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US4360531A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Substituted cycloalkanes
Assignee: Pharmacia and Upjohn Co
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Filing: 1981-04-09
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Granted: 1982-11-23
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Expires: 2001-04-09
Abstract
Abstract [2-Amino(substituted cycloaliphatic)]benzeneacetamide and benzamide compounds, e.g., trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide, have useful analgesic activity and low abuse or physical dependence liability, or are useful as chemical intermediates for producing such analgesic compounds. Processes for their preparation are disclosed. Pharmaceutical compositions and methods of use are also disclosed.
Inventors
- 👤 Moses W. McMillan
- 👤 Jacob Szmuszkovicz
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-09 09:26
CPC Classifications
C; C07; C07D; C07D295/00; C07D295/04; C07D295/12; C07D295/135; A; A61; A61P; A61P25/00; A61P25/04; C07D317/00; C07D317/08; C07D317/72; C07D327/00; C07D327/02; C07D327/06; C07D491/00; C07D491/02; C07D491/10; C07D493/00; C07D493/02; C07D493/10; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804
Claims Analysis
Total Claims: 29
Claim 1
Independent Claim
361 words
A compound of the formula ##STR9## wherein p and n are each full number integers of from 1 to 3, so that the resulting cycloaliphatic ring has five to seven carbon atoms; the wavy line bond (˜) between the nitrogen in the 2-position and the cycloaliphatic ring carbon indicates the bond can be either cis- or trans- with respect to each substituent on the cycloaliphatic ring; q is 0 or 1; X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C 1 to C 3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C 1 to C 3 -alkoxycarbonyl, C 1 to C 3 -alkanoyloxy, C 1 to C 3 -carboxacylamino [(-NHC(O)R 6 )]; R is hydrogen or C 1 to C 3 -alkyl; R 1 and R 2 , taken separately, are hydrogen, C 1 to C 3 -alkyl, allyl, R 1 and R 2 , taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl; R 3 , taken separately, is hydrogen, hydroxy,--OR 5 or OC(═O)R 6 ; R 4 , taken separately, is hydrogen; R 3 and R 4 , taken together, are selected from the group consisting of --ECH 2 CH 2 E--; =E, [--N˜OH], ═N˜OH and [-N˜OC(O)CH 3 ]═N˜OC(O)CH 3 ; wherein each E is bivalent sulfur or oxygen, and R 3 and R 4 cannot both be hydrogen at the same time; R 5 is C 1 to C 3 -alkyl; R 6 is hydrogen or C 1 to C 2 -alkyl; or an acid addition salt thereof, provided that when R is methyl, R 1 and R 2 , taken together with the nitrogen to which they are bonded, form a pyrrolidinyl, X and Y are each chlorine in the 3- and 4-positions of the phenyl ring, p is 1, n is 2, q is 1, E is oxygen, R 4 is hydrogen, then R 3 cannot be acetoxy and a 5-alpha orientation (on the same side of the cycloaliphatic ring as the amide nitrogen).
Claim 2
Dependent Claim
361 words
A compound of the formula ##STR9## wherein p and n are each full number integers of from 1 to 3, so that the resulting cycloaliphatic ring has five to seven carbon atoms; the wavy line bond (˜) between the nitrogen in the 2-position and the cycloaliphatic ring carbon indicates the bond can be either cis- or trans- with respect to each substituent on the cycloaliphatic ring; q is 0 or 1; X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C 1 to C 3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C 1 to C 3 -alkoxycarbonyl, C 1 to C 3 -alkanoyloxy, C 1 to C 3 -carboxacylamino [(-NHC(O)R 6 )]; R is hydrogen or C 1 to C 3 -alkyl; R 1 and R 2 , taken separately, are hydrogen, C 1 to C 3 -alkyl, allyl, R 1 and R 2 , taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl; R 3 , taken separately, is hydrogen, hydroxy,--OR 5 or OC(═O)R 6 ; R 4 , taken separately, is hydrogen; R 3 and R 4 , taken together, are selected from the group consisting of --ECH 2 CH 2 E--; =E, [--N˜OH], ═N˜OH and [-N˜OC(O)CH 3 ]═N˜OC(O)CH 3 ; wherein each E is bivalent sulfur or oxygen, and R 3 and R 4 cannot both be hydrogen at the same time; R 5 is C 1 to C 3 -alkyl; R 6 is hydrogen or C 1 to C 2 -alkyl; or an acid addition salt thereof, provided that when R is methyl, R 1 and R 2 , taken together with the nitrogen to which they are bonded, form a pyrrolidinyl, X and Y are each chlorine in the 3- and 4-positions of the phenyl ring, p is 1, n is 2, q is 1, E is oxygen, R 4 is hydrogen, then R 3 cannot be acetoxy and a 5-alpha orientation (on the same side of the cycloaliphatic ring as the amide nitrogen).
Claim 3
Dependent Claim
130 words
A compound according to claim 1 wherein p is 1 to 3, n is 1 to 3, q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position of the phenyl ring, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl or piperidinyl group; R 3 and R 4 are taken together to form the ring group --ECH 2 CH 2 E--, and each E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 4
Dependent Claim
15 words
A compound according to claim 2 which is trans-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-7-yl]benzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 5
Dependent Claim
15 words
A compound according to claim 2 which is trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 6
Dependent Claim
119 words
A compound according to claim 1 wherein p is 1 to 3; n is 1 to 3; q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl, or piperidinyl ring; R 3 and R 4 are taken together to form an =E substituent; E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 7
Dependent Claim
14 words
A compound of claim 5 which is trans-3,4-dichloro-N-methyl-N-[4-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, or a pharmaclogically acceptable salt thereof.
Claim 8
Dependent Claim
115 words
A compound according to claim 1 wherein p is 1 to 3; n is 1 to 3; q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl or piperidinyl ring; R 3 is hydrogen and R 4 is acetoxy; E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 9
Dependent Claim
14 words
A compound of claim 7 which is (1β,2β,4α)-3,4-dichloro-N-methyl-N-[4-(acetyloxy)-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 10
Dependent Claim
112 words
A compound of claim 1 wherein p is 1 to 3; n is 1 to 3; q is 0 or 1; each of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl, or piperidinyl ring; R 3 is hydrogen and R 4 is methoxy; E is oxygen, or an acid addition salt thereof.
Claim 11
Dependent Claim
14 words
A compound of claim 7 which is (1α,2β,5β)-N-[5-(acetyloxy)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzeneacetamide or a pharmacologically acceptable salt thereof.
Claim 12
Dependent Claim
122 words
A compound according to claim 1 wherein p is 1 to 3; n is 1 to 3, q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-positions of the phenyl ring, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; each of R 1 and R 2 is a C 1 to C 3 -alkyl; R 3 and R 4 are taken together to be the ring forming group --ECH 2 CH 2 E--, and each E is oxygen, or a pharmacologically acceptable salt thereof.
Claim 13
Dependent Claim
15 words
A compound according to claim 11 which is 4-bromo-N-[7-(dimethylamino)-1,4-dioxaspiro[4.5]dec-8-yl]-N-methylbenzamide, or a pharmacologically acceptable salt thereof.
Claim 14
Dependent Claim
17 words
A compound according to claim 11 wherein the compound is trans-3,4-dichloro-N-[7-(dimethylamino)-1,4-dioxaspiro[4.5]dec-8-yl]-N-methylbenzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 15
Dependent Claim
101 words
A compound according to claim 1 wherein p is 1 to 3; n is 1 to 3; q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position of the phenyl ring; R is C 1 to C 3 -alkyl; each of R 1 and R 2 is C 1 to C 3 -alkyl; one of R 3 and R 4 is hydrogen and the other of R 3 and R 4 is methoxy; E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 16
Dependent Claim
17 words
A compound according to claim 9 wherein the compound is 3,4-dichloro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 17
Dependent Claim
98 words
A compound according to claim 1 wherein p is 1 to 3; n is 1 to 3; q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position of the phenyl ring; R is hydrogen; each of R 1 and R 2 is a C 1 to C 3 -alkyl; R 3 and R 4 are taken together to form the --ECH 2 CH 2 E-- ring forming group, and each E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 18
Dependent Claim
11 words
A compound according to claim 16 where the compound is trans-3,4-dichloro-N-[7-(dimethylamino)-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide.
Claim 19
Dependent Claim
107 words
A compound according to claim 1 where the compound is one in which p is 1 to 3; n is 1 to 3; q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 is allyl; R 2 is C 1 to C 3 -alkyl; R 3 and R 4 are taken together to be the ring forming group --ECH 2 CH 2 E--, and each E is oxygen, or a pharmacologically acceptable salt thereof.
Claim 20
Dependent Claim
17 words
A compound according to claim 18 wherein the compound is trans-3,4-dichloro-N-methyl-N-[7-[methyl(2-propenyl)amino]-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 21
Dependent Claim
33 words
A composition useful in pharmaceutically effective dosage unit form for alleviating pain in warm blooded mammals which comprises a compound of Formula I in claim 1 in combination with a pharmaceutically acceptable carrier.
Claim 22
Dependent Claim
31 words
A method for alleviating pain which comprises administering to an animal suffering pain an effective amount of a compound of Formula I in claim 1 in a pharmaceutical dosage unit form.
Claim 23
Dependent Claim
24 words
A compound according to claim 1 wherein the compound is selected from the group consisting of: 4-bromo-N-[8-(dimethylamino)-1,4-dioxaspiro[4.5]dec-7-yl]-N-methylbenzamide 3,4-dichloro-N-[8-(dimethylamino)-1,4-dioxaspiro[4.5]dec-7-yl]-N-methylbenzamide, 3,4-dichloro-N-[8-(dimethylamino)-1,4-dioxaspiro[4.5]dec-7-yl]-benzeneacetamide, 4-bromo-N-[7-(dimethylamino)-1,4-dioxazpiro[4.5]-dec-8-yl]-benzamide, 4-bromo-N-[8-(dimethylamino)-1,4-dioxazpiro[4.5]-dec-7-yl]-benazmide, 4-bromo-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxazpiro[5.4]dec-7-yl]benzamide, 4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzamide, 3,4-dichloro-N-[5-(hydroxyimino)-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide,
Claim 24
Dependent Claim
10 words
4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]-dec-8-yl]benzeneacetamide, 3,4-dichloro-N-methyl-N-[8-(dimethylamino)-1,4-dioxaspiro[4.5]-dec-7-yl]benzeneacetamide, 3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-oxo-4-thiospiro[4.5]dec-7-yl]benzeneacetamide, N-[4-(acetyloxy)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 25
Dependent Claim
10 words
4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]-dec-8-yl]benzeneacetamide, 3,4-dichloro-N-methyl-N-[8-(dimethylamino)-1,4-dioxaspiro[4.5]-dec-7-yl]benzeneacetamide, 3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-oxo-4-thiospiro[4.5]dec-7-yl]benzeneacetamide, N-[4-(acetyloxy)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 26
Dependent Claim
142 words
A composition of claim 20 wherein the compound of Formula I is a compound of the formula ##STR10## wherein p is 1 to 3, n is 1 to 3, q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position of the phenyl ring, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl or piperidinyl group; R 3 and R 4 are taken together to form the ring group --ECH 2 CH 2 E--, and each E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 27
Dependent Claim
19 words
A composition of claim 27 wherein the compound of Formula I is trans-3,4-dichloro-N-methyl-N[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]-benzeneacetamide, or a pharmacologically acceptable salt thereof.
Claim 28
Dependent Claim
145 words
A method of claim 23 wherein the compound of Formula I in claim 1 is a compound of the formula ##STR11## wherein p is 1 to 3; n is 1 to 3; q is 0 or 1; at least one of X and Y is a halogen having an atomic number of from 9 to 35 in the 3- or 4-position of the phenyl ring, or both of X and Y are such a halogen in the 3- and 4-positions of the phenyl ring; R is C 1 to C 3 -alkyl; R 1 and R 2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl or piperidinyl group; R 3 and R 4 are taken together to form the ring group --ECH 2 CH 2 E--, and each E is oxygen; or a pharmacologically acceptable salt thereof.
Claim 29
Dependent Claim
16 words
A method of claim 29 wherein the compound is trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide or a pharmacologically acceptable salt thereof.
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