USE OF RENIN INHIBITORS FOR THE TREATMENT OF GLAUCOMA

Abstract: This invention relates to use of a compound of formula (I) wherein each symbol is as defined in the description, or its pharmaceutically acceptable salt, for treating glaucoma or reducing and/or controlling intraocular pressure.

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 ar 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 reducin 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]. wherein Rl 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 R-5 is hydrogen or acyl and R^ 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 Rl 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; R-3 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 : wherein R 7 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 R 7 and R-3 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 R 7 and R*3 and one as a substituent on lower alkyl for R 7 and R8 may include saturated or unsaturated, onocyclic or polycyclic one containing at least one hetero atom such as nitrogen atom, oxygen atom or sulfur atom, preferably N, 0 and/or S containing 5 or 6 membered heterocyclic group, in which the most preferable ones are morpholino, py idyl 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 R 7 , 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-l-yl, 1,2,3,6-tetrahydropyridin-l-yl, 1,2,3,4-tetrahydro- isoquinolin-2-yl, 1,2,3,4-tetrahydroguinolin-l-yl, hexamethyleneimino, l,4-diazabicyclo[4.3.0]nonan-4-yl, and the like. Suitable "mono- or di(lower)alkylamino" may be methylamino, ethyla ino, 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, methylamino- propionyl, dimethylaminobutyryl, etc. ] , lower alkoxy- (lower)alkanoyl [e.g. ethoxyacetyl, methoxypropionyl, ethoxypropionyl, etc. ], aroyl [e.g. benzoyl, toluoyl, etc. ] , cyclo(lower) lkylcarbonyl [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, ethylisopropylcarbamoyl, methylisobutylcarbamoyl, etc. ], heterocyclic(lower)- alkylcarbamoyl [e.g. picolylcarbamoyl, pyridylethyl- carbamoyl, thiazolylmethylcarbamoyl, morpholinomethyl- carbamoyl, 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. methoxy- carbonylmethylcarbamoyl, 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-l-piperazinylcarbonyl, 1,2,3,6-tetrahydro-l- 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 Rl, R2 and the attached nitrogen atom can be referred to the ones formed by R 7 , 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 methoxy- methyl, 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 R! to R^ are as follows : Rl is lower alkyl substituted with a substituent selected from the group consisting of a group of the formula : in which R 7 and R8 are each hydrogen or lower alkyl, or R 7 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 [in which R 7 and Rδ are taken together with the attached nitrogen atom to form morpholino, and R9 is lower alkyl], and R6 is hydrogen or lower alkyl, R-2 is hydrogen or lower alkyl, R-3 is hydrogen or lower alkyl, and R4 is lower alkyl. More preferred embodiments of the Symbols R! to R 4 are as follows : R! is C1-C4 alkyl substituted with a group of the formula : in which R 6 is C1-C4 alkyl, R 2 is C1-C4 alkyl, R 3 is C1-C4 alkyl, and R 4 is C1-C5 alkyl. Particularly, the most interesting compounds are 2(S)-[N α -[2(S)-{N-(2-morpholinocarbonylethyl)-N- methylaminocarbonyloxy>-3-phenylpropionyl]-N α -methyl-L- histidyl]amino-l-cyclohexyl-3(S)-hydroxy-6-methylheptane or its hydrochloride, 2(S)-[N α -[2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)- N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionyl]- N α -methyl-L-histidyl]amino-l-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride, and 2(S)-[N α -[2(S)-[N-methyl-N-{2-(N-isobutyryl-N- methylamino)ethyl}aminocarbonyloxy]-3-phenylpropionyl]- N -methyl-L-histidyl]amino-1-cyclohexy1-3(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 wer made at 0 (pretreat) and 1 hour after instillation of the test compound or vehicle. 2. Test Compound : 2(S)-[N α -[2(S)-[N-Methyl-N-[2-{N-(morpholino- carbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenyl- propionyl]-N α -methyl-L-histidyl]amino-l-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)-[N -[2(S)-(N-(2- orpholinocarbonylethyl)- N-methylaminocarbonyloxy}-3-phenylpropionyl]- N α -methyl-L-histidyl]amino-l-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)-[N α -[2(S)-[N-Methyl-N-[2-(N-(morpholino- carbonyl)-N-methylamino}ethyl]aminocarbonyloxy]- 3-phenylpropionyl]-N α -methyl-L-histidyl]amino-l- cyclohexyl-3(S)-hydroxy-6-methylheptane monohydrochloride 10 mg Benzalkoniu 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: CLAIMS 1. Use of a compound of the formula : -R 4 wherein 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 : R 5 A -N ^ 6 in which R is hydrogen or acyl and R is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the - group consisting of lower alkyl and acyl; and 2 R - 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 alkox (lower)alkyl, acyl(lower)alkyl, oxo and acyl; " is hydrogen or lower alkyl; and R 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)-[N -[2(S)-[N-methyl- N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]- a inocarbonyloxy]-3-phenylpropionyl]-N α -methyl-L- histidyl]amino-l-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 : wherein R "1" 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 : R 5 R 6 in which R is hydrogen or acyl and R is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and 2 R 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; 3 R is hydrogen or lower alkyl; and 4 R is lower alkyl; or its pharmaceutically acceptable salt. 4. An agent according to claim 3, which comprises 2(S)-[N α -[2-(S)-[N-methyl-N-[2-{N-(morpholino- carbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3- phenylpropionyl]-N α -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 : wherein R 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 : R 5 - 5 in which R is hydrogen or acyl and g R is hydrogen or lower alkyl; * aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and 2 R 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 alkox (lower)alkyl, acyl(lower)alkyl, oxo and acyl; 3 R is hydrogen or lower alkyl; and R is lower alkyl; or its pharmaceutically acceptable salt to mammals. 6. A method according to claim 5, which comprises administering 2(S)-[N α -[2-(S)-[N-methyl-N-[2-(N- (morpholinocarbonyl)-N-methylamino>ethyl]a ino- carbonyloxy]-3-phenylpropionyl]-N α -methyl-L- histidyl]amino-l-cyclohexyl-3(S)-hydroxy-6- methylheptane or its hydrochloride. 7. Use of a compound of the formula : a, N- -R 4 wherein R 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 : -N 5 in which R is hydrogen or acyl and g R is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and Δ 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, hydrox (lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; 3 R is hydrogen or lower alkyl; and 4 R 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)-[N α -[2-(S)-[N- methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}- ethyl]aminocarbonyloxy]-3-phenylpropionyl]-N α -methyl- L-histidyl]amino-l-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 : ι wherein R 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 : R " -N „6 5 in which R is hydrogen or acyl and R is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and 2 R 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; 3 R is hydrogen or lower alkyl; and 4 R 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)-[N α -[2-(S)-[N-methyl-N-[2-{N- (morpholinocarbonyl)-N-methylamino}ethyl]amino- carbonyloxy]-3-phenylpropionyl]-N α -methyl-L- histidyl]amino-l-cyclohex l-3(S)-hydroxy-6- methylheptane or its hydrochloride as an active ingredient.

Inventors: HATA TAKEHISA, KAGAYAMA AKIRA, TANAKA YOKO, HATA, TAKEHISA, KAGAYAMA, AKIRA, TANAKA, YOKO
Applicants: FUJISAWA PHARMACEUTICAL CO, FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61K38, A61P27, C07D233