US3282947A - Unsymmetrically substituted 3, 9-diazaspiro(5, 5)undecane compounds - Google Patents

Unsymmetrically substituted 3, 9-diazaspiro(5, 5)undecane compounds Download PDF

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US3282947A
US3282947A US196564A US19656462A US3282947A US 3282947 A US3282947 A US 3282947A US 196564 A US196564 A US 196564A US 19656462 A US19656462 A US 19656462A US 3282947 A US3282947 A US 3282947A
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diazaspiro
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undecane
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methyl
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Charles H Grogan
Leonard M Rice
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GESCHICKTER FUND FOR MEDICAL RESEARCH Inc
GESCHICKTER FUND MED RES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel heterocyolic nit-rogen compounds and, more specifically, to di azaspir-anes and to methods for their synthesis.
  • the instant application is also directed to 3,9-diazaspiro (5.5)undecanes. Unlike the compounds of Serial No. 47,613, however, the compounds of the instant invention are all unsymmetrical. That is to say, each of the two nitrogen atoms in the diazaspiro nucleus of the compounds of the present invention contains a different substituent.
  • Formula 1 illustrates the general structural formula of the first class of such compounds:
  • R is selected from the group consisting of alkyl, alkenyl, ary-l, aroyl, aralkyl, dialkyl (dialkenyl) amino-alkylene (alkenylene), heterocyclic alkyl, alkoxyalkyl, alkoxyalkenylene, cycloa-lkyl and cycloalkenylene.
  • R may be represented by any member of the groups set forth above, provided only that the solubility and chemical stability of the reactant containing the R constituent which is used to form the compound of Formula 1 is such as to permit that reactant to react under the prevailing reaction conditions to form 3,282,947 Patented Nov. 1, 1966 Otherwise, there is no limitathe desired diazaspirane. tion as to the value of R.
  • Alkyl alkyl groups of 1-22 carbon atoms.
  • Alkeny-l alkenyl groups of 1-22 carbon atoms.
  • Aryl phenyl; pyridyl; thienyl; furyl; quinolyl.
  • Aralkyl benzyl; fluorobenzyl;pyridylalkyl; phenylalkyl; benzhydryl; chlorobenzyl; isopropylbenzyl; ben- Ziloyl.
  • Heterocyclic alkyl pyrrolidino; piperidino; morpholino; N-alkyl piperazine; tetrahydrofurano; tetrahydropyrano alkyl.
  • Alkoxyalkyl methoxypropyl; ethoxyet hyl; methoxyhexyl.
  • Alkoxyalkenylene methoxyallyl; ethoxyallyl.
  • Cycloalkyl cyclohexyl; cyclopentyl; cycloh'exylmethyl; cy-clooctyl; cycloheptyl; cyclopropyl.
  • Cycloalkenylene cyclopentenyl; cyclohexenyl.
  • the second class of compounds of the present invention are represented by Formula 2 below:
  • R and R are selected from the group consisting of hydrogen and any of the groups previously described as representing R in connection with the compounds of Formula 1, except that R and R are never the same group.
  • the 3,9-diazaspiro(5.5)undecane nucleus of Formula 2 is unsymmetrically substituted by the substituent groups previously enumerated.
  • the compounds of the present invention are extremely valuable and versatile synthetic intermediates.
  • this hydrogen may be selectively replaced by a wide variety of substituents, including all those defined in connection with R in Formula 2 as well as other reactive groups such as alk-anols, epoxides, ureas, thioureas, or amides of pharmacologically active groups such as p-amzin-obenzoyl, diphenylaoety'l, tmopyl, benz-iloyl, which give to a wide variety of pharmaoologically active products such as local anesthetics [i.e., para-amino benzoate ester of 3 methyl-9-hydroxyethyl-3,9-diazaspiro- (5.5)undecane], antispasmodiics [
  • the compounds of the present invention may be prepared in a variety of ways. Among these methods of preparation are the following:
  • Example I .3-methyl-9-benzyl-3,9-diazaspiro(5 .5 undecane
  • 140 gm. (0.52 mole) of piperid-ine-1-methyl4,4diacetic aci-d diethyl ester was refluxed for 30-60 hours with a 4-5 molar excess of benzylamine.
  • Excess benzyllamine was distilled off and the residue heated to 200 C., at which temperature it was maintained for 2-4 hours.
  • the residue was vacuum distilled and 65 gm. of material (B.P. 185- 195 C./ 0.1 mm.) was obtained.
  • Example II .3 methyl-3,9-diazaspiro( .5 undecane This valuable intermediate was obtained from the compound of Example I by catalytic debenzylation. 43 gm. of 3-methyl-9-benzyl-3,9-diazaspiro(5.5 )undecane was dissolved in methanol and made acid with concentrated hydrochloric acid. 4 of palladium catalyst on charcoal was added and the mixture hydrogenated at 50- 60 psi. at 80 C. for 24 hours. All solvents were stripped and the syrupy residue dissolved in a minimum of water and made alkaline with saturated sodium hydroxide solution. The water solution was extracted several times with ether since the base is miscible with water.
  • the dihydrochloride melted at 319-320 C.
  • Example lII.3-methyl-9-(3-dim'ethylam inopropyl)- 3,9-diazaspiro(5 .5 undecane The amine, 3 methyl-3,9-diazaspiro(5.5)undecane, was readily alkyla-ted to the title compound by treatment with dimethylaminopropyl chloride in refluxing toluene in the presence of :a small amount of potassium iodide.
  • the title base was obtained and boiled at 95-105 C./0.1 mm. Its trihydrochloride melted at 318-319 C.
  • R and R are each selected from a different one of the group consisting of:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent 3,282,947 UNSYMMETRICALLY SUBSTITUTED 3,9-DIAZA- SPIRO(5,5)UNDECANE COMPOUNDS Charles H. Grogan, Falls Church, Va., and Leonard M.
Rice, Baltimore, Md., assignors to The Geschickter Fund for Medical Research, Inc., Washington, D.C., a corporation of New York No Drawing. Filed May 17, 1962, Ser. No. 196,564 6 Claims. (Cl. 260-293) The present invention relates to novel heterocyolic nit-rogen compounds and, more specifically, to di azaspir-anes and to methods for their synthesis.
In applicants copending application Serial No. 47,613, filed August 5, 1960 (now abandoned), are disclosed several classes of symmetrical 3,9diazaspiro(5.5)undecane compounds which are particularly useful medicinally. Broadly speaking, the 3,9-diazaspiro(5.5)undecanes disclosed in that application are divided into two classes, the first constituting a symmetrical secondary amine in which a hydrogen atom is attached to each nitrogen atom in the diazaspiro nucleus, the second constituting symmetrical tertiary amines in which both nitrogen atoms are substituted with the same group selected from alkyl and alkylene of 1 to 6 carbon atoms.
The instant application is also directed to 3,9-diazaspiro (5.5)undecanes. Unlike the compounds of Serial No. 47,613, however, the compounds of the instant invention are all unsymmetrical. That is to say, each of the two nitrogen atoms in the diazaspiro nucleus of the compounds of the present invention contains a different substituent.
While the compounds of the present invention are thus superficially related to those of Serial No. 47,613, there are basic fundamental differences between the two, which differences will be discussed in greater detail at a later point in this specification. Broadly speaking, 'however, it may be said that the compounds of the present invention are much more versatile in their usefulness than are those of Serial No. 47,613 and, in fact, the compounds of the present invention may even be used as an alternate source of preparation of the compounds of Serial No. 47,613. In addition, the compounds of the present invention have a distinct and valuable medicinal utility.
It is accordingly a primary object of the present invention to provide novel, pharmacologically active diazaspiranes and methods for their preparation.
It is another principal object of the present invention to provide unsymmetrical 3,9-diazaspiro( .5 )undecanes which are extremely versatile in their usefulness and which have substantial utility as intermediates for the formation of other organic compounds, both symmetrical and unsymmetrical.
These and further objects of the present invention will become more apparent as the description proceeds below and in connection with the appended claims.
The novel compounds of the present invention are divided into two classes. Formula 1 illustrates the general structural formula of the first class of such compounds:
In the above formula, R is selected from the group consisting of alkyl, alkenyl, ary-l, aroyl, aralkyl, dialkyl (dialkenyl) amino-alkylene (alkenylene), heterocyclic alkyl, alkoxyalkyl, alkoxyalkenylene, cycloa-lkyl and cycloalkenylene. Generally speaking, R may be represented by any member of the groups set forth above, provided only that the solubility and chemical stability of the reactant containing the R constituent which is used to form the compound of Formula 1 is such as to permit that reactant to react under the prevailing reaction conditions to form 3,282,947 Patented Nov. 1, 1966 Otherwise, there is no limitathe desired diazaspirane. tion as to the value of R.
Examples of preferred R substituents (though, as indicated, the broad classes listed are not so restricted) are as follows:
( 1) Alkyl: alkyl groups of 1-22 carbon atoms.
(2) Alkeny-l: alkenyl groups of 1-22 carbon atoms.
(3) Aryl: phenyl; pyridyl; thienyl; furyl; quinolyl.
(4) Aroyl: benzoyl;halobenzoyl.
(5) Aralkyl: benzyl; fluorobenzyl;pyridylalkyl; phenylalkyl; benzhydryl; chlorobenzyl; isopropylbenzyl; ben- Ziloyl.
(6) Dialkyl (dialkenyl) amino-alkylene (alkenylene): dimethylaminoethyl; diethylaminoethyl; dipropylaminoethyl; diethyleneamino-hexyl; dihexylaminopropylene.
(7) Heterocyclic alkyl: pyrrolidino; piperidino; morpholino; N-alkyl piperazine; tetrahydrofurano; tetrahydropyrano alkyl.
(8) Alkoxyalkyl: methoxypropyl; ethoxyet hyl; methoxyhexyl.
(9) Alkoxyalkenylene: methoxyallyl; ethoxyallyl.
(10) Cycloalkyl: cyclohexyl; cyclopentyl; cycloh'exylmethyl; cy-clooctyl; cycloheptyl; cyclopropyl.
(11) Cycloalkenylene: cyclopentenyl; cyclohexenyl.
The second class of compounds of the present invention are represented by Formula 2 below:
In Formula 2, R and R are selected from the group consisting of hydrogen and any of the groups previously described as representing R in connection with the compounds of Formula 1, except that R and R are never the same group. In other words, the 3,9-diazaspiro(5.5)undecane nucleus of Formula 2 is unsymmetrically substituted by the substituent groups previously enumerated.
The compounds of the present invention, and particularly those of Formula 1 in which one of the nitrogen substituents is hydrogen, are extremely valuable and versatile synthetic intermediates. For example, due to the unique activity of the hydrogen atom not possessed by the other substituents enumerated, this hydrogen may be selectively replaced by a wide variety of substituents, including all those defined in connection with R in Formula 2 as well as other reactive groups such as alk-anols, epoxides, ureas, thioureas, or amides of pharmacologically active groups such as p-amzin-obenzoyl, diphenylaoety'l, tmopyl, benz-iloyl, which give to a wide variety of pharmaoologically active products such as local anesthetics [i.e., para-amino benzoate ester of 3 methyl-9-hydroxyethyl-3,9-diazaspiro- (5.5)undecane], antispasmodiics [i.e., 3-benzyl-9 hydroxyethyl-3,9-diazaspiro(5.5)undecane tropa'be ester; 3-methyl- 9 benzyl-3,9-diazaspino(5.5)undecane], antihistaminics [i.e., 3 methyl 9-(pyridylet-hyl)-3,9diazaspiro(5 .5 )undecane], and hypotensives [i.e., trimethoxybenzoylamide of 3-methytl-3,9-diazaspiro(5 .5 )undecane] In addition, the compounds of Formula 1 can be used to obtain the compounds of oopending application Serial No. 47,613, as an alternative method of synthesis.
The compounds of the present invention may be prepared in a variety of ways. Among these methods of preparation are the following:
(1) Through reaction of the appropriate N-substituted piperidine 4,4-dicarboxylic acid esters with the appropriate primary amine, either at the reflux temperature of the mixture or in a pressure bomb as the properties of the amine may prescribe, followed by reduction to the corresonding N,N'-diisubstituted diazaspirane.
2) From the diazaspi-rane obtained in (1), when R is benzyl or other high boiling arylarnine, the desired N- subst-ituted, N-h-ydrogen amine may be obtained if desired by catalytically removing the N -group.
- invention.
Example I .3-methyl-9-benzyl-3,9-diazaspiro(5 .5 undecane 140 gm. (0.52 mole) of piperid-ine-1-methyl4,4diacetic aci-d diethyl ester was refluxed for 30-60 hours with a 4-5 molar excess of benzylamine. Excess benzyllamine was distilled off and the residue heated to 200 C., at which temperature it was maintained for 2-4 hours. The residue was vacuum distilled and 65 gm. of material (B.P. 185- 195 C./ 0.1 mm.) was obtained. This material, 3-metl1yl- 9-benzyl-3,9'-diazaspiro(5.5)undecane-8,l0-dione, was reduced in absolute ether with lithium aluminum hydride. After decomposition of the lithium aluminum hydridecomplex with water, filteration of the inorganic residue, drying the ether solution over sodium sulfate and stripplug of the ether, the title compound was obtained by uacuum distillation of the residue and had a'boiling point of 128-133 C./0.15 mm. There was obtained 51 gm. (87% yield) of the title compound (based on the dione).
The dihydrochloride of the title compound melted at 326-327 C.
Example II .3 methyl-3,9-diazaspiro( .5 undecane This valuable intermediate was obtained from the compound of Example I by catalytic debenzylation. 43 gm. of 3-methyl-9-benzyl-3,9-diazaspiro(5.5 )undecane was dissolved in methanol and made acid with concentrated hydrochloric acid. 4 of palladium catalyst on charcoal was added and the mixture hydrogenated at 50- 60 psi. at 80 C. for 24 hours. All solvents were stripped and the syrupy residue dissolved in a minimum of water and made alkaline with saturated sodium hydroxide solution. The water solution was extracted several times with ether since the base is miscible with water. The ether solution was dried over sodium sulfate and calcium hydride since the solution of the base in ether gels if water is presentl After drying overnight, the ether was stripped and the residue distilled to yield the title compound (B.P. 128-130 C.15 mm). This amine is a strong base, completely miscible with water and very rapidly absorbs carbon dioxide from the atmosphere to form a solid carbonate.
The dihydrochloride melted at 319-320 C.
Example lII.3-methyl-9-(3-dim'ethylam inopropyl)- 3,9-diazaspiro(5 .5 undecane The amine, 3 methyl-3,9-diazaspiro(5.5)undecane, was readily alkyla-ted to the title compound by treatment with dimethylaminopropyl chloride in refluxing toluene in the presence of :a small amount of potassium iodide. The title base was obtained and boiled at 95-105 C./0.1 mm. Its trihydrochloride melted at 318-319 C.
While, as previously pointed out, the compounds of the present invention are superficially similar to those of copending application Serial No. 47,613 in that both are 3,9- diazaspiro(5 .5 )undecanes, there are significant distinctions between the compounds of the two applications. For ex ample, the methods of preparation of the respective compounds are basically difierent firom one another. In the method of forming the symmetrical compounds of Serial No. 47,613, ammonia or a primary alkyl or alkenyl amine is reacted with the dianhydride of methane tetraacetic acid to form the corresponding bis-amic acid, the acid then being heated sufficiently to cyclize the acid to the bisamide, the amide then being reduced to the correspondinf diazaspi-rane. Such procedure, of course, results in a symmetrical diazaspirane, which would not be satisfactory to form the unsymmetrical diazaspi-ranes of the instant case. Furthermore, while it would superficially appear feasible to obtain the compounds of the present invention from the symmetrical bis-secondary amines of Serial No. 47,613, in practice this is not feasible. It is exceedingly difiicult to substitute a desired radical for one of the N-hydrogens without doing .so to the other. At best, a mixture of symmetrical and unsymmetrical diazaspiranes might result. Conversely, speaking, however, it is possible to prepare the compounds of Serial No. 47,613 starting with the unsymmetrical compounds of the instant case, particularly in the case where one of the nitrogen substi-tuents of the starting compound is hydrogen.
The invention may be embodied in other specific forms without departing trom the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description,
and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
What is claimed and desired to be secured by United States Letters Patent is:
1. A compound or the formula wherein R and R are each selected froma different one of the group consisting of:
(a) hydrogen (b) lower alkyl (c) aralkyl selected from the group consisting of pyridyl lower alkyl and phenyl lower alkyl (d) di-lower allrylam-ino lower alkylene (e) hydroxy lower alkylene.
2. 3-methyl-9-benzyl-3,9-diazaspiro(5.5)undecane.
3. 3-methyl-3,9-diazaspi-ro(5.5)undecane.
4. 3-methyl-9-(3 dimethylaminopropyl)3-,9+diazaspiro- (5 .5 undecane.
5. The para-amino benzoate ester of 3methyl-9-hlydroxyethyl-3,9-diazaspiro( 5.5 undecane.
6. 3 methyl 9(pyridyethyl)3,9 diazaspiro(5.5)undecane.
References Cited by the Examiner Backer et al.: Rec. Trav. Ohim., vol. 54, pages 194 to 199- (1935).
Chemical Abstracts 5th Decennical (Index, page 4089s (Index for Vol-s. 1947-1956).
Patterson: Capel'l Ring Index, ACS Monograph Series No. 84, Reinhold, 1940, p. 150, compound 1018.
Sury et al.: Helv. Chim. Acta, vol. 36, pages 1815-1820 (1953 WALTER A. MODANCE, Primary Examiner.
IRVING MARCUS, Examiner.
JOSEPH W. MOLASKY, AVRON 'D. SPEVACK,
Assistant Examiners.

Claims (1)

1. A COMPOUND OF THE FORMULA 3-R'',9-R-3,9-DIAZASPIRO(5,5)UNDECANE WHEREIN R AND R'' ARE EACH SELECTED FROM A DIFFERENT ONE OF THE GROUP CONSISTING OF: (A) HYDROGEN (B) LOWER ALKYL (C) ARALKYL SELECTED FROM THE GROUP CONSISTING OF PYRIDYL LOWER ALKYL AND PHENYL LOWER ALKYL (D) DI-LOWER ALKYLAMINO LOWER ALKYLENE (E) HYDROXY LOWER ALKYLENE.
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3341517A (en) * 1963-06-12 1967-09-12 Shell Oil Co Production and use of diazaspiroalkanes
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes
US5591748A (en) * 1991-06-07 1997-01-07 Smithkline Beecham Corporation Immunomodulatory azaspiranes
US5648366A (en) * 1993-05-06 1997-07-15 Merrell Pharmaceuticals Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines
US5672602A (en) * 1995-04-13 1997-09-30 Hoechst Marion Roussel, Inc. Substituted piperazine derivatives
US5922737A (en) * 1996-02-21 1999-07-13 Hoechst Marion Roussel, Inc. Substituted N-methyl-N-(4-(4-(1H-Benzimidazol-2-YL-amino) piperidin-1-YL)-2-(arlyl) butyl) benzamides useful for the treatment of allergic diseases
US5932571A (en) * 1996-02-21 1999-08-03 Hoechst Marion Roussel, Inc. Substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl) {1,4}diazepan-1-yl)-2-(aryl) butyl) benzamides useful for the treatment of allergic diseases
US5998439A (en) * 1996-02-21 1999-12-07 Hoescht Marion Roussel, Inc. Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases
US6194406B1 (en) 1995-12-20 2001-02-27 Aventis Pharmaceuticals Inc. Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease
US6211199B1 (en) 1995-11-17 2001-04-03 Aventis Pharmaceuticals Inc. Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases
EP1087770A4 (en) * 1998-06-15 2001-11-14 Merck & Co Inc Inhibitors of prenyl-protein transferase
US6329392B1 (en) 1994-08-25 2001-12-11 Aventis Pharmaceuticals, Inc. Substituted piperidines useful for the treatment of allergic diseases
US6423704B2 (en) 1995-12-20 2002-07-23 Aventis Pharmaceuticals Inc. Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases
US20040067930A1 (en) * 2002-07-05 2004-04-08 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US20060058328A1 (en) * 2004-08-20 2006-03-16 Bhatti Balwinder S Use of N-aryl diazaspiracyclic compounds in the treatment of addiction
WO2007133561A3 (en) * 2006-05-08 2008-10-02 Neurogen Corp Substituted azaspiro derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3341517A (en) * 1963-06-12 1967-09-12 Shell Oil Co Production and use of diazaspiroalkanes
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes
US5591748A (en) * 1991-06-07 1997-01-07 Smithkline Beecham Corporation Immunomodulatory azaspiranes
US5648366A (en) * 1993-05-06 1997-07-15 Merrell Pharmaceuticals Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines
US5661160A (en) * 1993-05-06 1997-08-26 Merrell Pharmaceuticals Inc. Substituted pyrrolidin-3-yl-alkyl-piperidines
US6329392B1 (en) 1994-08-25 2001-12-11 Aventis Pharmaceuticals, Inc. Substituted piperidines useful for the treatment of allergic diseases
US5672602A (en) * 1995-04-13 1997-09-30 Hoechst Marion Roussel, Inc. Substituted piperazine derivatives
US6211199B1 (en) 1995-11-17 2001-04-03 Aventis Pharmaceuticals Inc. Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases
US6423704B2 (en) 1995-12-20 2002-07-23 Aventis Pharmaceuticals Inc. Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases
US6194406B1 (en) 1995-12-20 2001-02-27 Aventis Pharmaceuticals Inc. Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease
US5932571A (en) * 1996-02-21 1999-08-03 Hoechst Marion Roussel, Inc. Substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl) {1,4}diazepan-1-yl)-2-(aryl) butyl) benzamides useful for the treatment of allergic diseases
US6297259B1 (en) 1996-02-21 2001-10-02 Aventis Pharmaceuticals Inc. Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl) benzamides useful for the treatment of allergic diseases
US5998439A (en) * 1996-02-21 1999-12-07 Hoescht Marion Roussel, Inc. Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases
US5922737A (en) * 1996-02-21 1999-07-13 Hoechst Marion Roussel, Inc. Substituted N-methyl-N-(4-(4-(1H-Benzimidazol-2-YL-amino) piperidin-1-YL)-2-(arlyl) butyl) benzamides useful for the treatment of allergic diseases
EP1087770A4 (en) * 1998-06-15 2001-11-14 Merck & Co Inc Inhibitors of prenyl-protein transferase
US20060217406A1 (en) * 2002-07-05 2006-09-28 Bhatti Balwinder S N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US6956042B2 (en) 2002-07-05 2005-10-18 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US20050272739A1 (en) * 2002-07-05 2005-12-08 Bhatti Balwinder S N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US20040067930A1 (en) * 2002-07-05 2004-04-08 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US7291731B2 (en) 2002-07-05 2007-11-06 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US7375110B2 (en) 2002-07-05 2008-05-20 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US20080214591A1 (en) * 2002-07-05 2008-09-04 Bhatti Balwinder S N-Aryl Diazaspirocyclic Compounds and Methods of Preparation and Use Thereof
EP2078718A1 (en) 2002-07-05 2009-07-15 Targacept, Inc. N-aryl diazaspiracyclic compounds and methods of preparation and use thereof
US7923559B2 (en) 2002-07-05 2011-04-12 Targacept, Inc. N-aryl diazaspirocyclic compounds and methods of preparation and use thereof
US20110105548A1 (en) * 2002-07-05 2011-05-05 Targacept, Inc. N-aryl diazaspirocyclic compounds and methods of preparation and use thereof
US20060058328A1 (en) * 2004-08-20 2006-03-16 Bhatti Balwinder S Use of N-aryl diazaspiracyclic compounds in the treatment of addiction
WO2007133561A3 (en) * 2006-05-08 2008-10-02 Neurogen Corp Substituted azaspiro derivatives
US20080247964A1 (en) * 2006-05-08 2008-10-09 Yuelian Xu Substituted azaspiro derivatives

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