENIN INHIBITORS FOR THE TREATMENT OF GLAUCOMA Technical Field
Glaucoma is a condition characterized by an increase in intraocular pressure. Increased intraocular pressure can lead to optic nerve damage and defects in the visual field. Blindness can result if the condition is left untreated.
This invention relates to new use of amino acid derivatives which inhibit renin for treating glaucoma or reducing and/or controlling intraocular pressure.
Accordingly, this invention provides new use of said amino acid derivatives for treating glaucoma or reducing and/or controlling intraocular pressure.
Further, this invention provides an agent and a pharmaceutical composition for treating glaucoma or reducing and/or controlling intraocular pressure, which comprises said amino acid derivatives.
Still further, this invention provides a method for treating glaucoma or reducing and/or controlling intraocular pressure, which comprises administering said amino acid derivatives to mammals.
Background Art
The amino acid derivatives used in this invention are known as renin inhibiting compounds and disclosed in
European Patent Publication No. 300189.
It has been disclosed (for example, in WO-87/02581, EP-A-0311012) that renin inhibitors are useful for
treating glaucoma, but there is still a need for useful methods and compositions for treating glaucoma or reducing and/or controlling intraocular pressure,
Disclosure of the Invention
The amino acid derivatives used in this invention can be represented by the following general formula [I].
2
R1
N-COO-CH-CON-CH-CONH-CH-CH-R4
[I] R2
R 3 O H wherein R1 is lower alkyl optionally substituted with
a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :
in which R5 is hydrogen or acyl and
R6 is hydrogen or lower alkyl;
aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and
R2 is hydrogen or lower alkyl; or
R1 and R2 are taken together with the attached
nitrogen atom to form a heterocyclic
group optionally substituted with substituent(s) selected from the group consisting of lower alkyl,
hydroxy(lower)alkyl, lower
alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl;
R3 is hydrogen or lower alkyl; and
R4 is lower alkyl;
and its pharmaceutically acceptable salt.
The term "lower" is intended to mean a group having to 7 carbon atom(s), unless otherwise provided.
Suitable "lower alkyl" may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl,
methylhexyl, heptyl, and the like.
Suitable "acyl" and "acyl" moiety in the term
"acyl (lower)alkyl" may be a group of the formula :
, R9-CO- and R9-SO2- , wherein R7 and R8 are each hydrogen, aryl, cyclo(lower)- alkyl, a heterocyclic group or lower alkyl optionally substituted with a substituent selected from the group consisting of lower alkoxycarbonyl, lower alkoxy, aryl and a heterocyclic group, or
R7 and R8 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with lower alkyl, and R9 is aryl, cyclo(lower)alkyl, lower alkyl optionally substituted with a substituent selected from the group consisting of lower alkoxy and mono- or di(lower)alkylamino, or lower alkoxy optionally substituted with a substituent selected from the group
consisting of lower alkanoyl and aryl, amino-protected or unprotected amino acid residue, or the like.
Suitable "aryl" may be phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl, and the like, in which preferabl one is phenyl.
Suitable "cyclo(lower)alkyl" is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or the like.
Suitable "heterocyclic group" for R7 and R8 and one as a substituent on lower alkyl for R7 and R8 may include saturated or unsaturated, monocyclic or polycyclic one containing at least one hetero atom such as nitrogen atom, oxygen atom or sulfur atom, preferably N, O and/or S containing 5 or 6 membered heterocyclic group, in which the most preferable ones are morpholino, pyridyl and thiazolyl.
Suitable "lower alkoxy" and "lower alkoxy" moiety in the term "lower alkoxycarbonyl" may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, in which more preferable one may be C1-C4 alkoxy.
Suitable "heterocyclic group" formed by R7, R8 and the attached nitrogen atom may be morpholino,
thiomorpholino, its 1-oxide or 1,1-dioxide,
pyrrolidin-1-yl, pyrazolidin-1-yl, piperidino,
piperazin-1-yl, pyrrolin-1-yl, thiazolidin-3-yl, its
1-oxide or 1,1-dioxide, oxazolidin-3-yl,
perhydropyridazin-1-yl, 1,4-dihydropyridin-1-yl,
1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydroguinolin-l-yl,
hexamethyleneimino, 1,4-diazabicyclo[4.3.0]nonan-4-yl, and the like.
Suitable "mono- or di(lower)alkylamino" may be methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino,
methylethylamino, methylisopropylamino, diethylamino, or the like.
Suitable "lower alkanoyl" may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 4-methylvaleryl, or the like.
Suitable "amino-protected or unprotected amino acid residue" may be glycyl, alanyl, b-alanyl, valyl, leucyl, isoleucyl, histidyl, prolyl, seryl, threonyl, cystyl, phenylalanyl, aspartyl, glutamyl, triptophyl, or the like each amino group of which may be protected by N-protectiv group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, etc.], substituted or
unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, aralkyl [e.g. trityl, benzyl, etc.] or the like.
Preferred examples of the above-mentioned acyl group may be lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
4-methylvaleryl, etc.], mono- or di (lower)alkylamino- (lower)alkanoyl [e.g. methylaminoacetyl, methylaminopropionyl, dimethylaminobutyryl, etc.], lower alkoxy- (lower)alkanoyl [e.g. methoxyacetyl, methoxypropionyl, ethoxypropionyl, etc.], aroyl [e.g. benzoyl, toluoyl, etc.], cyclo(lower)alkylcarbonyl [e.g.
cyclopropylcarbonyl, cyclobutylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl, etc.],
amino-protected or unprotected amino acid residue [e.g. glycyl, benzoylglycyl, t-butoxycarbonylglycyl,
t-butoxycarbonylleucyl, acetylleucyl, t-butoxycarbonylhistidyl, etc.], carbamoyl, mono- or di(lower)alkylcarbamoyl [e.g. methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl, methylisopropylcarbamoyl,
methylisobutylcarbamoyl, etc.], heterocyclic(lower)- alkylcarbamoyl [e.g. picolylcarbamoyl, pyridylethylcarbamoyl, thiazolylmethylcarbamoyl, morpholinomethylcarbamoyl, morpholinoethylcarbamoyl, etc.],
N-heterocyclic(lower)alkyl-N-lower alkylcarbamoyl [e.g. N-picolyl-N-methylcarbamoyl, N-pyridylethyl- N-methylcarbamoyl, N-morpholinomethyl-N-ethylcarbamoyl, N-morpholinoethyl-N-methylcarbamoyl, etc.],
ar(lower)alkylcarbamoyl [e.g. benzylcarbamoyl,
phenethylcarbamoyl, benzhydrylcarbamoyl, etc.],
N-ar(lower)alkyl-N-lower alkylcarbamoyl [e.g.
N-benzyl-N-methylcarbamoyl, N-phenethyl-N-methylcarbamoyl, N-phenethyl-N-ethylcarbamoyl, etc.], N-aryl-N-lower alkylcarbamoyl [e.g. N-phenyl-N-methylcarbamoyl, etc.], lower alkoxycarbonyl(lower)alkylcarbamoyl [e.g. methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, ethoxycarbonylethylcarbamoyl, etc.], lower alkoxy(lower)- alkylcarbamoyl [e.g. methoxymethylcarbamoyl,
methoxyethylcarbamoyl, ethoxypropylcarbamoyl, etc.], aroylcarbamoyl [e.g. benzoylcarbamoyl, toluoylcarbamoyl, etc.], heterocycliccarbamoyl [e.g. pyridylcarbamoyl, morpholinocarbamoyl, thiazolylcarbamoyl, etc.],
N-heterocyclic-N-lower alkylcarbamoyl [e.g. N-pyridyl- N-methylcarbamoyl, N-thiazolyl-N-methylcarbamoyl, etc.], heterocycliccarbonyl, preferably N-containing
heterocyclic-N-ylcarbonyl which may be substituted with lower alkyl [e.g. morpholinocarbonyl,
thiomorpholinocarbonyl, piperidinocarbonyl,
4-methyl-1-piperazinylcarbonyl, 1,2,3,6-tetrahydro-1- pyridylcarbonyl, etc.], lower alkoxycarbonyl [e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], mono(or di or tri)halo (lower)alkoxycarbonyl [e.g. iodoethoxycarbonyl, dichloroethoxycarbonyl,
trichloroethoxycarbonyl, trifluoromethoxycarbonyl, etc.], hydroxy(lower)alkoxycarbonyl [e.g. hydroxymethoxycarbonyl hydroxyethoxycarbonyl, hydroxypropoxycarbonyl,
hydroxybutoxycarbonyl, etc.], ar(lower)alkoxycarbonyl
[e.g. benzyloxycarbonyl, phenethyloxycarbonyl,
4-nitrobenzyloxycarbonyl, trityloxycarbonyl,
benzhydryloxycarbonyl, etc.], lower alkenyloxycarbonyl [e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.], lower alkanoyl (lower)alkoxycarbonyl [e.g. acetylmethoxycarbonyl propionylmethoxycarbonyl, acetylethoxycarbonyl, etc.], lower alkylsulfonyl [e.g. mesyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.], arylsulfonyl [e.g. phenylsulfonyl, tosyl, etc.], or the like.
Suitable "lower alkylthio" may be a straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, and the like, in which more preferable one may be C1-C4 alkylthio.
Suitable "heterocyclic group" formed by R1, R2 and the attached nitrogen atom can be referred to the ones formed by R7, R8 and the attached nitrogen atom as exemplified above.
Suitable "hydroxy(lower)alkyl" may be hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl,
hydroxybutyl, and the like.
Suitable "lower alkoxy(lower)alkyl" may be methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, and the like.
Suitable pharmaceutically acceptable salts of the compounds [I] are conventional non-toxic salts and includ an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. aspartic acid salt, glutamic acid salt, etc.], or the like.
The term "controlling intraocular pressure" means the regulation, attenuation and modulation of increased intraocular tension. The term also means that the
decrease, in the otherwise elevated intraocular pressure, obtained by the methods and compositions of the invention is maintained for a significant period of time as, for example, between consecutive doses of the composition of the invention.
Preferred embodiments of the Symbols R1 to R4 are as follows :
R1 is lower alkyl substituted with a substituent selected from the group consisting of a group of the formula :
,
in which R7 and R8 are each hydrogen or lower alkyl, or
R7 and R8 are taken together with the
attached nitrogen atom to form
morpholino,
and a group of the formula : in which R5 is hydrogen or a group of the formula N-CO- or R9-CO-
[in which R7 and R8 are taken together with the attached nitrogen atom to form morpholino, and R9 is lower alkyl], and
R6 is hydrogen or lower alkyl,
R2 is hydrogen or lower alkyl,
R3 is hydrogen or lower alkyl, and
R4 is lower alkyl.
More preferred embodiments of the Symbols R1 to R4 are as follows :
R1 is C1-C4 alkyl substituted with a group of the
formula :
in which R6 is C1-C4 alkyl,
R2 is C1-C4 alkyl,
R3 is C1-C4 alkyl, and
R4 is C1-C5 alkyl.
Particularly, the most interesting compounds are 2(S)-[Nα-[2(S)-{N-(2-morpholinocarbonylethyl)-N- methylaminocarbonyloxy}-3-phenylpropionyl]-Nα-methyl-L- histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane or its hydrochloride,
2(S)-[Nα-[2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)- N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionyl]- Nα-methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride, and
2(S)-[Nα-[2(S)-[N-methyl-N-{2-(N-isobutyryl-N- methylamino)ethyl}aminocarbonyloxy]-3-phenylpropionyl]- Nα-methyl-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride.
It is to be noted that the compound [I] may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
Now in order to show the utility of the compound [I] and pharmaceutically acceptable salts thereof in this invention, the test data of the representative compound of this invention is shown in the following.
Effect of Topically Administered Test Compound on Intraocular Pressure of Rabbits :
1. Test Method :
Male alino rabbits weighing 2.4 to 3.1 kg were used in this study.
0.2% solution of the test compound in saline was prepared and this solution or vehicle was applied
bilaterally. The total volume of 50 μl was applied in two portion of 25 μl , maintaining a waiting period of 5 minutes before the next administration.
Intraocular pressure (IOP) was measured using Alcon pneumatonograph . 10 μl of 0 .4% oxybuprocaine
hydrochloride was applied to the cornea to minimize discomfort during IOP measurements. IOP measurements were made at 0 (pretreat) and 1 hour after instillation of the test compound or vehicle.
2. Test Compound :
2 (S)-[Nα-[2(S)-[N-Methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionyl]-Nα-methyl-L-histidyl]amino-1-cyclohexyl-3 (S)- hydroxy-6-methylheptane monohydrochloride
(hereinafter referred to as Compound A)
Test Results :
The results show that the compound of this invention has activity of reducing the intraocular pressure and is useful for treating glaucoma.
For therapeutic purpose, the compounds [I] and pharmaceutically acceptable salts thereof of the present invention can be used in a form of pharmaceutical
preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically
acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solution (including ophthalmic solution), suspension, emulsion, ointment, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
And further, the compound [I] and pharmaceutically acceptable salts thereof of the present invention may be used in combination with other ingredients which control intraocular pressure such as beta-adrenergic antagonist [e.g. timolol, etc.], angiotensin converting enzyme inhibitor [e.g. captopril, enalapril, etc.], or the like.
While the dosage of the compounds [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating glaucoma or reducing and/or controlling intraocular pressure. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
Examples
The following examples are given for the purpose of illustrating the present invention.
Example 1
(Capsule)
2(S)-[Nα-[2(S)-(N-(2-Morpholinocarbonylethyl)-
N-methylaminocarbonyloxy}-3-phenylpropionyl]- Nα-methyl-L-histidyl]amino-1-cyclohexyl-3(S)- hydroxy-6-methylheptane monohydrochloride 5 mg
Lactose 80 mg
The above-mentioned ingredients were mixed and the mixture was encapsulated to provide the capsule.
Example 2
(Ophthalmic solution)
2(S)-[Nα-[2(S)-[N-Methyl-N-[2-(N-(morpholino- carbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-
3-phenylpropionyl]-Nα-methyl-L-histidyl]amino-1- cyclohexyl-3(S)-hydroxy-6-methylheptane
monohydrochloride 10 mg
Benzalkonium chloride 0.2 mg Sodium chloride 2.9 mg pH 4.5 Phosphate buffer a proper quantity
(total volume 1.0 ml)
The above-mentioned ingredients were mixed to provide 1.0 ml of the ophthalmic solution.

Claims (1)

  1. CLAIMS 1. Use of a compound of the formula :
    N-COO-CH-CON-CH-CONH-CH-CH-R4
    R3 H wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :
    in which R5 is hydrogen or acyl and
    R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and
    R2- is hydrogen or lower alkyl; or R1 and R2 are taken together with the
    attached nitrogen atom to form a heterocyclic group optionally
    substituted with substituent(s)
    selected from the group consisting of lower alkyl, hydroxy(lower) alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl;
    R3 is hydrogen or lower alkyl; and
    R4 is lower alkyl;
    or its pharmaceutically acceptable salt, for treating glaucoma or reducing and/or controlling intraocular pressure.
    2. Use according to claim 1 of 2(S)-[Nα-[2(S)-[N-methyl- N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]- aminocarbonyloxy]-3-phenylpropionyl]-Nα-methyl-L- histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride. 3. An agent for treating glaucoma or reducing and/or controlling intraocular pressure, which comprises a compound of the formula :
    1
    N-COO-CH-CON-CH-CONH-CH-CH-R4
    2
    R3 OH wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :
    in which R5 is hydrogen or acyl and
    R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and
    R2 is hydrogen or lower alkyl; or
    R1 and R2 are taken together with, the
    attached nitrogen atom to form a heterocyclic group optionally
    substituted with substituent( s)
    selected from the group consisting of lower alkyl, hydroxy(lower) alkyl, lower alkoxy(lower) alkyl, acyl(lower)alkyl, oxo and acyl;
    R3 is hydrogen or lower alkyl; and
    R4 is lower alkyl;
    or its pharmaceutically acceptable salt. 4. An agent according to claim 3, which comprises
    2(S)-[Nα-[2-(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3- phenylpropionyl]-Nα-methyl-L-histidyl3amino-1- cyclohexyl-3(S)-hydroxy-6-methylheptane or its
    hydrochloride.
    5. A method for treating glaucoma or reducing and/or
    controlling intraocular pressure, which comprises administering a compound of the formula :
    N-COO-CH-CON-CH-CONH-CH-CH-R4
    R3 OH wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :
    in which R5 is hydrogen or acyl and
    R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and
    R2 is hydrogen or lower alkyl; or
    R1 and R2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally
    substituted with substituent(s)
    selected from the group consisting of lower alkyl, hydroxy(lower) alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl;
    R3 is hydrogen or lower alkyl; and
    R4 is lower alkyl; or its pharmaceutically acceptable salt to mammals.
    6. A method according to claim 5, which comprises
    administering 2(S)-[Nα-[2-(S)-[N-methyl-N-[2-(N- (morpholinocarbonyl)-N-methylamino>ethyl]aminocarbonyloxy]-3-phenylpropionyl]-Nα-methyl-L- histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride. 7. Use of a compound of the formula :
    N-COO-CH-CON-CH-CONH-CH-CH-R4
    R3 OH wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl, hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :
    in which R5 is hydrogen or acyl and
    R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R2 is hydrogen or lower alkyl; or
    R 1 and R2 are taken together with the
    attached nitrogen atom to form a heterocyclic group optionally
    substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl;
    R3 is hydrogen or lower alkyl; and
    R4 is lower alkyl;
    or its pharmaceutically acceptable salt for
    manufacturing a medicament for treating glaucoma or reducing and/or controlling intraocular pressure.
    Use according to claim 7 of 2(S)-[Nα-[2-(S)-[N- methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}- ethyl]aminocarbonyloxy]-3-phenylpropionyl]-Nα-methyl- L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride.
    9. A pharmaceutical composition for treating glaucoma or reducing and/or controlling intraocular pressure, which comprises a compound of the formula :
    N-COO-CH-CON-CH-CONH-CH-CH-R 4
    R3 OH wherein R1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl, hydroxy, lower
    alkoxy, aryl, lower alkylthio and a group of the formula :
    in which R5 is hydrogen or acyl and
    R6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and
    R2 is hydrogen or lower alkyl; or R 1 and R2 are taken together with the
    attached nitrogen atom to form a heterocyclic group optionally
    substituted with substituent(s)
    selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl;
    R3 is hydrogen or lower alkyl; and R4 is lower alkyl;
    or its pharmaceutically acceptable salt as an active ingredient, in admixture with a carrier or excipient.
    10. A pharmaceutical composition according to claim 9,
    which comprises 2(S)-[Nα-[2-(S)-[N-methyl-N-[2-{N- (morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionyl]-Nα-methyl-L- histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride as an active ingredient.
AU31712/93A 1991-12-20 1992-12-18 Use of renin inhibitors for the treatment of glaucoma Ceased AU661748B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB919127041A GB9127041D0 (en) 1991-12-20 1991-12-20 New use
GB9127041 1991-12-20
PCT/JP1992/001656 WO1993012796A1 (en) 1991-12-20 1992-12-18 Use of renin inhibitors for the treatment of glaucoma

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AU3171293A true AU3171293A (en) 1993-07-28
AU661748B2 AU661748B2 (en) 1995-08-03

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JP (1) JPH07506807A (en)
KR (1) KR940703665A (en)
AU (1) AU661748B2 (en)
CA (1) CA2126211A1 (en)
GB (1) GB9127041D0 (en)
HU (2) HUT68175A (en)
MX (1) MX9207429A (en)
RU (1) RU94031479A (en)
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ZA (1) ZA929738B (en)

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WO1994025062A1 (en) * 1993-04-28 1994-11-10 Fujisawa Pharmaceutical Co., Ltd. Oral pharmaceutical compositions containing renin inhibitors
JP2004503540A (en) 2000-06-15 2004-02-05 ファルマシア・コーポレーション Dihydrostilbene alkanoic acid derivatives useful as integrin antagonists
US6476046B1 (en) 2000-12-04 2002-11-05 Sepracor, Inc. Diazabicyclo[4.3.0]nonanes, and methods of use thereof
MY133587A (en) 2002-05-29 2007-11-30 Glaxo Group Ltd Aromatic sulfones and their medical use
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
MX2013015274A (en) 2011-06-24 2014-03-31 Amgen Inc Trpm8 antagonists and their use in treatments.
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
CA3183740A1 (en) 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds

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US4906613A (en) * 1985-11-05 1990-03-06 Schering Corporation Antiglaucoma compositions and methods
US4921855A (en) * 1987-06-22 1990-05-01 Fujisawa Pharmaceutical Co., Ltd. New Histidyl amino acid derivatives, and pharmaceutical composition comprising the same
US4927807A (en) * 1987-10-06 1990-05-22 Abbott Laboratories Glaucoma treatment
US5151513A (en) * 1988-04-29 1992-09-29 E. R. Squibb & Sons, Inc. N-heterocyclic alcohol derivatives
IL99389A0 (en) * 1990-09-17 1992-08-18 Fujisawa Pharmaceutical Co Amino acid derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same

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WO1993012796A1 (en) 1993-07-08
EP0617622A1 (en) 1994-10-05
MX9207429A (en) 1993-06-01
RU94031479A (en) 1996-10-20
GB9127041D0 (en) 1992-02-19
ZA929738B (en) 1993-06-17
HU211939A9 (en) 1996-01-29
CA2126211A1 (en) 1993-07-08
AU661748B2 (en) 1995-08-03
JPH07506807A (en) 1995-07-27
HU9401833D0 (en) 1994-09-28
KR940703665A (en) 1994-12-12
HUT68175A (en) 1995-05-29

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