NZ233151A - Pyrrolidine derivatives as intermediates in the preparation of 7-((3-(aminomethyl)-3-alkyl)-1-pyrrolidinyl)-quinoline carboxylic acids - Google Patents

Pyrrolidine derivatives as intermediates in the preparation of 7-((3-(aminomethyl)-3-alkyl)-1-pyrrolidinyl)-quinoline carboxylic acids

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NZ233151A
NZ233151A NZ233151A NZ23315187A NZ233151A NZ 233151 A NZ233151 A NZ 233151A NZ 233151 A NZ233151 A NZ 233151A NZ 23315187 A NZ23315187 A NZ 23315187A NZ 233151 A NZ233151 A NZ 233151A
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acid
compound
methyl
formula
alkyl
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NZ233151A
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John Michael Domagala
Susan Elizabeth Hagan
Joseph Peter Sanchez
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Warner Lambert Co
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Priority claimed from US07/039,438 external-priority patent/US4771055A/en
Application filed by Warner Lambert Co filed Critical Warner Lambert Co
Publication of NZ233151A publication Critical patent/NZ233151A/en

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New Zealand Paient Spedficaiion for Paient Number £33151 % 2331 Under the provisions of Regulation 23 (1) the — Specification has been ante-dated to 9...^juyl... 19 &l~ /$ tAjxJiua* Initials Patents Form No. 5 NO DRAWINGS Priority Date(s): : ^}9. J.
Complete Specification Filed: 7* n. • % n•••••*•« Publication Date: '*'5 M'wi P.O. Journal. No NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PYRROLIDINE INTERMEDIATES IN THE PREPARATION OF 7-[ [3-(AMINOMETHYL) -3-ALKYL]-l-PYRROLIDINYL] -QUINOLINE- CARBOXYLIC ACIDS This is a divisional out of application 221021 dated 9 July 1987 We WARNER-LAMBERT COMPANY of 201 Tabor Road, Morris Plains, New Jersey 07950 United States of America, incorporated under the laws of Delaware, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement 1 -. JCif. #) _ APC032787 -2- 23 3 1 5 1 This invention relates to a pyrrolidine derivative which is an intermediate in the preparation of 7-[ [3-(aminomethyl)-3-alkyl) -1-pyrrolidinyl ] -quinoline-carboxylic acids.
It has been four.c that corresponding 7-[ [3-5 (aminomethyi )-3-alkyl]-1-pyrrolidinyl guinoline and naphthyridine derivatives have the same potent antibacterial activity against both gram-positive and gram-negative bacteria as compounds without the 3-alkyl group but, in addition, surprisingly 10 have better oral activity against both gram-positive and -negative bacteria.
This invention provides a compound of the formula HN CH-NRR 2 3 4 (III} wherein is hydrogen, alkyl of from one to three carbon atoms or cycloalkyl of from three to six carbon atoms; is hydrogen or alkyl of from one to three carbon atoms; and Rg 15 is alkyl of from one to three carbon atoms or cycloalkyl of from three to six carbon atoms.
Compounds of the formula (III) are intermediates in the preparation of a compound of the formula r4r^nch7^ ^ (i) I l2 wherein X is CH, CF, CC1, CNR3R4, or N; Y is H, 0R4, or -NR3R4; Ri is hydrogen or alkyl having from one to six carbon atoms; R2 is cyclopropyl or aryl; R3 is hydrogen, alkyl having from one to three carbon atoms or cycloalkyl having from three to six carbon atoms; R4 is hydrogen or alkyl having from one to three carbon atoms; and Rs is alkyl having from one to three carbon atoms or cycloalkyl having from three to six carbon atoms, or a pharmaceutically acceptable acid addition or base salt thereof.
-V.- APC032787 «D -3- 2331 5 1 In this specification, the term "aryl" includes a phenyl group unsubstituted or substituted by halogen, alkyl, 5 alkoxy, hydroxy, amino, mo no alkylamino, dialkylamino, or #trifluoromethyl- Preferred substituents are in the para-position and are fluoro, amino, monoalkyl, or dialJcylamino - Most preferred is the para-fluoro substituent.
The terms "alkyl groups" include both straight and branched carbon chains of from one to about six carbon atoms unless otherwise stated. Representative of such groups are methyl, ethyl, propyl, isopropyl, and the like.
The cycloalkyl groups comprise those having three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The alkoxy groups —: comprise both straight and branched carbon chains of 20 from one to about six carbon atoms unless otherwise specified. Representative of such groups are methoxv, ethoxy, propoxy, i-propoxy, t-butoxy, hexoxv, and the like.
The terms monoalkyl amino and dialkylamino — include amino substituted by one or two alkyl groups as defined above where each group is the same or different. Representative of such groups are me thy 1 amino, ethylamino, dimethyl amino, diethylamino, methylethylamino, and the like.
The term halogen includes fluorine, chlorine, bromine, and iodine unless otherwise specified.
The compounds of formula (I) exist in optically active forms. The pure R isomer, pure S isomer as well 35 as mixtures thereof; including the racemic mixtures, are contemplated by the invention. Additional assymmetric carbon atoms may be present in a substituent such as an alkyl group.
© APC032787 CO "4" 23 31 - The compounds of formula (I) are capable of forming both pharmaceutical^ acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or 5 organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. 10 Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.
Examples £>f suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, gluconic, fumaric, 15 succinic, ascorbic, maleic, lactic, methanesulfonic, and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc, salt in the conventional manner. The free base forms may be regenerated 20 by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized.
Dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate solutions are suitable for this purpose. The free base forms differ from their 25 respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Use of excess base where R' is hydrogen gives the corresponding basic 30 salt.
The compounds of formula (I) can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms and the like are equivalent to the 35 unsolvated forms for purposes of the invention.
Preferred compounds of formula (I) are those wherein X is CH, CF, CC1, CNR3R4, or N; Y is E, OR4, or -NR3R4 ; Ri is hydrogen; R2 mutSbm €► APC032787 233151 cyclopropyl, phenyl or phenyl substituted by halogen, alkyl, alkoxy, hydroxy, amino, mo no alkyl amine, dialkylamino, or trifluoromethyl; R3 and R4 are each independently hydrogen or alkyl of one to three carbon 5 atoms; and Rs is alkyl of one to three carbon atoms, or pharmaceutically acceptable acid addition or base salts thereof.
Other preferred compounds of formula (I) are those wherein Rj is cyclopropyl, phenyl or phenyl substituted in 10 the para-position by fluoro, amino, monoalkyl- or dialkylamino - Still other preferred compounds of formula (I) are those wherein R2 is cyclopropyl, phenyl, or para-fluorophenyl.
Further preferred compounds of formula (I) are those wherein X is CH, CF, CCl, CNH2, or N; Y is hydrogen or amino; Rx is hydrogen; R2 is cyclopropyl; r3 and R« are each independently hydrogen, methyl or ethyl, and Rs is methyl, or pharma-20 ceutically acceptable acid addition or base salts thereof.
Particularly valuable as orally active antibacterial agents are the following: "7- [ [3- (aminome thy 1)-3-methyl] -1-pyrrolidinyl] -1-cyclo-25 propyl-6,8-di fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid; -amino-7- [ [3- (aminome thy 1) -3-methyl ]-1-pyrrolidinyl]-1-cyclopropyl-6,8-di f luoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid; 30 7-[[3-(aminomethyl)-3-methyl]-1-pyrrolidinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic acid; 7- [ [3-(aminomethyl)-3-methyl]-1-pyrrolidinyl]-8-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-3-quinoline-35 carboxylic acid; 8 - amino -7- [ [ 3 - (aminomethyl) -3 -methyl ] -1 -pyr r 01 i diny 1 ] -l-cyclopropvl-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylic acid; APC032787 23 3151 l-cyclopropyl-6,8-di f luoro-1,4-dihydro-7- [3-methyl-3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quino-linecarboxylic acid; l-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-methyl-3-5 [(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-l,8-naphthyridine-3-carboxylic acid; 8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-7-[3-methyl-3-[ (methyl amino)methyl]-1-pyrrolidinyl]-4-oxo-3-quino-linecarboxylic acid; 10 8-amino-l-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-methyl-3 - [ (methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quino-linecarboxylic * acid; "7— £ [3 — (aminomethyl)-3-methyl ]-1-pyrrolidinyl]-1-cyclo-propyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic 15 acid; l-cyclopropyl-7- [3- [ (dimethyl amino )methyl ] -3-methyl-l-pyrrolidinyl ] -6,8-dif luoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid; 1 - cyci opr opy 1 - 7 - [ 3 - [ (dimethyl amino) methyl ] -3 -methyl -1 -20 pyrrolidinyl ] -6-fluoro-l, 4-dihydro-4-oxo-l, 8-naphthyri-dine-3-carboxylic acid; 8-chloro-l-cyclopropyl-7- [3- [ (dimethyl amino )methyl]-3-methyl-l-pyrrolidinyl]-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid; 25 8-amino-l-cyclopropyl-7-[3-[(dimethylamino)methyl]-3-methyl-l-pyrrolidinyl ] -6-fluoro-l, 4-dihydro-4-oxo-3-guinolinecarboxylic acid; l-cyclopropyl-7- [3- [ (dimethyl amino) methyl] -3 -methyl-1-pyrrolidinyl ] -6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-30 carboxylic acid; and l-cyclopropyl-6-fluoro-l,4-dihydro-7-[3-methyl-[(methyl-amino )methyl] -1-pyrrolidinyl] -4-oxo-3-quinolinecarboxylic acid.
The compounds of —-— Formula I may be prepared by reacting a compound of the formula APC032787 23 315 1 y o wherein X, Y, Rj, and R2 are as defined above and L is a leaving group which is preferably fluorine or chlorine with a compound of the formula m\J "CW4 (iii) in which ?3 , R4 and Rs are as defined above.
For purposes of this reaction, the aminomethyl or alkyl- aminomethyl substituent of the compound of formula III may, if desired, be protected by a group which renders it substantially inert to the reaction conditions. Thus, for example, protecting groups such as the following may 10 be utilized: carboxylic acyl groups such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, p,p,0-trichloro-ethoxycarbonyl, p-iodoethoxycarbonyl; aryloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxy-15 carbonyl, phenoxycarbonyl; silyl groups such as trimethylsilyl; and groups such as trityl, tetrahydro-pyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, D-toluenesulfonyl, and benzyl, may all be utilized. The protecting group may be removed, 20 after the reaction between Compound III and Compound II APC032787 233151 if desired, by procedures known to those skilled in the art. For example, the ethoxycarbonyl group may be removed by acid or base hydrolysis and the trityl group may be removed by hydrogenolysis.
The reaction between the compound of structural Formula II and a compound of Formula III or a suitably protected compound of Formula III, may be performed with or without a solvent, preferably at elevated temperature for a sufficient time so that the reaction is substan-10 tially complete. The reaction is preferably carried out in the presence of an acid acceptor such as an alkali metal or alkaline earth metal carbonate or Bicarbonate, a tertiary amine such as tri ethyl amine, pyridine, or picoline. Alternatively an excess of the compound of 15 Formula III may be utilized as the acid acceptor.
Convenient solvents for this reaction are nonreac-tive solvents such as acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethyl-formamide, dimethylacetamide, pyridine, picoline, water, 20 and the like. Solvent mixtures may also be utilized.
Convenient reaction temperatures are in the range of from about 20° to about 150°C; higher temperatures usually require shorter reaction times.
The starting compounds having structural Formula II 25 are known in the art or, if new, may be prepared from known starting materials by standard procedures or by variations thereof.
The compounds of Formula II wherein Y is -NR3R4 and 30 R3 and/or R4 are not hydrogen may be prepared from the known 5-amino guinolines or naphthyridines by an alkylation sequence shown below wherein L is a leaving group as previously defined.
APC032787 G 33151 NaH{or other base) <© Ila The 5-amino group is preferably acylated by triflucr-oacetic acid anhydride although other acyl moieties may be employed. The alkylation of R3 proceeds with the presence of sodium hydride or other nonnucleo-philic bases. Removal of the acyl activating group is accomplished with acid or base hydrolysis such as 2N hydrochloric acid in acetic acid. A second alkylation, if desired, with R4L, again in the presence of base such as, for example, potassium carbonate provides compounds of Formula II where both R3 and R4 are not hydrogen.
Alternatively, the 5-alkylamino compounds of Formula II may be prepared from the nitro or amino acids IV through reductive amination procedures as illustrated in the following scheme. Using appropriate APC032787 23 3151 <Q o nh2 F\^L/C°2H a*I L "X or N°2 ' co2h l ^ "x" iv ■ RCHO h2 or h~ rcho H2 catalyst F^L/c°2h -* ii control of the aldehyde equivalents mono and disubstituted amines may be obtained. The substituted amino acids may be converted to the desired compounds of Formula II by known methods.
The compounds of Formula II wherein Y is 0R4 may be prepared from the polysubstituted acids or esters by displacement of an ortho leaving group with 0R4 as shown: FvNj^Wj^C02Rl 0R3 -'X1* 0rt or3 C02R1 + ^CO-H h 2 ' ,.AA, lib -• '— »»—, APC022787 23 3151 The desired quinolines or naphthyridines of Formula II may then be prepared according to classical methods - The compounds of Formula III may be prepared according to the following general method. yR- CH~=C' 3 AgF r_N VCN + NC-CH2N-CH2Si(Me)3 + CH-Ph „+ 8«« » 2 R, 0 R3 5 j IpC-N l. Acid Activation J C02H Cn) \ 2. HNR3R4 Ph LiAlH4 L Ph ^oh f e / \^ch2nh2 / yCH,N |LiAlH4 H2 cat^ Ph I r5 r5 ch,nr,ra h2 /—(-ch2nr3r4 y ^CH2NR3R4 2 / o ~ o i III Pyrrolidine formation to D may be carried out by the known methods, [J. Org. Chem., 50 4006 (1985)].
When R3 and R4 are H, direct reduction of D with a 10 strong reducing agent, for example, lithium aluminum hydride, and catalytic hydrogenation affords III (R3R4=H). When R3 and R4 are not both hydrogen, then hydrolysis of nitrile D to the acid E is accomplished with strong acid as, for example, 6N HCl. 15 Using any of the methods available to one skilled in the art, the acid function of E may be activated via acid chloride formation, mixed anhydride formation, apc032737 233151 ester formation, or with dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole as examples. The activated acid is then coupled with an amine HNR3R4 to form the amide F. Reduction and removal of the benzyl protective 5 group affords compounds of Formula III where R3 and R4 are not both hydrogen.
The compounds of formula I display potent antibacterial activity against both gram-positive and -negative bacteria when tested by the microtitration 10 dilution method as described in Heifetz, et al, Antimicr. Agents & Chemoth., 6, 124 (1974), which is incorporated hferein by reference.
The advantage of the compounds of formula I has been observed when tested orally and compared to a standard quinolone where the 7-position contains a corresponding 3-aminomethylpyrro1idiny1 group without the additional 3-alkyl or cycloalkyl substituent. For example, the compound of Example 1 when compared to 7-[3-(aminomethyl)-1-pyrrolidinyl]-l-20 cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-guinoline-carboxylic acid, Compound A in the table below, has comparable in vitro activity but greater oral activity in mice when the measurement of ?DSo/ mouse protection data, was carried out according to the procedure 25 described below.
Therapeutic activities of the compounds were compared to acute mouse protection tests in which 18- to 22-g female Charles River CD-I mice were used. Oral or subcutaneous doses in twofold rising incremental series 30 were administered concurrently with bacterial challenge. Challenges were accomplished by the intraperitoneal injection of an estimated 100 medial lethal doses in 0.5 ml volumes of 5% hog gastric mucin or tryptic soy broth. Generally, >90% of the untreated controls died 35 within 48 to 72 hours. Final survival percentages, obtained after four to seven days of observation among groups of 8 to 16 mice, were pooled and used to estimate median protective doses (PDS0) by the log-probit method. Ideally a PO/SC ratio for a therapeutically relevant o .1 III apc032787 233151 antibacterial should be £5. Table 2 indicates the improvement in PO/SC ratio.
O 'MBWriB, r.w iw nar APC032787 O O 14 I TABLE 1 IN VITRO ANTIBACTERIAL ACTIVITY Minimal Inhibitory Concentration MIC (i.g/ml) o Organisms Compound Compound Compound Compound Compound Ex. 1 Ex. 2 Ex. 3 » Ex. 4 Ex. A Enterobacter cloacae MA 2646 .025 .1 i .1 .05 .8 Escherichia coli Vogel .05 .1 .4 .025 .2 Klebsiella pneumoniae MGH-2 .1 .1 .2 .05 .4 Proteus rettgeri M 1771 .2 .4 .8 .1 .8 Pseudomonas aeruginosa UI-18 .4 .8 .8 .2 .8 Staphylococcus aureus H 228 .013 .013 .05 .013 .1 Staphylococcus aureus UC-76 <.003 <.003 .013 < .003 .013 Streptococcus faecalis MGH-2 .013 .025 .05 .013 . 1 Streptococcus pneumoniae SV-1 .006 <.003 .025 < .003 .012 Streptococcus pyogenes C-203 .025 .013 .05 .013 .012 ro CM CM an APC032787 23 3151 TABLE 2 MOUSE CHEMOTHERAPY RESULTS Protective Dose 50% PD*n (ir.q/kq) Orcanism Compound E.
PO coli SC P. aerug. PO SC S. PO aureus SC S.
PO pyog. SC PO/SC Ratio A 13 1 >100 3 1 4 0.4 *10 Example 1 2 1 38 18 2 9 3 S3 The compounds of formula I . may be prepared and administered in a wide variety of oral, parenteral, 15 topical, and ophthalmic dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of 20 Formula I. Because of the superior oral activity of the compounds of formula 11 oral dosage forms are obviously preferred for administration.
For preparing pharmaceutical compositions from the compounds of formula I, . inert, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersable granules, capsules, cachets, suppositories, and ointments. A solid carrier can be one or more substances which may also act as diluents, 30 flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided solid which is in admixture with 35 the finely divided active compound. In the table the apc032787 2331 5 1 active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 5 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a lower melting wax, cocoa butter, and the 10 like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with 15 it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions suspensions and emulsions. As an example may be mentioned 20 water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous 25 solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active 30 component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Preferably, the pharmaceutical preparation is in 35 unit dosage form. In such form, the preparation is subdidivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the .package x APC032787 23315 1 containing discrete quantities of preparation, for example, packeted tablets, capsules, powders in vials or ampoules, and ointments in tubes or jars. The unit dosage form can also be a capsule, cachet, tablet, gel 5 or cream itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the 10 potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections "the* compounds of formula I are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. 15 A daily dose range of about 6 mg to about 14 mg per kilogram is preferred. The dosages-, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper 20 dosage for a particular situation is witbin the skill or the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circum-25 stances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The following nonlimiting examples illustrate the inventors' preferred methods for preparing the compounds 30 of formula I. example 1 7- f f 3-(Aminomethyl )-3-methyll-1-pyrrolidinyl 1 -l-cvclo-propyl-6,8-difluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylic acid A suspension of 1.0 g (3.53 mmol) of 1-cyclopropyl- 6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic t apc032 787 233151 acid, 40 ml of acetonitrile, 1.0 g (9.9 mmol) of triethylamine, and 0.70 g (6.15 mmol) of 3-methyl-3-pvrrolidineme than amine was refluxed for five hours, then stirred at room temperature overnight. The precipitate 5 was removed by filtration and washed with ether to give 1.25 g of the title compound, mp 245-247°C.
EXAMPLE 2 -Amino-7-\ r3-(aminomethyl)-3-methyll-l-pyrrolidinyl1-l-cyclopropyl-6,8-difluoro-l, 4-dihydro-4-oxo-3-qxiinoline-10 carboxylic " aci'd A suspension of 0.60 g (2.01 mmol) of 5-amino-l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-guinolinecarboxylic acid, 50 ml of acetonitrile, 0.60 g (6.0 mmol) of triethyl amine, and 0.30 g (2.63 mmol) of 15 3-methyl-3-pyrrolidinemethanamine was refluxed for six hours, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with ether to give 0.40 g of the title compound, mp 201-204°C.
EXAMPLE 3 7- T f 3- (Aminomethyl)-3-methyl ] -1-pyrrolidinyl 1 -1-cyclo-propyl-6-fluoro-l, 4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic acid To 1.0 g (3.5 mmol) of 7-chloro-l-cyclopropyl-6-f luoro-1,4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic 25 acid was added 12 ml of acetonitrile. One gram (9.9 mmol) of triethylamine and 0.7 g (6.1 mmol) of 3-methyl-3-pyrrolidinemethanamine. The mixture was refluxed for three hours, cooled, and filtered to give 1.18 g of the title compound, mp 257-259°C.
£?CG32787 -19-SXAMPLE 4 233151 7- T3 -(Antinomethvl)-3-methyl-1-pvrrolidinvl 1 -8-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3-quinoline-carboxylic acid O 5 To 1.05 g (3.50 mmol) of 8-chloro-l-cyclopropyl- 6,7-difluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic aciu was added IS ml of acetonitrile, 1.0 g (9.9 mmol) of triethyl amine and 0.7 g (6 mmol) of the 3-methyl-3-pyrrolidinemethanamine. The mixture was refluxed fj) 10 18 hours and cooled. Filtration gave 1.31 g of the title compound", mp 189-191°C.
In a similar manner, the following were prepared: 7- [ [3-(aminomethyl)-3-methyl]-1-pyrrolidinyl]-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic 15 acid, mp 250-252°C.; l-cyclopropyl-7-[3-[ (dimethyl-amino Jmethyl ] -3-methyl-1-pyrrolidinyl) -6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, and l-cyclopropyl-7- [3- [ (dimethylamino) methyl ] -3-me thy 1-1-pyrrolidiny ] -6-fluoro-l, 4-dihydro-4-oxo-l, 8-20 naphthyridine-3-carboxylic acid.
In a similar manner 7-[[3-(aminomethyl)-3-methyl]-1-pyrrolidinyl]-l-cyclopropyl-6,8-dif luoro-1,4-dihydro-5-methylamino-4-oxo-3-quinolinecarboxylic acid, 7-[[3-O (aminomethyl)-3-methyl ] -1-pyrrolidinyl ]-1-cyclopropyl- 6,8-difluoro-l, 4-dihydro-5-dimethylamino-4-oxo-3- quinolinecarboxylic acid and 7-[[3-(aminomethyl)-3-methyl]-1-pyrrolidinyl ]-l-cyclopropyl-6,8-dif luoro-1,4-dihydro-5-methoxy-4-oxo-3-guinolinecarboxylic acid, G are prepared from the 3-methyl-3-pyrrolidinemethanamine and the appropriate quinoline starting material.
PREPARATION OF STARTING MATERIALS EXAMPLE A 3-Methvl-l- (phenvlmethyl )-3-pyrrolidinecarbonitrile A suspension of 11.6 g (0.05 mole) of N-benzyl-N-35 (cyanomethyl)-N-[(trimethylsilyl)methyl]amine TJ. Org. ppc032787 233151 Chem., £g, 4006 (1985)], 3.5 g (0.052 mole) of methacrylonitrile, 7.0 g (0.055 mole) of silver fluoride, and 150 ml of acetonitrile was stirred overnight at room temperature in the dark. The mixture 5 was then diluted with chloroform (150 ml) and filtered through Celite. Concentration of the filtrate gave an oil which was subjected to silica gel chromatography using an 80:20 chloroform:ethyl acetate mixture as the eluent. The major fraction contained 2.5 g of the 10 titled compound EXAMPLE B 3 -Methyl -1- (phenylmethyl) -3 -pyrrol idinemethanamine To a solution of 2.0 g (10 mmol) of 3-methyl-l-(phenylmethyl)-3-pyrrolidinecarbontirile in 40 ml 15 tetrahydrofuran was added 0.38 g (10 mmol) of lithium aluminum hydride in portions under nitrogen. The reaction mixture was stirred at room temperature for 18 hours. To the resulting suspension were added 0.3 ml of water, 0.4 ml of 40% sodium hydroxide, and 1.4 ml of 20 water. The grainy precipitate was filtered and washed with tetrahydrofuran. The combined filtrates were concentrated to yield 1.9 g of the titled compound.
This material was used without further purification in the next step, see Example C.
PREPARATION OF COMPOUNDS OF FORMULA III 25 EXAMPLE C 3-Methyl-3-pyrrolidinemethanamine A suspension of 1.87 g (9 mmol) of 3-methyl-l-(phenylmethyl) -3-pyrro 1 idinemethanamine, 1.0 g of 20% palladium on carbon, and 100 ml of methanol was shaken 30 in an atmosphere of hydrogen at about 50 psi and at room temperature for 18 hours. The catalyst was filtered and the filtrate concentrated under reduced pressure to give 1.0 g of the titled compound.
APC032787 I3 3i~5 EXAMPLE D N, N, 3-Trimethy1-3-pyrrolidinemethanamine To 2.0 g (10 mmol) of 3-methyl-l-(phenylmethyl)-3-pyrrolidinecarbonitrile was added 25 ml of 6N HCl and 5 the mixture refluxed for 36 hours. It was concentrated to dryness and the residue was dissolved in water and the pH adjusted to 9.0. The water was extracted three times with dichloromethane. The water layer was then taken to pH 5.5 and the product was extracted into 10 dichloromethane which was dried (MgS04) and concentrated. The compound was treated with an excess of oxalyl chloride in 25 ml of tetrahydrofuran with 1.0 ml of dimethylformamide added. When gas evolution was complete excess dimethylami ne was added to form the 15 N,N-3-trimethyl-l-(phenylmethyl)-3-pyrrolidinecarboxamide which was isolated as a viscous oil from concentration and water workup. The crude product was then reduced using lithium aluminum hydride and deprotected with hydrogenation as described in Examples B and C to give 20 the title compound which was purified by distillation. In a similar fashion N,3-dimethyl-3-pyrrolidine-methanamine was also prepared.
PREPARATIONS OF COMPOUNDS OF FORMULA II EXAMPLE E l-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-(methyl-25 ami no)-4-oxo-3-quinolinecarboxylic acid A solution of 5.9 g (20 mmol) of 5-amino-l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 20 ml of trifluoroacetic anhydride, and 100 ml of trifluoro acetic acid was 30 stirred at room temperature overnight. The solution was evaporated to dryness and the residue was triturated with water and filtered to give 7.55 g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-5-[(trifluoroacetyl)amino]-3-quinolinecarboxylic acid, 35 mp 188°. 233151 A solution of 5.53 (14.0 mmol) of the trifluoro-acetyl intermediate above, 55 ml of DMF and 1.42 g (30.9 mmol) of 50% sodium hydride was stirred at 50-55° for 35 minutes. To this mixture was added 2.8 ml (45 mmol) of iodomethane with continued stirring at 50-55° for two hours and for three hours at room temperature. The reaction mixture was evaporated and the residue was triturated with water and filtered. The solid was dissolved with 60 ml of acetic acid and 30 ml of 6N HCl was added and the solution was heated under reflux for two hours. The solution was concentrated and the residual oil was treated with isopropanol to give 3.0 g of the title compound, mp 205-7°. example f 1-Cyclopropyl-6,7,8-trifluoro-l,4-dihvdro-5-dimethylami nn-4-oxo-3-guinolinecarboxylic acid 2-(Dimethyl amino)-3,4,5,6-tetrafluorobenzoic acid A solution of 10.0 g (41.8 mmol) of 2-nitro- 3,4,5,6-tetrafluorobenzoic acid, 10 ml of 37% formaldehyde solution, 1.5 g of Raney nickel and 100 ml of ethanol was hydrogenated until TLC indicated absence of starting material. The reaction mixture was filtered and evaporated to an oil which was recrystallized with ethylacetate-hexane to give 2.15 g of the title compound, mp 110-112°. An additional 2.28 g, mp 90-100° was isolated from the filtrate. 2-(Dimethylamino)-3,4,5,6-tetrafluorobenzovl chloride To a suspension of 4.22 g (17.8 mmol) of 2-(dimethylamino)-3,4,5,6-tetrafluoro-benzoic acid and 85 ml of dichloromethane, added 1.7 ml (19.5 mmol) of oxalyl chloride. After the bubbling subsided, five drops of DMF was added and the solution was stirred at room temperature for 21 hours. The solution was evaporated to 4.8 g of an oil which was used in the next step without purification.
APC032787 3151 2-(Dimethyl amino)-3,4,5,6-tetrafluoro-g-oxo-benzene-propanoic acid, ethyl ester To a solution of 4.76 g (36 mmol) of malonic acid monoethyl ester and 75 ml of TEF at -35° was added 25 ml 5 (40 mmol) of 1.5N n-butyl lithium solution. The remaining 25 ml (40 mmol) of 1.5N butyllithium solution was added at 0°. After cooling to -78°, a solution of the 4.8 g of 2-(dimethylamino)-3,4,5,6-tetrafluoro-benzoyl chloride in 50 ml of THF was added to the 10 dilithio malonate over a 15 minute period. The reaction mixture was stirred for 1.75 hours while the temperature came up to -30°. The reaction mixture was poured into ice, water, and 50 ml of IN HCl. The mixture was extracted with ether and the ether extract was washed 15 with H20, 5% NaHC03, and HCl. After drying over MgS04 the ether solution was concentrated to 4.4 g of oily product. NMR spectra indicated the desired product. 2-(Dimethylamino)-a-(ethoxymethylene)-3,4,5,6-tetra-fluoro-6-oxo-benzenepropanoic acid, ethyl ester 20 A solution of 4.4 g (14.3 mmol) of the crude ketoester, 3.57 ml (21.5 mmol) of triethylorthoformate, and 25 ml of acetic anhydride was heated under reflux for two hours. The solution was evaporated to 5.2 g of oil which was used in the next step without 25 purification. a - T (Cyclopropylamino )methylene 1 -2- (dimethyl ami no) -3,4,5,6-tetrafluoro-6-oxo-benzenepropanoic acid, ethyl ester To a solution of 5.2 g (14.3 mmol) of the above 30 crude product in 50 ml of t-butanol was added 1.2 ml (17 mmol) of cyclopropylamine. The reaction solution was stirred for 18 hours at room temperature. The reaction mixture was filtered to give 0.12 g of the title compound, mp 122-4°. TLC of the filtrate showed 35 it to be the same as the solid.
APC032787 SV31 5^ - (Dimethylamino) -l-cyclopropyl-6,7,8-trifluoro-1.4— dihydro-4-oxo-3-quinolinecarboxylic acid To the above filtrate was added 1.7 g (15 mmol) of potassium t-butoxide and the mixture was stirred at room 5 temperature for 1.5 hours. TLC showed no change in reactants. An additional 1.7 g (15 mmol) of potassium t-butoxide was added and the reaction mixture was heated at 50-55° for two hours. After TLC indicated the reaction was complete, the solution was evaporated to 10 4 g of an oil. This oil was heated with 100 1 6N HCl for three hours on the steam bath. The solution was evaporated and" the residue was recrystallized from isopropanol to give 0.3 g of the title compound, mp 160-3°. An additional 1.0 g of solid was added from 15 the filtrate.
EXAMPLE G l-Cyclopropyl-6,7,8-trif luoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid To 22.4 g (100 mmol) of the 2-methoxy-3,4,5,6-20 tetrafluorobenzoic acid prepared as in [J. Fluorine Chem., 28 361 (1985)] was added 400 ml of tetrahydrofuran, 1 ml of dimethylformamide, and 13 ml of oxalylchloride. The acid chloride mixture as concentrated, diluted with 100 ml of tetrahydrofuran, 25 and added to a solution of the dilithio anion of malonic acid monoethylester (200 mmol) in 800 ml of tetrahydrofuran at -70°C. The reaction was stirred for one hour at -30°C, poured over ice and dilute hydrochloric acid and taken into dichloromethane. The product was isolated 30 by an extraction at pH 7, followed by drying the dichloromethane (MgS04) and concentration. The crude product was then treated neat with 2.5 equivalents of triethylorthoformate and 2.8 equivalents of acetic anhydride at 150° for two hours. The mixture was 35' . concentrated and at room temperature a slight excess of cyclopropylamine (6.0 g) was added in 150 ml of t-butanol. The mixture was stirred overnight. To this

Claims (7)

    APC032787 -25- 213151 mixture was added 11.3 g of potassium t-butoxide and the temperature brought to 50°C. The mixture was concentrated after 18 hours and the residue treated with 100 ml of acetic acid and 100 ml of 4N hydrochloric acid. From this mixture after four hours at 100°C, 12.7 g of the title compound precipitated. *33151;26;WHAT WE CLAIM IS:;
  1. I. A compound of the formula;_NB D;£ "3*'4 (III) wherein R^ is hydrogen, alkyl of from one to three carbon atoms or cycloalkyl of from three to six carbon atoms; is hydrogen or alkyl of from one to three carbon atoms; and R^ is alkyl of from one to three carbon atoms or cycloalkyl of from three to six carbon atoms.
  2. 2. A compound according to claim 1 wherein and are each independently hydrogen, methyl or ethyl, and is methyl.
  3. 3. A compound according to claim 1 which is 3-methyl-3-pyrrolidine methanamine; or N,N,3-trimethy1-3-pyrrolidinemethanamine.
  4. 4. A process for the preparation of a compound of formula III as defined in claim 1, the process comprising the steps of (a) reducing a nitrile of the formula , in which is as defined in claim 1 and Ph is phenyl, with a strong reducing agent and subjecting the reduction product to catalytic hydrogenation to produce a compound of the formula III in which R^ and R^ are hydrogen; or ^Ph - 27 - 233 (b) hydrolysing a nitrile of the formula in which and Ph are as defined above, with a strong acid to provide the corresponding acid; activating the acid function of the corresponding acid and reacting it with HNR3R4, in which R^ and are as defined in claim 1 but are not both hydrogen; reducing the reaction product with a strong reducing agent; and subjecting the reduction product to catalytic hydrogenation to produce a compound of formula III in which R^ and R^ are not both hydrogen.
  5. 5. A process according to claim 4 and substantially as described in this specification with reference to the reaction scheme on page 11 and example C or example 0.
  6. 6. A compound of formula III as defined in claim 1 whenever produced by a process according to claim 4 or claim 5.
  7. 7. An acid addition salt of a compound according to any one of claims 1 to 3 and 6. BALDWIN, SON & CAREY
NZ233151A 1986-07-28 1987-07-09 Pyrrolidine derivatives as intermediates in the preparation of 7-((3-(aminomethyl)-3-alkyl)-1-pyrrolidinyl)-quinoline carboxylic acids NZ233151A (en)

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US88999486A 1986-07-28 1986-07-28
US07/039,438 US4771055A (en) 1986-07-28 1987-04-21 7-[[3-(aminomethyl)-3-alkyl]-1-pyrrolidinyl]-quinoline-carboxylic acids
NZ221021A NZ221021A (en) 1986-07-28 1987-07-09 7-((3-(aminomethyl)-3-alkyl)-1-pyrrolidinyl)-quinoline and naphthyridine derivatives and pharmaceutical compositions containing such

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