MX2008006694A - Pharmaceutical for use in the treatment of ureterolithiasis - Google Patents

Abstract

The object is to provide a pharmaceutical useful for the remission of a pain caused by ureterolithiasis, the acceleration of removal of a calculus present in the ureter from the body or the like. Disclosed is a therapeutic pharmaceutical for ureterolithiasis, which has a potent inhibitory effect on the contraction of the ureter and comprises an indoline derivative represented by the general formula (I) or a salt thereof as an active ingredient:(I) wherein R represents an aliphatic acyl which may have a substituent and may have an unsaturated bond, a hydroxyalkyl, an aliphatic acyloxyalkyl, a lower alkyl which may have a lower alkoxy, a carboxy, a lower alkoxycarbonyl, an aryl-substituted lower alkoxycarbonyl, a carbamoyl, a monoalkyl- or dialkyl-substituted carbamoyl or a cyano as a substituent, an aromatic acyl which may have be substituted, a furoyl or a pyridylcarbonyl;R1represents a cyano or carbamoyl;and R2represents a lower alkyl which may have a halogen, a cyano or a aryl as a substituent.

Description

DRUG FOR USE IN TREATMENT OF URETEROLITHIASIS Field of the Invention The present invention relates to pharmaceutical compositions for the treatment of ureteral lithiasis, which comprise as indoline derivatives of active ingredient represented by the general formula: [Chemistry 1] in the formula, R represents a saturated or unsaturated aliphatic acyl group which may have as a substituent one or more halogen atoms, a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group, or a aryl group; a hydroxyalkyl group; an aliphatic acyloxyalkyl group; a lower alkyl group having as a substituent a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a substituted lower arylalkoxycarbonyl group, a carbamoyl group, a mono- or di (lower alkyl) -carbamoyl substituted group or a cyano group; an aromatic acyl group which may have one or more halogen atoms as a substituent; a furoyl group or a pyridylcarbonyl group; R1 represents a cyano group or a carbamoyl group; and R2 represents a lower alkyl group which may have as one substituent one or more halogen atoms, a cyano group or an aryl group; or a pharmaceutically acceptable salt thereof and the like. More particularly, the present invention relates to pharmaceutical compositions useful for relieving pain caused by ureteral stones, facilitating the exclusion of ureteral stones, which relieve hydronephrosis or reducing resistance during insertion of the ureteroscope and the like, which comprises as an active ingredient. (-) - 1- (3-hydroxypropyl) -5 - ((2R) -2 - ([2- (. {2 - [(2,2,2-trifluoroethyl) oxy] phenyl) oxy) etl ] amino) propyl) -2,3-dihydro-1 H -indole-7-carboxamide (generic name: silodosin) to a pharmaceutically acceptable salt thereof or the like, and the like. Prior Art of the Invention Ureteral lithiasis means a condition in which a fallen kidney stone is present in the ureter. The main symptoms are colic, hematuria, anuria, hydronephrosis and nephropathy (see, for example, reference of No-patent 1). The treatment of ureteral lithiasis includes drug therapies such as lithotryptic and analgesics in colic attack and the like, and surgical therapies such as extracorporeal shock wave lithotripsy (ESWL), lithotripsy with an endoscope and the like. Analgesics and antispasmodics are prescribed for pain that is a major symptom in ureteral lithiasis. However, the analgesic is a temporary symptomatic treatment of pain and radical treatment can not be expected with the drug. In addition, the effect of antispasmodics such as an anticholinergic agent is not necessarily sufficient. Therefore, an agent is desired, which facilitates the exclusion of ureteral stones and revives pain by its potent inhibitory effect against ureteral contraction. In relation to the adrenoreceptor (AR), the a1A, a1B and OID subtypes are known- Since the OID-R mRNA and protein are expressed more highly than those of a1A- and a1B-ARs in smooth human ureteral muscle, a? D -AR is thought to contribute primarily to ureteral contractile function (see reference of No-patent 2). In addition, it has been reported that antagonists of a-i-AR, tamsulosin hydrochloride, terazosin and doxazosins are effective for the exclusion of calculi and pain in patients with ureteral stones. It is considered that the effects were produced by the antagonism in a1D-ARs (see references of Non-patent 3 and 4). a1A-AR is present in the prostate, whereas a? D-AR is abundantly present in the blood vessel as well as the prostate (see reference No-patent 5). The two subtypes of the receptor participate in the contractile function (see reference of No-patent 6). In fact, it is known that tamsulosin hydrochloride decreases blood pressure more strongly than the compound represented by general formula (I) above in anesthetized dogs (see reference of Non-patent 7). Thus, the application of tamsulosin hydrochloride for the treatment of ureteral stones is thought to give rise to a problem in cardiovascular systems. It has been reported that the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof exerts a blocking effect of selective a1A-AR (see reference of Non-patent 8), has an inhibitory effect against the contraction of the urethral smooth muscle and is useful as an agent for the treatment of dysuria accompanied by benign hyperplasia of the prostate and the like (for example, see Patent References 1 to 4). However, no relationship between the blocking effect of a1A-AR and ureteral stones has been known. Furthermore, it has not been known, reported or suggested that these compounds inhibit ureteral contraction or be useful as an agent for the treatment of ureteral lithiasis. Patent Reference 1: Japanese Patent Publication H6-220015; Patent Reference 2: Patent Publication No. 99-brochure 15202; Patent Reference 3: Patent Publication No. 00-brochure 247998; Patent Reference 4: Patent Publication No. 05-brochure 85195; Non-Reference Patent 1: Hyojun Hinyokikagaku (Standard urology), 6th edition, Igakusyoin, May 15, 2002, pp. 229-237; Patent of Non-Reference 2: Neurourol Urodyn, 2005, Vol. 24, pp.142-148; Patent of Non-Reference 3: J. Urol., 2003, Vol.170, pp. 2202-2205; Patent of Non-Reference 4: J. Urol., 2005, Vol. 173, pp. 2010-2012; Patent of Non-Reference 5: J. Pharmacol. Exp. Ther., 1995, Vol.275, pp.1035-1042; Patent of Non-Reference 6: Eur. J. Pharmacol., 1996, Vol. 318, pp.117-122; Patent of Non-Reference 7: Int. J. Urol., 2001, Vol.8, pp. 177-183; Patent No. 8: J. Pharmacol. Exp. Ther., 1999, Vol.291, pp.81-91. Description of the Invention Problems and Solved by the Invention The object of the present invention is to provide pharmaceutical compositions for the treatment of ureteral lithiasis. Means to Solve Problems The present inventors have seriously studied the above problems, and surprisingly found that silodosin which has little blocking effect of a1D-AR has a strong inhibitory effect against ureteral contraction and is useful for relieving pain caused by stones. ureteral, facilitating the exclusion of ureteral stones or supporting the insertion of the ureteroscope, thereby forming the basis of the present invention. That is, the present invention relates to: [1] a pharmaceutical composition for the treatment of ureteral lithiasis, comprising as an active ingredient an indoline derivative represented by the general formula: in the formula, R represents a saturated or unsaturated aliphatic acyl group which may have as a substituent one or more halogen atoms, a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group, or a aryl group; a hydroxyalkyl group; an aliphatic acyloxyalkyl group; a lower alkyl group having as a substituent a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a substituted lower aryl-alkoxycarbonyl group, a carbamoyl group, a mono od (lower alkyl) -carbamoyl substituted group or a group cyano; an aromatic acyl group which may have one or more halogen atoms as a substituent; a furoyl group or a pyridylcarbonyl group; R1 represents a cyano group or a carbamoyl group; and R2 represents a lower alkyl group which may have as one substituent one or more halogen atoms, a cyano group or an aryl group; or a pharmaceutically acceptable salt thereof; [2] a pharmaceutical composition as described in the above [1] wherein the indoline derivative is silodosin; [3] a pharmaceutical composition as described in the above [1] or [2], wherein the pharmaceutical composition is for relieving pain caused by ureteral stones, facilitating the exclusion of ureteral stones, relieving hydronephrosis or reducing resistance during the insertion of the ureteroscope; [4] a pharmaceutical composition as described in any of the above [1] to [3], which is an agent for the inhibition of ureteral contraction; [5] a method for the treatment of ureteral lithiasis, comprising administering an effective amount of an indoline derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof; [6] a method as described in the previous [5] wherein the indoline derivative is silodosin; [7] a use of an indoline derivative represented by the general formula (I) above or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition for the treatment of ureteral lithiasis; [8] a use as described in the previous [7] wherein the indoline derivative is silodosin; and similar. Effect of the Invention The pharmaceutical compositions of the present invention exert a strong inhibitory effect against ureteral contraction and are useful for the treatment of ureteral lithiasis or the like. further, the compounds represented by the general formula (I) above of an active ingredient of the pharmaceutical composition of the present invention are highly selective inhibitors of a? A-AR compared to a1D-AR (see reference of Non-patent 8), and thus, it is considered that they can be an agent for the treatment of ureteral lithiasis, which has a lower cardiovascular effect. Brief Description of the Drawings [Figure 1] Figure 1 shows inhibitory effect against ureteral contraction. The horizontal and vertical axes show the concentrations of phenylephrine (log M) and ureteral contraction (%), respectively. In the figure, each curve shows the response curve of the concentration for phenylephrine (Control: control group) (open circle), in the presence of 3 x 10 ~ 10 mol / l (closed square), 1 x 10'9 mol / l (closed triangle) or 3 x 10 ~ 9 mol / l (closed circle) of compound 1. Best Mode for Practicing the Invention In general formula (I) above, the term "lower alkyl" means linear-chained alkyl or branched that has 1 to 6 carbon atoms; by term "hydroxyalkyl" means straight-chained or branched alkyl having 2 to 6 carbon atoms and a hydroxyl group with the proviso that the hydroxyl group exists in a position other than position a, the term "alkoxy" means alkoxy linear-chained or branched having 1 to 6 carbon atoms; and the term "cycloalkyl" means cyclic alkyl of 5 to 7 members, respectively. In addition, the term "aryl" means an aromatic hydrocarbon group such as phenyl, naphthyl or the like; the term "aromatic acyl" means acyl or carboxylic acid having an aryl having the same meaning as defined above; the term "saturated or unsaturated aliphatic acyl" means acyl of linear-chained or branched alkylcarboxylic acid having 2 to 7 carbon atoms or acyl of straight-chained or branched alkenylcarboxylic acid having 3 to 7 carbon atoms; and the term "aliphatic acyloxy" means an alkylcarbonyloxyalkyl having a hydroxyl group substituted by the above aliphatic acyl group and 4 to 13 carbon atoms with the proviso that the aliphatic acyloxy group exists in a position other than the a position, respectively . In addition, the term "furoyl" means 2-furoyl or 3-furoyl; the term "pyridylcarbonyl" means 2-pyridylcarbonyl, 3-pyridylcarbonyl or 4-pyridylcarbonyl; and the term "halogen atom" means a fluorine atom, a chlorine atom or a bromine atom, respectively. In addition, the indoline derivatives of general formula (I) can be prepared by the method described in Patent Reference 1. As the indoline derivatives, silodosin as mentioned above, ie, (-) - 1- (3-hydroxypropyl) ) -5 - ((2R) -2-. {(2- ( {2 - [(2,2,2-trifluoroethyl) oxy] phenyl) oxy) ethyl] amino) propyl) -2.3- dihydro-1 H-indole-7-carboxamide (from time to time, hereinafter referred to as "compound 1") is preferable.

As the pharmaceutically acceptable salt of the above indoline derivative, for example, in the case of a compound having a carboxy group, a salt with an inorganic base such as sodium, potassium, calcium or the like, a salt with an organic amine such as morpholine, piperidine or the like can be illustrated. In addition, among the indoline derivatives, in the case of a compound wherein the substituent R is a substituted or unsubstituted acyl group or a furoyl group, an additive salt with a monoacid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid , benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, succinic acid, tartaric acid, 2,4-dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, (+) - camphorsulfonic acid, (-) - camphorsulfonic acid , 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 1-butanesulfonic acid, fumaric acid, glutamic acid, aspartic acid and the like can be illustrated. In addition, among the n-doline derivatives, in the case of a compound wherein the substituent R is a substituted alkyl group or a pyridylcarbonyl group, an additive salt with a monoacid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, 2,4-dimethylbenzenesulfonic acid, 2,5-dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, (+) - camphorsulfonic acid, (-) - camphorsulfonic acid, 4-chlorobenzenesulfonic acid, 2- Naphthalenesulfonic acid, 1-butanesulfonic acid, fumaric acid, glutamic acid, aspartic acid and the like can be illustrated. The pharmaceutical composition of the present invention can be suitably prepared to be mixed with or diluted and dissolved with suitable pharmaceutical excipients such as fillers, disintegrants, binders, lubricants, diluents, buffers, isotonizing agents, antiseptics, wetting agents, emulsifiers, dispersing agents, stabilizing agents. , auxiliary solvents and the like, and formulate the mixture according to conventional methods. As a dosage form of the pharmaceutical composition of the present invention, for example, a formulation for oral administration such as powders, granules, fine granules, dry suspensions, tablets, capsules and the like; A formulation for parenteral administration such as injections, patches, suppositories and the like can be illustrated, and a formulation for oral administration is preferable. The dosage of an indoline derivative represented by the general formula (I) above can be appropriately decided depending on the body weight, age, sex and degree of diseases of each patient. For example, a dosage in an adult human is within the range of 1 to 100 mg per day, preferably 1 to 50 mg per day in the case of oral administration. The dosage of silodosin in an adult human is in the range of 2 to 32 mg per day, preferably 4 to 16 mg per day in the case of oral administration. The daily dose can be divided into one to two or more doses per day and administered. The pharmaceutical compositions of the present invention exert an inhibitory effect against ureteral contraction, and thus, they are useful for the treatment of ureteral lithiasis. In the present description, the ureteral lithiasis includes the ureteral lithiasis diagnosed due to the presentation of pain, bleeding in the urine and anuria as well as the ureteral lithiasis diagnosed using ultrasonography, flat abdominal radiography, intravenous urography, CT or similar. In addition, the treatment of ureteral lithiasis includes a use as an inhibitor of ureteral contraction to relieve pain caused by ureteral stones including colicky and dull pain as well as, facilitating the exclusion of ureteral stones, relieving hydronephrosis or reducing resistance during insertion of the ureteroscope and the like. Examples The present invention is further illustrated in detail by the following examples and reference example. Nevertheless, the present invention is not limited thereto. [Reference example 1] Quantification of mRNA expression in hamster ureter Bilateral ureters were isolated from the 8-week-old male Syrian hamster and the RNA was extracted using ISOGEN (Nippon Gene, Toyama). The heart and aorta were isolated from the 8-week-old male Syrian hamster and mRNAs were extracted for cDNA cloning of the three subtypes (ca, The primers were designed on the basis of sequence information for the a1 -AR hamster ( J04084), the rat a1a-AR (NM_017191) and the rat a1d-AR (NM_024483) using Primer Express Primer 2.0 (Applied Biosystems, Chiba) The prepared primers are shown as sequence No. 1 and 2 (a1a), No. 3 and (a?), And No. 5 and 6 (a1d). The cDNAs are synthesized from the total RNA (1 μg) in the heart and aorta, using the RT reagent mixture (Two-step RT-PCR RT Reaction Mix, Applied Biosystems). Since then, the cDNAs have been amplified with the PCR reagent mixture (AccuPrime (registered trademark Registered) Taq DNA Polymerase High Fidelity, Invitrogen). Partial ai-AR plasmids were prepared using pCRII-TOPO (registered trademark Registered) and used as a standard in quantitative RT-PCR in real time. The primers and Taq Man tests for the arRNA sequences of hamster were designed using the Primer Express Primer (Applied Biosystems). Prepared primers are shown as sequence No. 7 and 8 (a1a), No. 10 and 11 (a1), and No. 13 and 14 (a1d), and the tests are shown as sequence No. 9 (a? a), No. 12 (a-?) and No. 15 (a1d). The cDNAs were synthesized from the total RNA with the RT reagent mixture (Applied Bisosystems; Two-step RT-PCR RT Reaction Mix). The cDNAs were used as a template and were measured using the Taq Man Universal PCR Master mix (Applied Bisosystems). All samples were measured in duplicate. The result is shown in Table 1. The expression of a1d-AR mRNA (88.1%) was the most abundant of the three subtypes of c ^ -AR in the hamster ureter. [Table 1] Subtype mRNA expression level index (copies / ng total of RNA) Expression (%) Oía 30.8 ± 7.5 10.7 Chb 3.5 ± 1.3 1.2 Q? D 254.5 ± 113.0 88.1 [Reference Example 2] The inhibitory effects of several a, -AR antagonists were tested using the same method as the last mentioned Example 1. Tamsulosin hydrochloride (a1A 1D-AR antagonist), naftopidil (a1D-AR antagonist), BMY-7378 (a1D-AR antagonist) and chloroethylclonidine (B-AR antagonist) were used. As a result, surprisingly, although compound 1 is a selective a1A-AR antagonist, it exhibited the high pA2 value as shown in table 2.

[Table 2] α-TAR Blocker Selectivity of subtype pA- Compound 1 O? A 9.44 Oí A / 1 D hydrochloride 9.85 tamsulosin naftopidil OID 6.54 chloroethylclonidine dlB < 5 [Example 1] The hamsters were sacrificed by rapid exsanguination under anesthesia with ether and the right and left ureters were isolated. The right and left ureters were removed from connective tissue in Krebs solution, and were made in tubular preparations. The ureteral preparation was suspended in an organic bath containing the Krebs solution maintained at 37 ° C and continuously gasified with a mixed gas of 95% oxygen and 5% carbon dioxide. An initial resting tension of 0.1 g was placed. The voltage was measured isometrically with a force transducer and recorded with a polygraph. After the tension was placed, the preparation was treated with each concentration of compound 1. Approximately 30 minutes later, 0.5 mol / l of phenylephrine (1 x 10"7 and more) was cumulatively added in 0.5-increments of registration and the Response curves of the concentration were obtained.The contraction before the addition of 1 x 10'3 mol / l 1 x 10"7 of phenylephrine and after the addition of 1 x 103 mol / l of phenylephrine was expressed as 0% and 100%, respectively. As shown in Figure 1, compound 1 of the low concentrations caused by the concentration dependent on a parallel right shift of the concentration-response curve for phenylephrine in the isolated hamster ureter. That is, compound 1 inhibited the induced ureteral contraction of phenylephrine in concentration in a dependent manner, showing that compound 1 is useful for relieving pain and facilitates the exclusion of ureteral stones and the like. As mentioned above, it was shown that the indoline derivative represented by the above general formula (I) as represented by Compound 1 or the pharmaceutically acceptable salts thereof inhibit the ureteral contraction induced by phenylephrine in a concentration-dependent manner and are useful to relieve pain caused by ureteral stones, facilitating the exclusion of ureteral stones or similar. Industrial Applicability The pharmaceutical compositions of the present invention are extremely useful as an agent for the treatment of ureteral lithiasis and the like. Free Text of Sequence Listing <Sequence No.1 > Sequence No.1 represents the 5'-primer used in the cloning of the partial sequence corresponding to the a1a-hamster adreceptor. < Sequence No.2 > Sequence No. 2 represents the sequence of the 3'-primer used in the cloning of the partial sequence corresponding to the a1a-hamster adrenaline receptor. < Sequence No.3 > Sequence No.3 represents the sequence of the 5'-primer used in the cloning of the partial sequence corresponding to the α- β-adrenoceptor of hamster. < Sequence No.4 > Sequence No.4 represents the sequence of the 3'-primer used in the cloning of the partial sequence corresponding to the αβ-adrenoceptor of hamster. < Sequence No.5 > Sequence No.5 represents the sequence of the 5'-primer used in the cloning of the partial sequence corresponding to the a1d-adrenoceptor of hamster. < Sequence No.6 > Sequence No.6 represents the sequence of the 3'-primer used in the cloning of the partial sequence corresponding to the a1d-adrenoceptor of hamster. < Sequence No. 7 > Sequence No. 7 represents the sequence of the 5'-primer TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the mRNA of the quantitative hamster aia-adrenoreceptor. < Sequence No. 8 > Sequence No. 8 represents the sequence of the 3'-primer TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the quantitative hamster α-adrenoceptor mRNA. < Sequence No. 9 > Sequence No. 9 represents the TaqMan test sequence (a registered trademark) used in quantitative real-time RT-PCR to the quantitative hamster a1a-adrenoceptor mRNA. < Sequence No.10 > Sequence No.10 represents the sequence of the 5'-primer TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the quantitative hamster dib-adrenoceptor mRNA. < Sequence No.11 > Sequence No.11 represents the sequence of the 3'-primer TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the mRNA of the quantitative hamster a-ib-adrenoceptor. < Sequence No.12 > Sequence No.12 represents the TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the quantitative hamster a1b-adrenoceptor mRNA. < Sequence No.13 > Sequence No.13 represents the sequence of the 5'-primer TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the mRNA of the quantitative hamster a-d-adrenoceptor. < Sequence No.14 > Sequence No.14 represents the sequence of the 3'-primer TaqMan (a registered trademark) used in quantitative real-time RT-PCR to the a1d-adrenoceptor mRNA of quantitative hamster. < Sequence No.15 > Sequence No. 15 represents the TaqMan test sequence (a registered trademark) used in quantitative real-time RT-PCR to the quantitative hamster a1d-adrenoceptor mRNA.

Claims (8)

1. A pharmaceutical composition for the treatment of ureteral lithiasis, comprising as an active ingredient an indoline derivative represented by the general formula: [Chemistry 1] in the formula, R represents a saturated or unsaturated aliphatic acyl group which may have as a substituent one or more halogen atoms, a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group, or a aryl group; a hydroxyalkyl group; an aliphatic acyloxyalkyl group; a lower alkyl group having as a substituent a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a substituted lower aryl-alkoxycarbonyl group, a carbamoyl group, a lower mono (lower alkoyl) -carbamoyl substituted group or a cyano group; an aromatic acyl group which may have one or more halogen atoms as a substituent; a furoyl group or a pyridylcarbonyl group; R1 represents a cyano group or a carbamoyl group; and R2 represents a lower alkyl group which may have as one substituent one or more halogen atoms, a cyano group or an aryl group; or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition according to claim 1, wherein the indoline derivative is silodosin.

3. A pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is for relieving pain caused by ureteral stones, facilitating the exclusion of ureteral stones, relieving hydronephrosis or reducing resistance during ureteroscope insertion.

4. A pharmaceutical composition according to any of claims 1 to 3, which is an agent for the inhibition of ureteral contraction. .

5. A method for the treatment of ureteral lithiasis, comprising administering an effective amount of an indoline derivative represented by the general formula: [Chemistry 2] in the formula, R represents a saturated or unsaturated aliphatic acyl group which may have as a substituent one or more halogen atoms, a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group, or a aryl group; a hydroxyalkyl group; an aliphatic acyloxyalkyl group; a lower alkyl group having as a substituent a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a substituted lower aryl-alkoxycarbonyl group, a carbamoyl group, a substituted mono- or di (lower alkyl) -carbamoyl group or a cyano group; an aromatic acyl group which may have one or more halogen atoms as a substituent; a furoyl group or a pyridylcarbonyl group; R1 represents a cyano group or a carbamoyl group; and R2 represents a lower alkyl group which may have as one substituent one or more halogen atoms, a cyano group or an aryl group; or a pharmaceutically acceptable salt thereof.

6. A method according to claim 5, wherein the indoline derivative is silodosin.

7. A use of an indoline derivative represented by the general formula: [Q umica 3] in the formula, R represents a saturated or unsaturated aliphatic acyl group which may have one or more halogen atoms, a hydroxy group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group as a substituent. , or an aryl group; a hydroxyalkyl group; an aliphatic acyloxyalkyl group; a lower alkyl group having as a substituent a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a substituted lower arylalkoxycarbonyl group, a carbamoyl group, a mono- or di (lower alkyl) -carbamoyl substituted group or a cyano group; an aromatic acyl group which may have one or more halogen atoms as a substituent; a furoyl group or a pyridylcarbonyl group; R1 represents a cyano group or a carbamoyl group; and R2 represents a lower alkyl group which may have as one substituent one or more halogen atoms, a cyano group or an aryl group; or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition for the treatment of ureteral lithiasis.

8. A use according to claim 7, wherein the indoline derivative is silodosin.