TWI322148B - Benzo [g] guinoline derivatives - Google Patents

Description

1322148 A7 B7 V. INSTRUCTIONS (2) Tables S and 1^ are sulfhydryl groups. In another aspect, the present invention provides a process for the manufacture of a compound of the formula and an acid addition salt thereof, which is produced from a compound of formula II:

Wherein A, B, X, Y&R1 are as defined above, and the rule 3 is (c) 4) alkyl, the alkoxy group is converted to a hydroxyl group, and thus the compound of formula I obtained is free base or acid addition. The salt form was restored. This reaction can be achieved according to known methods, e.g., using hydrobromic acid or a tribromination shed. In formula II, r3 is preferably a fluorenyl group. The reaction mixture can be obtained according to the above method, and the compound can be obtained according to a known method. Acid addition salts can be made from free bases by known methods, and vice versa. Suitable acid addition salts for use in accordance with the present invention include, for example, hydrochloric acid. The starting compound of formula II wherein ruthenium and osmium are each η can be made from a compound according to formula 1113. -5- A7

COOMe

HI, wherein R3 is as defined above, for example, as described in Example 1.

The Ilia compound is a compound of the formula η which is known or can be known by a similar method (wherein the formation of an additive is formed by the compound of the formula Illb.)

Wherein R3 is as defined above and the IIIb compound is produced by a similar method known or known in the art. The compound of the formula I and its physiologically acceptable acid addition salt, as hereinafter referred to as the preparation of the present invention, which exhibit valuable pharmacological properties in animal tests, are therefore useful as medicaments. Specifically, when the concentration of the agent ', according to the present invention, is 丨〇 to i 〇〇 μΜ, the intraocular pressure of the rabbit is lowered. The ca_2.5 kg male rabbit was fixed in a cage, the head was free, the solution containing the test compound was dropped into the right eye, and the placebo solution was dropped into the left eye (2 drops each, ie ca. 40 μΐ) . First of all, it contains Novoseine (0.4%) and Fluorium (Fluorescein) __-6- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1322148 A7

V. Description of the Invention (The preparation of the present invention may be used in any convenient way, in a mad manner, in a mad manner, for example, in a parenteral form, such as in the form of an injectable solution or suspension; or in a gastrointestinal manner, Oral, for example in the form of a lozenge or capsule. "= side to 2% topical application to the eye is more, preferably about 5% of the eye solution, and more preferably about 0.01 to 0 1%. The agent maintains the compound in contact with the surface of the eye for a sufficient period of time to allow the compound to penetrate the cornea and the inner region of the eye. The pharmaceutically acceptable eye excipient may be, for example, oil f, vegetable oil, or in capsules. The present invention provides a preparation of the present invention for use as a medicament for the treatment of t-eye and myopia. The present invention provides for the use of the preparation of the invention for the production of glaucoma and myopia therapeutic agents. In a further aspect, In an individual in need of such treatment, the invention provides a method of treating glaucoma and myopia comprising administering to the individual a therapeutically effective amount of a formulation of the invention. The invention also relates to the disclosure of The progress of any of the compounds is in any independent and/or dependent on the scope of the patent application as disclosed below. The invention is illustrated by the following examples, the temperature being given in degrees Celsius and being uncorrected. Example 1 11 1(^11卜1-甲棊-30-{4-甲一-1pyrimidin-2-yl 1you^^ _6-radio-1,2,3,4,4&(1,5,10 , 1〇36-八氤芏 and "£11>sets<> Lin-8- 1322148 A7 B7 V. Inventive Note (6) a) [3R, 4aR, 10aRl-l-mercapto-3β-face group Methyl-methyl-l, 2.3, 4.4 aa, 5, 10'10aB- octopus rg]» contends in the ping of 5.78 g (2〇111\1) [311,4311,1〇] Small methyl-3-3|3-methoxycarbonyl-6-methoxy-1,2,3,4,4,6,5,1〇,1〇4_octahydrobenzo[g]quinoline 100 ml of toluene solution, add 12 ml of SDBA solution in a drop of argon at room temperature (70% in 42 ° C, 42 mM) and then drop 1 by drip 〇ml of Na〇H (30%) was added to the ice-cooled reaction mixture, and the crystal of the sink was transferred out, washed with water and benzene, and dried to obtain the title compound mp. 148.; [α]20〇=-120. (c=0.425, in ethanol) b) L3R, 4aR, 1 OaRl-1 -methyl-3 β-methyl ketone oxygen methyl·6· A gas, 1, 2, 3, 4.4 & 〇 6, 5.10.10& 8 - eight certificates, 'burial 『 call, arguing, 12 ml (153 mM) of methylthio chloride at room temperature The method was added to a solution containing 20 g of the compound obtained in a) (76.5 mM) in 150 ml of a pyridine solution, and the temperature was maintained below 451 with ice cooling, and after stirring at room temperature for 2 hours, it was saturated at 〇t. KHC03 solution The pH of the solution was adjusted to pH 7-8, extracted with ethyl acetate, dried over an excess of NazSO4, filtered, and concentrated by evaporation. The title compound was crystallized and used directly in the next step. . c) U^.4aR, 10aR 卜 1-methyl-3β-{4-methyl^1^ pyrimidine yi-yl-:6·methoxy group 6 g of the compound obtained in b) (1 7.7 mM) A solution of 3.4 g (27 mM) of 2-mercapto-4-mercapto-1,3-pyrimidine in 60 ml of dimethyl decylamine was mixed with 6 ml of 2N NaOH at 65. 〇Stirring for 18 hours-9 - This paper scale applies to the SS standard (CNS) A4 size (21GX 297 mm) ' . 1322148 A7 B7 V. Description of the invention ('The obtained suspension is concentrated by evaporation' crude product Crystallization, the suspension was cooled to 5-1 ° C, washed with ethyl acetate and dried. Chromatographic analysis was carried out in a silicone containing 10% ethanol and 0.01% NH32 ethyl acetate. d) d4aILl^RM-mercapto-3β]4-methyl-1,3-pyrimidin-2-yl}indole 1-6- by|:^2,3.4.43\<;1丨0.1〇 3 8-octahydrogen stupid and "£1, 40 ml of boron tribromide (in 2 m methane, concentration 1 M), slowly added to the solution containing 4.06 at -40 ° C The suspension was stirred at room temperature for 2 hours, and neutralized with NH3, and 150 ml of dioxane with 100 mg of the obtained product (11 mM) in 250 ml of di-methane. The mixture of isopropyl alcohol is extracted, dried over excess NazSO4, filtered and concentrated by evaporation. The title compound is crystallized. "When evaporating, it corresponds to the crystallization of hydrogen chloride from 1:1. / ethanol obtained. Μ_ρ·254.; [oc]20D=-90. (c = 0.540, ethanol/water in 1:1). C20H25N3OS (HC1), MW=39 1.97. -10- This paper scale applies to China National Standard (CNS) A4 Specification (210X 297 mm)

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Claims (1)

P-7(4)|Quantity 1322148 A8 Patent application No. 091114805 B8 OQ Chinese patent application scope replacement (September 95) D8, patent application scope Wherein A and B each are deuterium or together form an additional bond, X is CH2, Y is S, and Ri is 11 or (Cw) alkyl, which is in the form of a free base or an acid addition salt. 2. A compound according to claim 1 wherein A and B each represent hydrazine, X is CH2, Y represents S, and the heart represents (Cm) alkyl. 3. The compound of claim 2, wherein & represents sulfhydryl. 4. A compound of claim 1 in the form of a free test or a pharmaceutically acceptable acid addition salt for use in the treatment of glaucoma and myopia. 78934-950922.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Ι322Ι4» A8 B8 C8 D8 Patent application garden 5—type as defined in the first paragraph of the patent application scope Process for the preparation of a compound or a salt thereof, which comprises the conversion step of converting an alkoxy group in a compound of formula II to a hydroxyl group: Among them, A, Β, X, 丫 and! ^ As defined in the first paragraph of the patent application, R.3 is (Ci-4) alkyl, and the resulting compound of formula I in the form of a free test or acid addition salt is recovered. 6. A pharmaceutical composition for treating glaucoma and myopia comprising a compound as claimed in claim 1 in the form of a free base or a pharmaceutically acceptable acid addition salt, and a pharmaceutical carrier or Thinner. 7. Use of a compound according to claim 1 in the form of a free base or a pharmaceutically acceptable acid addition salt for the manufacture of a medicament for the treatment of glaucoma and myopia. 78934-950922.DOC This paper size applies to China National Standard (CNS) A4 specification (210 X mm).