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US3678109A - Certain cyclohexylformamidines - Google Patents

Certain cyclohexylformamidines Download PDF

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US3678109A
US3678109A US3678109DA US3678109A US 3678109 A US3678109 A US 3678109A US 3678109D A US3678109D A US 3678109DA US 3678109 A US3678109 A US 3678109A
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dimethyl
formamidine
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carbon
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Richard N Knowles
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E I du Pont de Nemours and Co
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E I du Pont de Nemours and Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/918Repellent
    • Y10S514/92Mammal

Abstract

Cyclohexylformamidines of the formula: WHEREIN R1 is alkyl, cycloalkyl, bicycloalkyl, or tricycloalkyl, R2 is hydrogen or alkyl, R3 is alkyl, and R4 is alkyl and can be joined with R3 to form a saturated ring. Typical is N,N-dimethyl-N''-(4-cyclohexylmethylcyclohexyl)formamidine useful for repelling animals.

Description

O Unlted States Patent [151 3,678,109 Knowles [4 July 18, 1972 l CERTAIN OTHER PUBLICATIONS CYCLOHEXYLFORMAMDINES Bredereck et al. Angew. Chem. vol. 73, p. 493 1961) ODlZ5 [72] Inventor: Richard N. Knowles, Hockessin, Del.

Primary Examiner-Leland A. Sebastian [73] Asslgnees E. l. du Pont de Nemours and Company, A"0mey Herben w Larson Wllmmgton, Del.

[22] Filed: Aprll 20, 1967 AC [21 1 App]. No.: 634,037 Cyclohexylformamidines of the formula:

52 u.s.c|. ..260/564 R, 260/239 R, 260/239 A, 260/239 E, 260/239 B, 260/240 G, 260/293 R, N .1: N E 424/244, 424/267, 424/274, 424/326 s [51] Int. Cl ..C07c 123/00 m4: [58] Field of Search ..260/564, 240 G, 239, 326-385,

260/293, 239 R, 239 A, 239 B, 239 E, 293 R, 240

564 R wherein R is alkyl, cycloalkyl, bicycloalkyl, or tricycloalkyl, [56] References Cited R2 is hydrogen or alkyl,

UNITED STATES PATENTS Ra alkyland R 1s alkyl and can be jomed vmh R to form a saturated 2,653,169 9/1953 Hurwitz et a1. ..260/561 3,267,097 8/1966 Kuhle et al ....260/564 Typical i NNdimethYLN' (4.cyclohexylmethylcyclohexyl) 3,205,262 9/1965 Seefelder et a1. ....260/564 f r amjdine useful for repelling animals. 3,189,648 6/1965 Geyvrich ....260/564 2,211,280 8/1940 Martin et a1. ..260/564 8 Claims, No Drawings CERTAIN CYCLOI-IEXYLFORMAMIDINES BACKGROUND OF THE INVENTION The following applications relate to compounds containing cyclohexyl ring structures and having utility as animal repellants:

Application Serial Nos. 1966, filed March 1, 1966,

574,276, filed Aug. 18, 1966, 574,495, filed Aug. 18, 1966, 574,496, filed Aug. I8, 1966, 574,498, filed Aug. I8, I966,

now abandoned, and 574,499, filed Aug. 18, 1966.

I have now discovered an additional class of compounds containing a cyclohexyl ring structure and having utility as animal repellants.

SUMMARY OFTHE INVENTION I have discovered that animal repellant activity is shown by the following compounds:

wherein R is alkyl of three through eight carbon atoms, cycloalkyl of four through nine carbon atoms, cycloalkylalkyl of five through carbon atoms, bicycloalkyl of seven through 10 carbon atoms or tricycloalkyl of 10 through ll carbon atoms,

R is hydrogen or alkyl containing one through three carbon atoms,

R is alkyl containing one through four carbon atoms, and

R is alkyl containing one through four carbon atoms and can be joined with R to form a saturated hydrocarbon rmg.

The dotted line in Formula (1) denotes those compounds where R and R are joined.

Preferred because of excellent animal irritant activity at low rates of application are those compounds of Formula (I) wherein R is hydrogen and R and R are not joined.

Particularly preferred because of outstanding animal irritant activity at low use rates are the cis and trans isomers of N,N-dimethyl-N'-(4-cyclohexylmethylcyclohexyl)formamid mes.

UTILITY Compounds of this invention cause potent irritation to animal tissue, particularly to the mucous membranes.

Animals exposed to the above compounds show signs of severe respiratory irritation. These compounds have two advantages over currently used riot control agents such as orthochlorobenzylidenemalonitrile (CS) and 2- chloroacetophenone (CN) as well as over currently used animal repellants such asdried blood for deer, allylisothiocyanate for dogs and zinc dithiocarbamateamine complex for rodents. One, the compounds are more potent at low concentrations and two, provide residual activity over longer periods of time.

Compounds of this invention and particularly cis/trans mixtures of N,N-dimethyl-N'-( 4-cyclohexylmethylcyclohexyl)formamidine have potential use as riot control agents, dog repellants, deer repellants, rodent repellants and for contaminating caves or underground tunnels.

PREPARATION The compounds of this invention are prepared by the reaction of an amine with an amide diethylacetal. This reaction is illustrated below. R R R and R, are as defined in Formula The amide diethylacetals and formamidines are prepared according to the method of H. Bredereck, F. Eflenberger and G. Simchen; Angew. Chem, 73, 493( 196/).

The desired formamidine is prepared by refluxing an amine with the amide diethylacetal according to Reaction I for one to two hours, and then the solution is distilled. The first cut consists of ethanol; the formamidine is then distilled at reduced pressure. The amine intermediates can be prepared according to the following synthetic route.

R, isasdefined in Formula(l) R|0c1+ R o III 0 KOH mom-Q-c CH:

The Friedel Crafts reaction (II) is run by carefully adding the acid chloride to a stirring mixture of aluminum chloride in benzene. A slight molar excess of catalyst is used; benzene serves as both a solvent and reactant. The acid chloride is added at a rate so as to keep the temperature of the slurry at about 30-40 C. The mixture is stirred for 1 additional hour after all of the acid chloride is added, and then water is slowly added to decompose the catalyst. Sufficient water is added so that all the solids are dissolved. The phenylalkyl ketone is isolated from the benzene solution and is purified by distillation.

The Wolff-Kishner reduction (III) is run in 2-(2-ethoxyethoxy)ethanol using a modification of the procedure given by J. Cason et al. in Organic Synthesis, Collective Volume IV, John Wiley and Sons, New York, (1963), p. 510. Once the reactants are mixed, they are heated to reflux for a period of three to 5 hours. The reflux temperature is generally in the l30-l40 C. range. After completion of the reflux period, the

solution is cooled and poured into 3 to 4 volumes of water. The alkylbenzene product is extracted with pentane, and purified by distillation.

The Friedel-Crafts reaction (IV) is run by mixing approximately equimolar quantities of the reactants together in hexane or nitromcthane at less than C. The stirring mixture is slowly allowed to warm to room temperature, and after hydrogen chloride evolution subsides, the mixture is refluxed several hours. Water is then added slowly to decompose the catalyst. A sulficient quantity of water is then added so that all of the solids are dissolved. The desired acetophenone derivative is isolated from the organic phase and purified by distillation. Gas-liquid chromatography on an F & M Model 500 Gas Chromatograph using a 2 feet Xl/4 of an inch O.D. stainless steel column, containing l0% Carbowax M on 6080 mesh Diatoport T indicates that about 98 percent of the acetophenone is the 1,4-isomer and 2 percent is the 1,2- isomer. The 1,2-isomer has the shorter retention time.

The haloform reaction (V) is run by slowly adding a cold 5" C.) sodium hypochlorite solution to a stirring solution of 2 the acetophenone derivative in methanol. This is a modification of the procedure used by E. E. Royals, Joumal American Chemical Society," Volume 69, p. 841(1947), for the haloform reaction of a-ionone. After the sodium hypochlorite solution is added, the mixture is warmed to room temperature, and left standing over night. The mixture is heated to reflux, and the distillate collected until the pot temperature rises to 95-97 C.; most of the methanol is distilled. The pot is then cooled to room temperature.

In those reactions where R does not have a large molecular weight, such as cyclobutyl, the sodium benzoate derivative remains dissolved; however, when R is of a larger molecular weight, such as n-octyl, the sodium benzoate derivative precipitates as a soapy solid. Sulfur dioxide is bubbled into the alkaline pot concentrate until the pH drops below 3. The precipitated benzoic acid derivative is either filtered and washed with water, or extracted with methylene chloride depending on whether or not the benzoic acid is easily filterable or is of a soapy nature. Some of these benzoic acid derivatives can be recrystallized from acetonitrile or pentane, and some are purified merely by trituration with cold pentane.

The catalytic hydrogenation (V1) is performed at 1 to 4 atmospheres of hydrogen using platinum oxide as catalyst and glacial acetic acid as solvent. A Parr Hydrogenation Apparatus is suitable for these reactions. This reaction produces a cis/trans isomer mixture of about 2 or 3 to l. The cis and trans designation refers to the relationship of the 4-alkyl substituent and carboxylic acid group on the cyclohexane ring; this is illustrated below.

R 1C H2 cis C 0 2H R 0 II;

trans The Schmidt reaction (Vll) is perfonned by dissolving the cyclohexane carboxylic acid derivative in a mixture of chloroform and concentrated sulfuric acid. Sodium azide is then added in small portions to the stirring mixture at a rate sufficient to keep the reaction temperature between C. and 45 C. The mixture is stirred at about 45 to 50 C. until the bubbling nearly stops (1 to 3 hours). The mixture is then transferred to a separatory funnel, and the lower, gelatinous sulfuric acid layer is slowly dripped into ice. The amine sulfate precipitates as a soapy material which slowly crystallizes. The chloroform should be kept away from the ice water mixture since it makes the work-up much more difficult. Those amines which crystallize as the hemi-sulfates or sulfates are filtered and washed with water. It is convenient to store the amines as their salts. Those amine salts which fail to crystallize are converted to the free bases by making the sulfuric acid solution alkaline, and extracting the amine with dichloromethane. The amine is then purified by distillation. The Schmidt reaction proceeds without changing the cis/trans product ratio.

An alternative synthesis route for these amine intermediates can be used when the appropriately substituted aniline derivatives are available. This route is illustrated below.

VIII

The hydrogenation (VIII) can be performed on a Parr Hydrogenation Apparatus using platinum oxide as catalyst and glacial acetic acid as solvent. The cis :trans ratio of the cyclohexylamine product is about 1 :1

COMPOSITIONS Compounds of this invention can be administered alone, but are generally contained in a composition with an inert diluent non-toxic to animals. The diluent selected depends on the route of administration.

Emulsifying agents can be used with the diluent and compound of Formula (1) to aid in dispersion of the active ingredient. Emulsifying agents that could be used include alkylaryl polyethoxy alcohols, alkyl and alkylaryl polyether alcohols, polyoxyethylene sorbitol or sorbitan fatty esters, polyethylene glycol fatty esters, fatty alkylol amide condensates, amine salts of fatty alcohol sulfates plus long chain alcohols and oil soluble petroleum sulfonates.

The amount of emulsifying agent in the composition will range from 0.1 to 20 percent by weight.

Since the compounds of the present invention would generally be administered by vapor or spray application, the compositions will contain a liquid diluent such as water, acetone, hexane, gasoline, kerosene, other hydrocarbon oils, alcohols or other liquids generally used in pharmaceutical preparations.

The amount of active ingredient in the composition will vary from 0.005 percent by weight to percent or even higher. The diluent will generally constitute the major proportion of the composition and the amount of active ingredient will be less than 50 percent by weight. The exact concentration of the active ingredient will depend on the mechanism used for administration and will be easily understood by one knowledgeable in pharmaceutical application rates.

APPLICATION A quantity of active ingredient sufficient to cause irritation to animal tissue is to 6,000 micrograms per liter of air at exposure of 1 minute. It is expected that this rate applies to all animals. Rates of over 6,000 micrograms per liter of air at exposure of l minute kill 50 percent of the mice which are treated.

The following additional examples are provided to more particularly explain the invention.

EXAMPLE I A solution of 10.6 g. (54mmoles) of 4-cyclohexyl-methylcyclohexylamine and 8.1 g. (55mmole) of dimethyl-formamide diethylacetal is refluxed for 1 -%hours in a 50 ml. round bottom flask. The ethanol is then distilled; about 3.8 ml. of ethanol is collected. The oil remaining in the pot is then distilled in vacuum. The N,N-dimethyl-N -(4-cyclohexylmethylcyclohexyl)formamidine boils at 123 C. at a pressure of0.3 mrn. ofmercury (n LSOIO).

Gas-liquid chromatography on an F & M Model 500 Gas the ratio of about 4 to l.

H, l2.l;N,ll.2%

anal. calc'd. for C,,H,.N,:

Mice are treated by aerosol exposure to this cis/trans mixture of N,N-dimethyl-N'-(4-cyclohexylmethylcyclohexylformamidine in the following manner: The compound is administered as an aerosol into a 2.8 liter chamber. The exposure chamber consists of a 2.8 liter bell jar over a nebullizer inserted through the floor of the chamber. Mice are exposed for five minutes to 350 micrograrnsper liter of air 1,750 Ct). The compound is dissolved in 1.4 ml. of acetone and during a span of 20 seconds the compound is sprayed up into the chamber. No further air is transferred into or out of the chamber during the S-minute-exposure.

After this exposure, irritant effects are observed in all mice exposed, but not in controls exposed to 1.4 ml. of acetone 2 alone. Irritant effects can be described as the presence of one or more of the following reactive signs:

a. abnormal gait, including rubbing of the nose on .he floor while running about b. depression c. dyspnea.

EXAMPLES 2 15 The following compounds are made in a manner like that of N,N-dimethyl-N'-(4-cyc1ohexylmethylcyclohexyl)-formamidine of Example 1 by substituting a like amount by weight of the appropriate amine and amide diethylacetal for a the 4-cyclohexylmethylcyclohexylamine and dimethylforrriamide diethylacetal of Example 1. They produce like irritant effects.

2. N,N-diethy1-N-( 4-n-hexylcyclohexyl)formamidine. 3. N,N-dipropyl-N'-[4-(2-[2.2.1 ]-bicycloheptylmethyl)- cyclohexyl1formamidine. 4. N,N-dibutyl-N-[4-iso-butylcyclohexyl]formamidine. 5. N,N-dimethyl-N'-[4-cyclopentylmethylcyclohexyl] acetamidine. 6. N,N-dimethyl-N'-[4-(3-cyclopentylpropyl)cyclohexyl1- formamidine. 7. N,N-dimethyl-N'-[4-n-octylcyclohexyl)butyramidine.

N,N-dimethyl-N-[4-( l'-adamantylmethyl )cyclohexyl] formamidine. 9. N,N-pentamethylene-N'-(4-cyclobutylmethylcyclohexyl)-formamidine. 10. N,N-dimethyl-N'-( 4-n-butylcycl ohexyl)t'ormamidine.

11. N,N-tetramethylene-N'-(4-cyclohexylmethylcyclohexyl )-formamidine'.

l 2. N,N-dimethylene-N 4-n-hexylcyclohexyl)acetamidine.

mamidine.

l4. N,N-dimethyl-N'-(4-[3-cyclopentylpropyllcyclohexyl)- formamidine. l5. N-N-Dimethyl-N'-(4-cycloheptylmethyl)formamidine.

EXAMPLE 16 young adult male guinea pigs weighing 250-300 grams.

aerosol is generated by feeding the solution of test compound through a commercial paint sprayer jet at the rate of 10 ml./min., and dispersing the spray with a stream of air having a flow rate of 44 liters/min. supplied at a pressure of 2 pounds/sq.inch. The efficiency of forming respirable partic es ranges from 10 to 40 percent. This aerosol gives a concentration of N,N-dimethyl-N-(4-cyclohexylmethyl-cyclohexyl)formamidine in the chamber of 2.1 rug/liter. The particles in the aerosol have a mass median diameter of 1.3 microns with a standard geometric deviation of 2.0 microns.

The guinea pigs exposed to this aerosol for 1 minute experienced dyspnea characterized by a cough-like spasm which lasts for 2 hours. The guinea pigs also tried to escape from the chamber and exhibited face pawing. No adverse effects are 5 seen 24 hours after the exposure.

1 claim: 1. A compound of the formula:

11 R1 R3. 1 1 R -N=C-- N I 1r R4 wherein R is selected from the group consisting of alkyl of three through eight carbon atoms, cycloalkyl of four through nine carbon atoms, cycloalkylalkyl of five through 10 carbon atoms, bicycloalkyl of seven through 10 carbon atoms and tricycloalkyl of 10 through 1 1 carbon atoms,

R is selected from the group consisting of hydrogen and alkyl containing one through three carbon atoms,

R, is alkyl containing one through four carbon atoms, and

R is alkyl containing one through four carbon atoms; and R and R can be joined to form a saturated hydrocarbon ring containing two through eight carbon atoms.

2. A compound according to claim 1 which is N,N-

dimethyl-N'-(4-cyclohexylmethylcyclohexyl)formamidine.

3. A compound according to claim 1 which is N,N-

dimethyl-N'-(4-cyclohexylmethylcyclohexyl)acetamidine.

4. A compound according to claim 1 which is N,N-

o dimethyl-N-(4-n-hexylcyclohexyl)formamidine. 2-[

N,N-octamethylene-N-( 4-n-butylcyclohexyl)for- 5. A compound according to claim 1 which is N,N dimethyl-N'-[4-(2-[2.2.l l-bicycloheptylmethyl)cyclohexyl]- formamidine.

6. A compound according to claim 1 which is N,N- dimethyl-N'-(4-[ l-adamantylmethyl ]cyclohexyl )formamidine.

7. A compound according to claim 1 which is N,N- dimethyl-N-(4-n-octylcyclohexyl)formamidine.

8. A compound according to .claim 1 which is N,N- dimethyl-N'-(4-n-butylcyclohexyl)formamidine.

Claims (7)

  1. 2. A compound according to claim 1 which is N,N-dimethyl-N''-(4-cyclohexylmethylcyclohexyl)formamidine.
  2. 3. A compound according to claim 1 which is N,N-dimethyl-N''-(4-cyclohexylmethylcyclohexyl)acetamidine.
  3. 4. A compound according to claim 1 which is N,N-dimethyl-N''-(4-n-hexylcyclohexyl)formamidine. 2-(
  4. 5. A compound according to claim 1 which is N,N-dimethyl-N''-(4-(2-( 2.2.1)-bicycloheptylmethyl)cyclohexyl)-formamidine.
  5. 6. A compound according to claim 1 which is N,N-dimethyl-N''-(4-(1-adamantylmethyl)cyclohexyl)formamidine.
  6. 7. A compound according to claim 1 which is N,N-dimethyl-N''-(4-n-octylcyclohexyl)formamidine.
  7. 8. A compound according to claim 1 which is N,N-dimethyl-N''-(4-n-butylcyclohexyl)formamiDine.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4251655A (en) * 1978-03-29 1981-02-17 Mcneilab, Inc. Substituted N-iminomethylpiperidines
US4656038A (en) * 1985-02-11 1987-04-07 Biogenesis Laboratories, Inc. Animal repellent and method of manufacture of same
US5104872A (en) * 1989-08-22 1992-04-14 Nihon Hohyaku Co., Ltd. N-(substituted benzyloxy) imine derivatives and method of use thereof
US6025355A (en) * 1997-05-19 2000-02-15 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
US6242198B1 (en) 1996-07-25 2001-06-05 Cambridge Neuroscience, Inc. Methods of treatment of eye trauma and disorders
US6756389B2 (en) 1996-08-09 2004-06-29 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2211280A (en) * 1937-07-08 1940-08-13 Geigy Ag J R Water-soluble nitrogenous compounds and a process for their manufacture
US2653169A (en) * 1952-06-11 1953-09-22 Rohm & Haas N-n'-dichloro-1, 8-diformamido-p-menthane
US3189648A (en) * 1962-04-11 1965-06-15 Du Pont Process for preparing n, n-dialkyl-n'-arylamidines
US3205262A (en) * 1965-09-07 Production of n,n -disubstitutes> formamidines
US3267097A (en) * 1965-03-25 1966-08-16 Bayer Ag Halocarbonic and aryl formamidines and process for their production

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3205262A (en) * 1965-09-07 Production of n,n -disubstitutes> formamidines
US2211280A (en) * 1937-07-08 1940-08-13 Geigy Ag J R Water-soluble nitrogenous compounds and a process for their manufacture
US2653169A (en) * 1952-06-11 1953-09-22 Rohm & Haas N-n'-dichloro-1, 8-diformamido-p-menthane
US3189648A (en) * 1962-04-11 1965-06-15 Du Pont Process for preparing n, n-dialkyl-n'-arylamidines
US3267097A (en) * 1965-03-25 1966-08-16 Bayer Ag Halocarbonic and aryl formamidines and process for their production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4251655A (en) * 1978-03-29 1981-02-17 Mcneilab, Inc. Substituted N-iminomethylpiperidines
US4656038A (en) * 1985-02-11 1987-04-07 Biogenesis Laboratories, Inc. Animal repellent and method of manufacture of same
US5104872A (en) * 1989-08-22 1992-04-14 Nihon Hohyaku Co., Ltd. N-(substituted benzyloxy) imine derivatives and method of use thereof
US6770668B2 (en) 1996-02-15 2004-08-03 N. Laxma Reddy Pharmaceutically active compounds and methods of use
US6514990B2 (en) 1996-02-15 2003-02-04 Scion Pharmaceuticals, Inc. Pharmaceutically active compounds and methods of use
US6358993B1 (en) 1996-02-15 2002-03-19 Cenes Pharmaceuticals, Inc. Pharmaceutically active nitrogen ring compounds and methods of use thereof
US6358696B1 (en) 1996-07-25 2002-03-19 Mcburney Robert N. Methods of treatment of eye trauma and disorders
US6242198B1 (en) 1996-07-25 2001-06-05 Cambridge Neuroscience, Inc. Methods of treatment of eye trauma and disorders
US6673557B2 (en) 1996-07-25 2004-01-06 Mcburney Robert N. Methods of treatment of eye trauma and disorders
US6756389B2 (en) 1996-08-09 2004-06-29 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
US20050209222A1 (en) * 1996-08-09 2005-09-22 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
US7423059B2 (en) 1996-08-09 2008-09-09 Wyeth Pharmaceutically active compounds and methods of use
US6025355A (en) * 1997-05-19 2000-02-15 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use

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