SYNTHESIS OF QUATERNARY SALT COMPOUNDS

• US 20090112004A1
• Filed: 10/22/2008
• Published: 04/30/2009
• Est. Priority Date: 10/26/2007
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Roessler, Armin, Faessler, Roger, Casco-Cancian, Sergio, Sorgi, Kirl L., Vladislavic, Anita, Xiao, Tong, Palmer, David C.
• Granted Patent: US 8,168,829 B2
• Time in Patent Office: Days
• US Class Current: 549/424
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 307/85 attached in position 2
• CPC Class Codes: C07D 309/04 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 311/58 other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 311/92 Naphthopyrans; Hydrogenated naphthopyrans
• CPC Class Codes: C07D 313/08 condensed with one six-membered ring
• CPC Class Codes: C07D 333/36 Nitrogen atoms
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 335/02 not condensed with other rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention is directed to a process, having a reduced environmental impact, for preparing phenylamino substituted quaternary salt compounds that are CCR2 antagonists.

Claims

1. A process for preparing a quaternary chloride salt compound of Formula (I):

wherein

A is carbonyl;

X is a bond or —

CH═

CH—

;

R₁ is selected from aryl, C₅-C₁₅cycloalkyl or heterocyclyl,

wherein said aryl is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, alkoxycarbonyl, cyano, halogen or phenyl optionally substituted by lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, alkoxycarbonyl, cyano or halogen,

wherein said C₅-C₁₅cycloalkyl is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen, or

wherein said heterocyclyl is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, aryl, aryl-lower alkyl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen; and

wherein n is 0, 1, 2, 3 or 4;

Y is a bond or —

CH₂—

;

X₂ is —

(CH₂)_m—

, wherein m is 1 or 2;

R₂ is —

N⁺(R₄R₅)-ZR₃;

Z is —

(CH₂)_p—

wherein p is 0, 1 or 2;

R₃ is selected from aryl, C₅-C₁₅cycloalkyl or heterocyclyl,

wherein said aryl is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen,

wherein said C₅-C₁₅cycloalkyl is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen, or

wherein said heterocyclyl is optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen; and

wherein, when said heterocyclyl is attached via a carbon atom ring member and a heteroatom ring member is adjacent to said carbon atom, then p is 1 or 2; and

R₄ and R₅ are each individually lower alkyl or lower alkenyl;

or

alternatively, R₄ and R₅ combine with the nitrogen atom of Formula (I) to form a heterocyclyl ring of 5 to 9 total ring atoms optionally containing an oxygen ring atom, wherein the heterocyclyl ring nitrogen atom is substituted with one of lower alkyl or lower alkenyl to form a quaternary salt, and wherein -ZR₃ is absent and the heterocyclyl ring is optionally substituted with aryl optionally substituted with one or more lower alkyl, —

(CH₂)_n—

CF₃, lower alkoxy, aryl, halogen-substituted aryl, alkoxycarbonyl, cyano or halogen;

comprising the steps of;

Step A. reacting a Compound A1 with a Compound A2, optionally in the presence of an aqueous base, to provide a Compound A3;

Step B. reacting Compound A3 in the presence of an acid to provide a Compound A4;

Step C. reacting Compound A4 with a Compound A5 in a solvent to provide Compound A6, representative of the compound of Formula (I);

2. The process of claim 1, wherein the optional aqueous base is Na₂CO₃ (at a concentration of about 7.2%) and Compound A1 is reacted with Compound A2 in acetone at a reaction temperature in a range of from about 35°

C. to about 42°

C.

3. The process of claim 1, wherein Compound A1 is reacted with Compound A2 in the presence of Na₂CO₃ (at a concentration of about 7.2%) in acetone at a reaction temperature in a range of from about 35°

C. to about 42°

C.

4. The process of claim 1, wherein Compound A3 is reacted in the presence of an acid such as neat concentrated HCl or concentrated HCl in a ratio with a solvent selected from the group consisting of THF, EtOH and acetone at a reaction temperature in a range of from about room temperature to about 45°

C.

5. The process of claim 4, wherein the ratio of THF:

HCl is about 1;

1 at a reaction temperature of about room temperature.

6. The process of claim 4, wherein the ratio of EtOH:

conc. HCl is about 1;

1 at a reaction temperature of about room temperature.

7. The process of claim 4, wherein the ratio of acetone:

HCl is about 1;

1, or about 3;

1, or about 4;

1, or about 5.4;

1, or about 6;

1, or about 7.7;

1, or about 12.8;

1 at a reaction temperature of about RT, or about 30°

C., or about 35°

C., or about 40°

C., or about 45°

C.

8. The process of claim 1, wherein the acid may be an inorganic acid chloride selected from SOCl₂/THF or SOCl₂/CHCl₃/Pyridine(cat.)

9. The process of claim 1, wherein Compound A3 is reacted in the presence of concentrated HCl in a 3:

1 ratio with acetone at a reaction temperature in a range of from about 45°

C. to about 50°

C.

10. The process of claim 1, wherein Compound A4 is reacted with a Compound A5 in a solvent selected from acetone or EtOH at a reflux temperature that is less than or about the boiling point of the solvent.

11. The process of claim 10, wherein Compound A5 is 4-DMATHP Compound B5 reacted with Compound A4 in acetone at said reflux temperature.

12. The process of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

(E)-(4-{[3-(3-bromo-phenyl)-acryloylamino]-methyl}-benzyl)-cyclohexyl-dimethyl-ammonium chloride,

{4-[(3-bromo-benzoylamino)-methyl]-benzyl}-cyclohexyl-dimethyl-ammonium, chloride

cyclohexyl-dimethyl-{4-[(3-trifluoromethyl-benzoylamino)-methyl]-benzyl}-ammonium chloride,

(E)-(4-{[3-(3,4-dichloro-phenyl)-acryloylamino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-(4-{[3-(3-bromo-phenyl)-acryloylamino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-benzoylamino-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[3-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[3-(3-bromo-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,3-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,5-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2,6-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(2-chloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

(2S)-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

(2R)-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-ylmethyl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-ethyl-methyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3,4-dichloro-benzoylamino)-benzyl]-methyl-propyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3,5-dichloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-bromo-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-2-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-4-fluoro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-4-methoxy-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-4-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-chloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-cyano-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(3-methoxy-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(4-chloro-2-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(4-chloro-3-trifluoromethyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(4-chloro-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-(5-chloro-2-methyl-benzoylamino)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{2-[4-(3,4-dichloro-benzoylamino)-phenyl]-ethyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{2-[4-(3-bromo-benzoylamino)-phenyl]-ethyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{3-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3,4-dichloro-benzoylamino)-methyl]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{4-[3-(3,5-difluoro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-thiopyran-4-yl)-ammonium chloride,

(E)-{4-[3-(3-chloro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{4-[3-(3-fluoro-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-{4-[3-(4-bromo-phenyl)-acryloylamino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(E)-1-(4-{[3-(3,4-dichloro-phenyl)-acryloylamino]-methyl}-benzyl)-1-methyl-piperidinium chloride,

(E)-1-(4-{[3-(3-bromo-phenyl)-acryloylamino]-methyl}-benzyl)-1-methyl-piperidinium chloride,

1-[4-(3,4-dichloro-benzoylamino)-benzyl]-1-methyl-piperidinium chloride,

1-[4-(3,4-dichloro-benzoylamino)-benzyl]-1-methyl-pyrrolidinium chloride,

(E)-1-{3-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-1-methyl-piperidinium chloride,

(E)-1-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-1-methyl-piperidinium chloride,

(E)-1-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-4-(2-methoxy-phenyl)-1-methyl-piperazin-1-ium chloride,

(E)-1-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-1-methyl-piperidinium chloride,

1-methyl-1-[3-(3-trifluoromethyl-benzoylamino)-benzyl]-piperidinium chloride,

(E)-1-methyl-1-{4-[3-(3-trifluoromethyl-phenyl)-acryloylamino]-benzyl}-piperidinium chloride,

(E)-4-(4-{[3-(3,4-dichloro-phenyl)-acryloylamino]-methyl}-benzyl)-4-methyl-4-morpholin-4-ium chloride,

4-[4-(3,4-dichloro-benzoylamino)-benzyl]-4-methyl-morpholin-4-ium chloride,

(E)-4-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-4-methyl-morpholin-4-ium chloride,

(E)-4-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-4-methyl-morpholin-4-ium chloride,

(E)-4-methyl-4-(4-{[3-(3-trifluoromethyl-phenyl)-acryloylamino]-methyl}-benzyl)-morpholin-4-ium chloride,

(E)-dimethyl-(tetrahydro-pyran-4-yl)-(4-{[3-(3-trifluoromethyl-phenyl)-acryloylamino]-methyl}-benzyl)-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)- [3-(3-trifluoromethyl-benzoylamino)-benzyl]-ammonium chloride,

(E)-dimethyl-(tetrahydro-pyran-4-yl)-[4-(3-m-tolyl-acryloylamino)-benzyl]-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)- [4-(3-trifluoromethyl-benzoylamino)-benzyl]-ammonium chloride,

(E)-dimethyl-(tetrahydro-pyran-4-yl)-{4-[3-(3-trifluoromethyl-phenyl)-acryloylamino]-benzyl}-ammonium chloride,

dimethyl-[4-(3-methyl-benzoylamino)-benzyl]-(tetrahydro-pyran-4-yl)-ammonium chloride,

cycloheptyl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

(E)-cyclohexyl-{4-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-ammonium chloride,

(E)-{4-[3-(3-bromo-phenyl)-acryloylamino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

[4-(3-bromo-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-[4-(3-trifluoromethyl-benzoylamino)-benzyl]-ammonium chloride,

cyclohexyl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

[4-(3-chloro-4-fluoro-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-[4-(2,3-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

cyclohexyl-[4-(2,6-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

[4-(3-chloro-4-methoxy-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

[4-(3-chloro-4-methyl-benzoylamino)-benzyl]-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-[4-(2,5-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

cyclopentyl-[4-(3,4-dichloro-benzoylamino)-benzyl]-dimethyl-ammonium chloride,

(E)-cyclohexyl-{3-[3-(3,4-dichloro-phenyl)-acryloylamino]-benzyl}-dimethyl-ammonium chloride,

(E)-cyclohexyl-{3-[3-(4-fluoro-phenyl)-acryloylamino]-benzyl}-dimethyl-ammonium chloride,

dimethyl-(tetrahydro-pyran-4-yl)-{4-[(4′

-trifluoromethyl-biphenyl-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-dimethyl-{4-[(4′

-methyl-biphenyl-3-carbonyl)-amino]-benzyl}-ammonium chloride,

dimethyl-{4-[(4′

-methyl-biphenyl-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(biphenyl-4-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(naphthalene-1-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(naphthalene-2-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

ethyl-methyl-{4-[(naphthalene-2-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

methyl-{4-[(naphthalene-2-carbonyl)-amino]-benzyl}-propyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(7-bromo-naphthalene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(7-bromo-naphthalene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(6-bromo-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6-bromo-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

(4-{[(6-bromo-2H-chromene-3-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5,7-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(5,7-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(6-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(6-methoxy-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(6-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-{4-[(6-methoxy-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

(2R)-{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

(2S)-{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

(2S)-bicyclo[2.2.1]hept-2-yl-{4-[(6-chloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-{4-[(6,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

dimethyl-{4-[(8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(7,8-dichloro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cycloheptyl-dimethyl-ammonium chloride,

{4-[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclopentyl-dimethyl-ammonium chloride,

(4-{[(6-chloro-8-methyl-2H-chromene-3-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(6-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-{4-[(5-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-{4-[(6-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-{4-[(8-fluoro-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-{4-[(7-methyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-{4-[(7-methoxy-2H-chromene-3-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(6-tert-butyl-2H-chromene-3-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

cyclohexyl-dimethyl-{4-[(5-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

cyclohexyl-dimethyl-{4-[(8-trifluoromethyl-2H-chromene-3-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

1-{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-1-methyl-pyrrolidinium chloride,

{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

4-{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-4-methyl-morpholin-4-ium chloride,

{4-[(3H-benzo[f]chromene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-ylmethyl)-ammonium chloride,

(4-{[(3H-benzo[f]chromene-2-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[(3-bromo-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3-bromo-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3-bromo-8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

1-{4-[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-1-methyl-pyrrolidinium chloride,

cyclohexyl-{4-[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[(8,9-dihydro-7H-benzocycloheptene-6-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-(4-{[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-methyl}-benzyl)-(tetrahydro-pyran-4-yl)-ammonium chloride,

[4-( {[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl)-benzyl]-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(benzofuran-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

(4-{[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-benzyl)-cyclohexyl-dimethyl-ammonium chloride,

{4-[(5-chloro-benzofuran-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5-chloro-benzofuran-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

{4-[(benzofuran-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride,

dimethyl-{4-[(1-methyl-1H-indole-2-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(5-bromo-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

dimethyl-{4-[(1-methyl-1H-indole-3-carbonyl)-amino]-benzyl}-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(1-benzyl-1H-indole-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-dimethyl-{4-[(1-methyl-1H-indole-2-carbonyl)-amino]-benzyl}-ammonium chloride,

{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride, (2S)-{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-furan-2-ylmethyl)-ammonium chloride,

bicyclo[2.2.1]hept-2-ylmethyl-{4-[(5-chloro-1H-indole-2-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

cyclohexyl-{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

bicyclo[2.2.1]hept-2-yl-{4-[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-benzyl}-dimethyl-ammonium chloride,

(4-{[(7,8-dichloro-2,3-dihydro-benzo[b]oxepine-4-carbonyl)-amino]-methyl}-benzyl)-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(3-chloro-benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(2,5-dichloro-thiophene-3-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-dimethyl-(tetrahydro-pyran-4-yl)-ammonium chloride,

{4-[(benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride, and

{4-[(3-chloro-benzo[b]thiophene-2-carbonyl)-amino]-benzyl}-cyclohexyl-dimethyl-ammonium chloride.

13. A process for preparing a quaternary chloride salt compound of Formula (Ia):

comprising the steps of;

Step A. reacting a Compound B1 with a Compound B2, optionally in the presence of an aqueous base, to provide a Compound B3;

Step B. reacting Compound B3 in the presence of an acid to provide a Compound B4;

Step C. reacting Compound B4 with 4-(dimethylamino)tetrahydropyran Compound B5 in a solvent to provide the compound of Formula (Ia), representative of the compound of Formula (I);

14. The process of claim 13, wherein the optional aqueous base is Na₂CO₃ (at a concentration of about 7.2%) and Compound B1 is reacted with Compound B2 in acetone at a reaction temperature in a range of from about 35°

C. to about 42°

C.

15. The process of claim 13, wherein Compound A1 is reacted with Compound A2 in the presence of Na₂CO₃ (at a concentration of about 7.2%) in acetone at a reaction temperature in a range of from about 35°

C. to about 42°

C.

16. The process of claim 13, wherein Compound B3 is reacted in the presence of an acid such as neat concentrated HCl or concentrated HCl in a ratio with a solvent selected from the group consisting of THF, EtOH and acetone at a reaction temperature in a range of from about room temperature (RT) to about 45°

C.

17. The process of claim 16, wherein the ratio of THF:

HCl is about 1;

1 at a reaction temperature of about room temperature.

18. The process of claim 16, wherein the ratio of EtOH:

conc. HCl is about 1;

1 at a reaction temperature of about room temperature.

19. The process of claim 16, wherein the ratio of acetone:

HCl is about 1;

1, or about 3;

1, or about 4;

1, or about 5.4;

1, or about 6;

1, or about 7.7;

1, or about 12.8;

1 at a reaction temperature of about RT, or about 30°

C., or about 35°

C., or about 40°

C., or about 45°

C.

20. The process of claim 13, wherein the acid may be an inorganic acid chloride selected from SOCl₂/THF or SOCl₂/CHCl₃/Pyridine(cat.)

21. The process of claim 13, wherein Compound B3 is reacted in the presence of concentrated HCl in a 3:

1 ratio with acetone at a reaction temperature in a range of from about 45°

C. to about 50°

C.

22. The process of claim 13, wherein Compound B4 is reacted with 4-DMATHP Compound B5 in a solvent selected from acetone or EtOH at a reflux temperature that is less than or about the boiling point of the solvent.

23. The process of claim 22, wherein Compound B4 is reacted with Compound B5 in acetone at said reflux temperature.

24. A compound selected from the group consisting of:

3,4-dichloro-N-(4-hydroxymethyl-phenyl)-benzamide, and

3,4-dichloro-N-(4-chloromethyl-phenyl)-benzamide.