US2003144256A1PendingUtilityA1
Male anti-fertility agents
Est. expiryOct 8, 2018(expired)· nominal 20-yr term from priority
A61P 15/16A61K 31/195A61K 31/203A61K 31/47A61K 31/382A61K 31/196A61K 31/00A61K 31/353A61K 31/695
51
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Claims
Abstract
Methods and compositions for inhibiting or preventing spermatogenesis in a male mammal. Also disclosed are compounds and formulations for use in such methods.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for inhibiting the ability of a male mammal to conceive progeny, comprising: regularly administering to said male mammal an effective amount of an RAR antagonist or inverse agonist for a period of time effective to sufficiently reduce or eliminate spermatozoa in the semen of said male mammal.
2 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
wherein
X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
X is [C(R 1 ) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
R 2 is independently hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
R 3 is independently hydrogen, lower alkyl of 1 to 6 carbons or F, and;
m is an integer having the value of 0-3, and;
o is an integer having the value of 0-3, and;
Z is —C═C—,
—N═N—,
—N═CR 1 —,
—CR 1 ═N,
—(CR 1 ═CR 1 ) n′ — where n′ is an integer having the value 0-5,
—CO—NR 1 —,
—CS—NR 1 —,
—NR— 1 —CO,
—NR— 1 —CS,
—COO—,
—OCO—;
—CSO—;
—OCS—;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or
when Z is —(CR 1 ═CR 1 ) n′ — and n′ is 3, 4 or 5 then Y represents a direct valence bond between said (CR 2 ═CR 2 ) n′ group and B;
A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, and
R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons.
3 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
wherein
X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
X is [C(R) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
R 2 is independently hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
R 3 is independently hydrogen, lower alkyl of 1 to 6 carbons or F, and;
m is an integer having the value of 0, 1, 2, or 3, and;
o is an integer having the value of 0, 1, 2, or 3, and;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, and;
A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, and;
R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0, 1, 2, 3, 4 or 5, and;
R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and;
R 16 is H, lower alkyl of 1 to 6 carbons, and;
R 17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR 11 , and;
p is zero or 1, with the proviso that when p is 1 then there is no R 17 substituent group, and m is an integer between, and including, 0 and 2.
4 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where
X is C(R 1 ) 2 or O, and;
R 1 is H or alkyl of 1 to 6 carbons, and;
R 2 is independently lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
m is an integer having the value of 0-3, and;
R 3 is independently lower alkyl of 1 to 6 carbons or F, and;
o is an integer having the value of 0-3, and;
s is an integer having the value of 1-3, and;
R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, and;
R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , COR 8 , NR 8 CON(R 8 ) 2 , OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, an alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and; t is an integer having the values of 0, 1, 2, 3, 4, or 5, and; the CONH group is in the 6 or 7 position of the benzopyran, and in the 2 or 3 position of the dihydronaphthaline ring, or a pharmaceutically acceptable salt of said compound.
5 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where
X is C(CH 3 ) 2 or O, and; R 2 is H or Br, and; R 2′ and R 2″ independently are H or F, and; R 3 is H or CH 3 , and; R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
6 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
wherein X 1 is: —C(R 1 ) 2 —, —C(R 1 ) 2 —C(R 1 ) 2 —, —S—, —O—, —NR 1 —, —C(R 1 ) 2 —O—, —C(R 1 )—S—, or C(R 1 )—NR 1 —; and
R 1 is independently H or alkyl of 1 to 6 carbons; and
R 2 is optional and is independently defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; and
m is an integer between, and including, 0 and 4; and
n is an integer between, and including, 0 and 2; and
o is an integer between, and including, 0 and 3; and
R 3 is H, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; and
R 4 is (R 5 ) p -phenyl, (R 5 ) p -naphthyl, (R 5 ) p -heteroaryl where the heteroaryl group is five-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S, and N; and
p is an integer between, and including, 0 and 5; and
R 5 is optional and is defined as independently F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , N(R 8 )CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8 , an alkyl group having from 1 to 10 carbons, an alkenyl group having from 1 to 10 carbons and 1 to three double bonds, alkynyl group having from 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have from 1 to 6 carbons; and
Y is a phenyl or naphthyl group, or a heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or Y is —(CR 3 ═CR 3 ) r —; and
r is an integer between, and including, 1 and 3; and
A is (CH 2 ) q where q is an integer from 0-5, lower branched chain alkyl having from 3 to 6 carbons, cycloalkyl having from 3 to 6 carbons, alkenyl having from 2 to 6 carbons and 1 or 2 double bonds, alkenyl having from 2 to 6 carbons and 1 or 2 triple bonds, with the proviso that when Y is —(CR 3 ═CR 3 ) r — then A is (CH 2 ) q and q is 0; and
B is H, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 ,—CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6alkyl ) 3 , wherein R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl, where the alkyl groups has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 8 and R 10 independently are H, a lower alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is a divalent alkyl radical of 2-5 carbons.
7 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where
X 1 is S or O;
X 2 is CH or N;
R 2 is H, F, CF 3 or alkoxy of 1 to 6 carbons;
R 2 * is H, F, or CF 3 ;
R 8 is H, or lower alkyl of 1 to 6 carbons;
R 14 is unsubstituted phenyl, thienyl or pyridyl, or phenyl, thienyl or pyridyl substituted with one to three R 15 groups, where R 15 is lower alkyl of 1 to 6 carbons, chlorine, CF 3 , or alkoxy of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
8 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
wherein
X 2 is CH or N, and;
R 2 is H, F, or OCH 3 , and;
R 2 * is H or F, and;
R 8 is H, or lower alkyl of 1 to 6 carbons, and;
R 41 is selected from the group consisting of phenyl, 4-(lower-alkyl)phenyl, 5-(lower alkyl)-2-thienyl, and 6-(lower alkyl)-3-pyridyl where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
9 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where
R 2 * is H or F;
R 8 is H, or lower alkyl of 1 to 6 carbons, and
R 14 is selected from the group consisting of phenyl, and 4-(lower-alkyl)phenyl, where lower alkyl has 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
10 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
11 . The method of claim 1 wherein the RAR antagonist or inverse agonist has the chemical structure:
where R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
12 . The method of claim 1 wherein said RAR antagonist or inverse antagonist has the chemical structure:
Y 3 (R 4 )—X—Y 1 (R 1 R 2 -Z-Y 2 (R 2 )-A-B
Where Y 1 is phenyl, naphthyl, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazonyl, ozazolyl, imidazolyl, and pyrrazolyl, said phenyl, naphthyl, and heteroaryl groups being substituted with an R 1 group, and further substituted or unsubstituted with one or two R 2 groups;
R 1 is C 1-10 alkyl, 1-ademantyl, 2-tetrahydropyranoxy, trialkylsilanyloxy where alkyl has up to 6 carbons, OH, alkoxy where the alkyl group has up to 10 carbons, alkylthio where the alkyl group has up to 10 carbons, or OCH 2 OC 1-6 alkyl;
R 2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , CF 2 CF 3 , OH, OR 3 , NO 2 , N(R 3 ) 2 , CN, N 3 , COR 3 , NHCOR 3 , COOH, or COOR 3;
X is (C(R 3 ) 2 , S, SO, SO 2 , O or NR 3;
Z is
—C≡C—,
—N═N—,
—N(O)═N —,
—N═N(O)—,
—N═CR 3 —,
—CR 3 ═N,
—(CR 3 ═CR 3 ) n — where n is an integer having the value 0-5,
—CO—NR 3 —,
—CS—NR 3 —,
—NR 3 —CO,
—NR 3 —CS,
—COO—,
—OCO—;
—CSO—;
—OCS—; or
—CO—CR 3 ═R 3 —O,
R 3 is independently H or lower alkyl of 1 to 6 carbons;
Y 2 is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one or two R 2 groups, or
when Z is —(CR 3 ═CR 3 ) n — and n is 3, 4 or 5 then Y 2 represents a direct valence bond between said —(CR 3 ═CR 3 ) n group and B;
Y 3 is phenyl, naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one to three R 4 groups, where R 4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 triple bonds, F, Cl, Br, I, NO 2 , CN, NR 3 , N 3 , COOH, COOC 1-6 alkyl, OH, SH, OC 1-6 alkyl, and SC 1-6 alkyl;
A is (CH 2 ) q where q is from 0-5, lower branched alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl, having 2-6 carbons and 1-2 double bonds, alkynyl having 2-6 carbons and 1 to 2 triple bonds, and
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.
13 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where n is an integer from 1 to 10.
14 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
where n is an integer from 1 to 10.
15 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
16 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
17 . The method of claim 1 wherein said RAR antagonist or inverse agonist has the chemical structure:
18 . The method of claim 1 wherein said period of time is thirty days or more.
19 . The method of claim 1 wherein said RAR antagonist or inverse agonist is administered daily.
20 . The method of claim 1 wherein said RAR antagonist or inverse agonist is administered orally.
21 . The method of claim 1 wherein said RAR antagonist or inverse agonist is administered topically.
22 . The method of claim 1 wherein said RAR antagonist or inverse agonist inhibits transcriptional activation of two or less retinoic acid receptors selected from the group consisting of:
a) an RARα receptor;
b) an RARβ receptor; and
c) an RARγ receptor.
23 . A method for inhibiting spermatogenesis in a male mammal, comprising: administering to said male mammal an effective amount of a composition comprising an RAR antagonist or inverse agonist over a period of time effective to prevent conception.
24 . A contraceptive effective to inhibit spermatogenesis in a male mammal comprising:
a) an RAR antagonist or inverse agonist, and b) a pharmaceutically acceptable excipient.
25 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
wherein
X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
X is [C(R 1 ) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
R 2 is independently hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
R 3 is independently hydrogen, lower alkyl of 1 to 6 carbons or F, and;
m is an integer having the value of 0-3, and;
o is an integer having the value of 0-3, and;
Z is —C≡C—,
—N═N—,
—N═CR 1 —,
—CR 1 ═N,
—(CR 1 ═CR 1 ) n′ — where n′ is an integer having the value 0-5,
—CO—NR 1 —,
—CS—NR 1 —,
—NR 1 —CO,
—NR 1 —CS,
—COO—,
—OCO—;
—CSO—;
—OCS—;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or
when Z is —(CR 1 ═CR 1 ) n′ — and n′ is 3, 4 or 5 then Y represents a direct valence bond between said (CR 2 ═CR 2 ) n′ group and B;
A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 1 1, CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, and
R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons.
26 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
wherein
X is S, O, NR′ where R′ is H or alkyl of 1 to 6 carbons, or
X is [C(R 1 ) 2 ] n where R 1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between, and including, 0 and 2, and;
R 2 is independently hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
R 3 is independently hydrogen, lower alkyl of 1 to 6 carbons or F, and;
m is an integer having the value of 0, 1, 2, or 3, and;
o is an integer having the value of 0, 1, 2, or 3, and;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, and;
A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, and;
R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0, 1, 2, 3, 4 or 5, and;
R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and;
R 16 is H, lower alkyl of 1 to 6 carbons, and;
R 17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR 1 , and;
p is zero or 1, with the proviso that when p is 1 then there is no R 17 substituent group, and m is an integer between, and including, 0 and 2.
27 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where
X is C(R 1 ) 2 or O, and;
R 1 is H or alkyl of 1 to 6 carbons, and;
R 2 is independently lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons, and;
m is an integer having the value of 0-3, and;
R 3 is independently lower alkyl of 1 to 6 carbons or F, and;
o is an integer having the value of 0-3, and;
s is an integer having the value of 1-3, and;
R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, and;
R 15 is independently H, F, Cl, Br, I, NO 2 , N(R 8 ) 2 , COR 8 , NR 8 CON(R 8 ) 2 , OCOR 8 , OR 8 , CN, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, an alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons, and;
t is an integer having the values of 0, 1, 2, 3, 4, or 5, and; the CONH group is in the 6 or 7 position of the benzopyran, and in the 2 or 3 position of the dihydronaphthaline ring, or a pharmaceutically acceptable salt of said compound.
28 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where
X is C(CH 3 ) 2 or O, and;
R 2 is H or Br, and;
R 2′ and R 2″ independently are H or F, and;
R 3 is H or CH 3 , and;
R 8 is H, lower alkyl of 1 to 6 carbons; and
wherein
X 1 is: —C(R 1 ) 2 —, —C(R 1 ) 2 —C(R 1 ) 2 —, —S—, —O—, —NR 1 —, —C(R 1 ) 2 —O—, —C(R 1 ) 2 —S—, or C(R 1 )—NR 1 —; and
R 1 is independently H or alkyl of 1 to 6 carbons; and
R 2 is optional and is independently defined as lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; and
m is an integer between, and including, 0 and 4; and
n is an integer between, and including, 0 and 2; and
o is an integer between, and including, 0 and 3; and
R 3 is H, lower alkyl of 1 to 6 carbons, F, Cl, Br or I; and
R 4 is (R 5 ) p -phenyl, (R 5 ) p -naphthyl, (R 5 ) p -heteroaryl where the heteroaryl group is five-membered or 6-membered and has 1 to 3 heteroatoms selected from the group consisting of O, S, and N; and
p is an integer between, and including, 0 and 5; and
R 5 is optional and is defined as independently F, Cl, Br, I, NO 2 , N(R 8 ) 2 , N(R 8 )COR 8 , N(R 8 )CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8 , an alkyl group having from 1 to 10 carbons, an alkenyl group having from 1 to 10 carbons and 1 to three double bonds, alkynyl group having from 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have from 1 to 6 carbons; and
Y is a phenyl or naphthyl group, or a heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups, or Y is —(CR 3 ═CR 3 ) r ; and
r is an integer between, and including, 1 and 3; and
A is (CH 2 ) q where q is an integer from 0-5, lower branched chain alkyl having from 3 to 6 carbons, cycloalkyl having from 3 to 6 carbons, alkenyl having from 2 to 6 carbons and 1 or 2 double bonds, alkenyl having from 2 to 6 carbons and 1 or 2 triple bonds, with the proviso that when Y is —(CR 3 ═CR 3 ) r — then A is (CH 2 ) q and q is 0; and
B is H, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 ,—CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6alkyl ) 3 , wherein R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl, where the alkyl groups has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 8 and R 10 independently are H, a lower alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is a divalent alkyl radical of 2-5 carbons;
29 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where
X 1 is S or O;
X 2 is CH or N;
R 2 is H, F, CF 3 or alkoxy of 1 to 6 carbons;
R 2 * is H, F, or CF 3 ;
R 8 is H, or lower alkyl of 1 to 6 carbons;
R 14 is unsubstituted phenyl, thienyl or pyridyl, or phenyl, thienyl or pyridyl substituted with one to three R 15 groups, where R 15 is lower alkyl of 1 to 6 carbons, chlorine, CF 3 , or alkoxy of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound; and
wherein
X 2 is CH or N, and;
R 2 is H, F, or OCH 3 , and;
R 2 * is H or F, and;
R 8 is H, or lower alkyl of 1 to 6 carbons, and;
R 14 is selected from the group consisting of phenyl, 4-(lower-alkyl)phenyl, 5-(lower alkyl)-2-thienyl, and 6-(lower alkyl)-3-pyridyl where lower alkyl has 1 to 6 carbons; and
where
R 2 * is H or F;
R 8 is H, or lower alkyl of 1 to 6 carbons, and
R 14 is selected from the group consisting of phenyl, and 4-(lower-alkyl)phenyl, where lower alkyl has 1 to 6 carbons, and pharmaceutically acceptable salts thereof.
30 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
31 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where R 8 is H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt of said compound.
32 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
Y 3 (R 4 )—X—Y 1 (R 1 R 2 )-Z-Y 2 (R 2 )-A-B
Where Y 1 is phenyl, naphthyl, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazonyl, ozazolyl, imidazolyl, and pyrrazolyl, said phenyl, naphthyl, and heteroaryl groups being substituted with an R 1 group, and further substituted or unsubstituted with one or two R 2 groups;
R 1 is C 1-10 alkyl, 1-ademantyl, 2-tetrahydropyranoxy, trialkylsilanyloxy where alkyl has up to 6 carbons, OH, alkoxy where the alkyl group has up to 10 carbons, alkylthio where the alkyl group has up to 10 carbons, or OCH 2 OC 1-6 alkyl;
R 2 is lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , CF 2 CF 3 , OH, OR 3 , NO 2 , N(R 3 ) 2 , CN, N 3 , COR 3 , NHCOR 3 , COOH, or COOR 3;
X is (C(R 3 ) 2 , S, SO, SO 2 , O or NR 3;
Z is
—C≡C—,
—N═N—,
—N(O)═N—,
—N═N(O)—,
—N═CR 3 —,
—CR 3 ═N,
—(CR 3 ═CR 3 ) n — where n is an integer having the value 0-5,
—CO—NR 3 —,
—CS—NR 3 —,
—NR 3 —CO,
—NR 3 —CS,
—COO—,
—OCO—;
—CSO—;
—OCS—; or
—CO—CR 3 ═R 3 —O.
R 3 is independently H or lower alkyl of 1 to 6 carbons;
Y 2 is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one or two R 2 groups, or when Z is —(CR 3 ═CR 3 ) n — and n is 3, 4 or 5 then Y 2 represents a direct valence bond between said —(CR 3 ═CR 3 ) n group and B;
Y 3 is phenyl, naphthyl, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being unsubstituted or substituted with one to three R 4 groups, where R 4 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 triple bonds, F, Cl, Br, I, NO 2 , CN, NR 3 , N 3 , COOH, COOC 1-6 alkyl, OH, SH, OC 1-6 alkyl, and SC 1-6 alkyl;
A is (CH 2 ) q where q is from 0-5, lower branched alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl, having 2-6 carbons and 1-2 double bonds, alkynyl having 2-6 carbons and 1 to 2 triple bonds, and
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, or Si(C 1-6 alkyl) 3 , where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11 is lower alkyl, phenyl or lower alkylphenyl, R 12 is lower alkyl, and R 13 is divalent alkyl radical of 2-5 carbons, and pharmaceutically acceptable salts thereof.
33 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where n is an integer from 1 to 10, and pharmaceutically accept6able salts thereof.
34 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
where n is an integer from 1 to 10, and pharmaceutically acceptable salts thereof.
35 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
36 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
37 . The contraceptive of claim 24 , wherein said RAR antagonist or inverse agonist has the structure:
38 . The contraceptive of claim 24 wherein said excipient is optimized for epidermal delivery.
39 . The contraceptive of claim 24 wherein said RAR antagonist or inverse agonist is dissolved in a triglyceride preparation.
40 . The contraceptive of claim 38 wherein said excipient comprises an emulsion comprising benzyl alcohol, medium chain triglycerides, Carbomer 1342, sorbitan monooleate, Carbomer 934P, and EDTA.
41 . The contraceptive of claim 24 wherein said excipient is optimized for systemic delivery.
42 . The contraceptive of claim 24 wherein said excipient is optimized for oral delivery.Join the waitlist — get patent alerts
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